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 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. Epithelial cells line the follicles, which could be cuboidal, columnar depending on the state of activity. These cells could develop abnormal growth causing follicular malignancy. Thyroid cancer is one of the most common endocrine tumors and classifies as either differentiated or undifferentiated cancer. 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, and it accounts for 10 to 15% of all thyroid cancer. The undifferentiated types are rare when compared to the differentiated type.
Follicular thyroid cancer is a tumor of the follicular cells that are lined by cuboidal epithelial cells and have capsular and vascular invasive properties. Compared to follicular carcinoma, follicular adenoma is benign and occurs more commonly with a ratio estimated to be 5 to 1. This article will focus more on the follicular type of thyroid cancer, discussing the etiology, epidemiology, histology, evaluation, staging, and complications of follicular thyroid cancer.
The cause of thyroid cancer has links to radiation exposure, iodine intake, diabetes, obesity, Hashimoto thyroiditis, exogenous estrogen use, and dietary choices. After the 1986 Chernobyl explosion, many radiation-induced cancers were observed and among them was thyroid cancer. The position of the thyroid makes it a 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. Apart from nuclear radiation, individuals can also get exposure through X-rays and CT-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. In some studies like the one reported by Knobel et al. in 2007, they found that iodine intake was a predisposing factor for thyroid cancer. In another study by Fortner J.G et al., the observation was that iodine deficiency could lead to thyroid epithelial cell carcinomas. Diabetes and obesity shares links with the rise in thyroid cancer. Hashimoto thyroiditis has also been reported to cause thyroid cancer because it leads to an increase in the production of pro-inflammatory cytokines and oxidative stress. Diet choices play a significant role in the incidence of thyroid cancer. Food such as cabbage, broccoli, cauliflower, chicken, pork, and poultry have been found to cause an increased incidence of thyroid cancer while vegetables such as persimmons and tangerines have a negative correlation with thyroid cancer incidence. Too much multivitamin use has been shown to cause an increased incidence of thyroid cancer due to iodine content. High nitrate or nitrite containing food has also been shown to increase the incidence of thyroid cancer.
Some occupations also correlate with an increased incidence of thyroid cancer. Occupational exposure to radiation, pesticides, and working in the textile industry may also have increased association with thyroid cancer.
Thyroid cancer ranks as the ninth most common cancer and accounts for 3.8% of all new cancer cases in the United States. In 2017, the number of new cases of thyroid cancer was projected to be 56780 with females having a higher incidence compared to males. Follicular thyroid cancer is the second most common cause of thyroid cancer, and it accounts for 4% to 39% of all thyroid cancers. Follicular thyroid cancer is more common in older females, with a female to male ratio of 3 to 1, and an average age of 60. Some studies report the incidence of follicular thyroid cancer to be approximately 10% in iodine sufficient areas and 25 to 40% in areas of iodine deficiency. In the United States, the incidence of follicular thyroid cancer has decreased due to the elimination of iodine deficiency.
Patients with thyroid carcinoma will have an enlargement of the thyroid gland due to the presence of a nodule in either or both thyroid lobes. They can be symptomatic with either hypothyroid or hyperthyroid characteristics.
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 micro-calcification, poorly defined margins, and vascular patterns with the dominant intranodular flow, as opposed to perinodular. CT and MRI are used to evaluate extrathyroidal tumor extension but not for the thyroid nodule itself. The sample received from fine needle aspiration or core biopsy is then viewed 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 mainly on the histologic findings of the pathologist. Thyroid carcinoma is classified to be follicular if invasive and contains mostly follicles. Histologic findings of pathologist have been reported to vary leading to controversy in the classification of follicular thyroid carcinoma.
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, thyrotropin suppressing medications are recommended. A study reported a 2.1 fold increase of 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 radiation. For patients with metastasis to bones and soft tissue, either radiotherapy or chemotherapy or both are indicated after the total thyroidectomy. Chemotherapy that has been reported to control tumor progression and prolong progression-free survival includes tyrosine kinase inhibitor such as sorafenib, lenvatinib, vandetanib, and cabozantinib. Thyroglobulin levels are measured to monitor for recurrence.
Differential diagnosis of follicular thyroid carcinoma includes a follicular variant of papillary thyroid carcinoma, papillary thyroid carcinoma, and follicular adenoma. There is a controversy with the pathologic diagnosis of follicular thyroid carcinoma and identification could differ from one pathologist to the other. This controversy is due to two factors including the degree of nuclear atypia and the degree of capsular or vascular invasion.
The TNM staging system is used to classify differentiated thyroid carcinoma. The T describes the size of the tumor. Tx indicates that primary tumor cannot be assessed, T0 means tumor not palpable, T1 means less than 1cm, T2 means 1 to 4cm, T3 indicates greater than 4cm, and T4 means any tumor size with extrapyramidal invasion. The N signifies lymph node involvement. Nx signifies regional adenopathy is not assessable, NO means no palpable cervical adenopathy, N1 means ipsilateral cervical adenopathy, N2 means contralateral or bilateral cervical adenopathy, N3 means fixed cervical nodes. M means metastases with M0 indicative of no distant metastases and M means distant metastases. Follicular thyroid carcinoma classifies into stages from stage I through stage 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 described over 45 years of age with T4, N0, MO, and stage IV describes any T, N, M1.
The thyroid cancer death rate has remained steady even with the increase in the incidence. It is one of the lowest mortality cancers in the United States. In 2017, an estimated 2010 death occurred due to thyroid cancer compared to more than 150000 deaths from lung cancer. Follicular thyroid cancer has a worse prognosis compared to papillary thyroid cancer due to its higher incidence of distant metastasis and patients presenting with more advanced stage disease. Even though follicular thyroid cancers have distant metastasis, metastasis to lymph nodes is uncommon, and occurrence is estimated to be fewer than 10%. 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. 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%. Some studies also report that the survival rate ranges from 46% to 97% also depending on the degree of capsular or vascular invasion. The mortality rate of follicular thyroid carcinoma range from 5 to 15% and those with capsular invasive characteristics have an overall worse prognosis compared to those without invasion.
The complication involved in follicular thyroid cancer is metastasis. Studies have reported metastasis to mostly to bones, lungs and lymph nodes. In a study done by Parasmeswaran et al. (2017), they found that 42% of their subjects had metastasis to the bones, 33% to the lungs and 8% to the lymph nodes. The incidence of distance metastasis in follicular thyroid carcinoma is estimated to be 6 to 20%.
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. This will cause hoarseness of patient voice. There are also reports of hematoma and keloid formation in some patients after the surgery.
Because the patient is undergoing total thyroidectomy, hypothyroidism will develop, and patients will require thyroxin replacement therapy.
Although the prognosis of thyroid cancer has been reported to be good compared to other forms of cancer, the mention of the word "cancer" will still be a concern for most patients. For instance, most patients will still opt for surgical removal of the thyroid even if they have the non-invasive follicular thyroid cancer that can be followed due to its slow growth. Patients and their physicians need to work together to decide the best treatment option. Knowledge gained by patients will enable them to make better decisions about their health.
The incidence of thyroid cancer has increased over the past few decades which is attributed to over-diagnoses. As a result in 2017, USPTF recommends against the screening of thyroid cancer with either neck palpation or ultrasound in asymptomatic patients. In 2015, American thyroid association recommended active surveillance of low-risk thyroid carcinomas with serial ultrasound and that not all patients require surgery. Also, the organization released guidelines in 2015, not to biopsy thyroid nodules that are less than 1cm. Physicians including nurse practitioners and other healthcare professionals should be aware of these guidelines; this will prevent potential harm to patient from overtreatment of low-risk thyroid cancers and appropriate treatment to those patients who have high-risk disease. Reportedly, the overall cost of thyroid cancer in 2019 would be 18 to 21 billion dollars due to surgery cost. Not all thyroid neoplasms require surgery and physicians should keep this in mind when managing patients who develop thyroid cancer.
|||Lee J,Yi S,Kang YE,Kim HW,Joung KH,Sul HJ,Kim KS,Shong M, Morphological and Functional Changes in the Thyroid Follicles of the Aged Murine and Humans. Journal of pathology and translational medicine. 2016 Nov; [PubMed PMID: 27737529]|
|||Liu Y,Su L,Xiao H, Review of Factors Related to the Thyroid Cancer Epidemic. International journal of endocrinology. 2017; [PubMed PMID: 28555155]|
|||Parameswaran R,Shulin Hu J,Min En N,Tan WB,Yuan NK, Patterns of metastasis in follicular thyroid carcinoma and the difference between early and delayed presentation. Annals of the Royal College of Surgeons of England. 2017 Feb; [PubMed PMID: 27659362]|
|||McHenry CR,Phitayakorn R, Follicular adenoma and carcinoma of the thyroid gland. The oncologist. 2011; [PubMed PMID: 21482585]|
|||Williams D, Radiation carcinogenesis: lessons from Chernobyl. Oncogene. 2008 Dec; [PubMed PMID: 19956182]|
|||Furukawa K,Preston D,Funamoto S,Yonehara S,Ito M,Tokuoka S,Sugiyama H,Soda M,Ozasa K,Mabuchi K, Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure. International journal of cancer. 2013 Mar 1; [PubMed PMID: 22847218]|
|||Knobel M,Medeiros-Neto G, Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arquivos brasileiros de endocrinologia e metabologia. 2007 Jul; [PubMed PMID: 17891233]|
|||FORTNER JG,GEORGE PA,STERNBERG SS, Induced and spontaneous thyroid cancer in the Syrian (golden) hamster. Endocrinology. 1960 Mar; [PubMed PMID: 13855794]|
|||Choi WJ,Kim J, Dietary factors and the risk of thyroid cancer: a review. Clinical nutrition research. 2014 Jul; [PubMed PMID: 25136535]|
|||Aschebrook-Kilfoy B,Ward MH,Della Valle CT,Friesen MC, Occupation and thyroid cancer. Occupational and environmental medicine. 2014 May; [PubMed PMID: 24604144]|
|||Nguyen QT,Lee EJ,Huang MG,Park YI,Khullar A,Plodkowski RA, Diagnosis and treatment of patients with thyroid cancer. American health [PubMed PMID: 25964831]|
|||Roman BR,Morris LG,Davies L, The thyroid cancer epidemic, 2017 perspective. Current opinion in endocrinology, diabetes, and obesity. 2017 Oct; [PubMed PMID: 28692457]|
|||Lo CY,Chan WF,Lam KY,Wan KY, Follicular thyroid carcinoma: the role of histology and staging systems in predicting survival. Annals of surgery. 2005 Nov; [PubMed PMID: 16244545]|
|||King AD, Imaging for staging and management of thyroid cancer. Cancer imaging : the official publication of the International Cancer Imaging Society. 2008 Mar 25; [PubMed PMID: 18390389]|
|||Cipriani NA,Nagar S,Kaplan SP,White MG,Antic T,Sadow PM,Aschebrook-Kilfoy B,Angelos P,Kaplan EL,Grogan RH, Follicular Thyroid Carcinoma: How Have Histologic Diagnoses Changed in the Last Half-Century and What Are the Prognostic Implications? Thyroid : official journal of the American Thyroid Association. 2015 Nov; [PubMed PMID: 26440366]|
|||McHenry CR,Sandoval BA, Management of follicular and Hürthle cell neoplasms of the thyroid gland. Surgical oncology clinics of North America. 1998 Oct; [PubMed PMID: 9735140]|
|||Loh KC,Greenspan FS,Gee L,Miller TR,Yeo PP, Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. The Journal of clinical endocrinology and metabolism. 1997 Nov; [PubMed PMID: 9360506]|
|||Raue F,Frank-Raue K, Thyroid Cancer: Risk-Stratified Management and Individualized Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Oct 15; [PubMed PMID: 27742787]|
|||Thompson LD,Wieneke JA,Paal E,Frommelt RA,Adair CF,Heffess CS, A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature. Cancer. 2001 Feb 1; [PubMed PMID: 11169933]|
|||Hassan A,Khalid M,Riaz S,Nawaz MK,Bashir H, Follicular Thyroid Carcinoma: Disease Response Evaluation Using American Thyroid Association Risk Assessment Guidelines. European thyroid journal. 2015 Dec; [PubMed PMID: 26835430]|
|||Mihailovic J,Stefanovic L,Malesevic M, Differentiated thyroid carcinoma with distant metastases: probability of survival and its predicting factors. Cancer biotherapy [PubMed PMID: 17600472]|
|||D'Avanzo A,Treseler P,Ituarte PH,Wong M,Streja L,Greenspan FS,Siperstein AE,Duh QY,Clark OH, Follicular thyroid carcinoma: histology and prognosis. Cancer. 2004 Mar 15; [PubMed PMID: 15022277]|
|||Takano T, Natural history of thyroid cancer [Review]. Endocrine journal. 2017 Mar 31; [PubMed PMID: 28154351]|