Follicular Thyroid Carcinoma

Updated: Jun 18, 2020
  • Author: Luigi Santacroce, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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Overview

Practice Essentials

Follicular thyroid carcinoma (FTC) is the second most common cancer of the thyroid, after papillary carcinoma. Follicular and papillary thyroid cancers are considered to be differentiated thyroid cancers; together they make up 95% of thyroid cancer cases.

FTC and other thyroid neoplasms arising from follicular cells (adenomas, papillary/follicular carcinoma, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]) show a broad range of overlapping clinical and cytologic features. FTC resembles the normal microscopic pattern of the thyroid, and a clear distinction between benign and malignant disease based solely on cytological examination of a needle biopsy specimen may be difficult.

For this reason, a surgical procedure to remove all or a large portion of the thyroid gland may be necessary to obtain sufficient tissue for a definitive diagnosis of FTC. Pathological examination showing capsular or vascular invasion may be required for this determination.

Papillary/follicular carcinoma must be considered a variant of papillary thyroid carcinoma (mixed form). Hurthle cell carcinoma should be considered a variant of FTC.

Despite its well-differentiated characteristics, FTC may be overtly or minimally invasive. In fact, FTC tumors may spread easily to other organs. About 11% of patients with FTC have metastases beyond the cervical or mediastinal area on initial presentation

Life expectancy of affected patients is related to their age; the prognosis is better for younger patients than for patients who are older than 45 years. Patients with FTC are more likely to develop lung and bone metastases than are patients with papillary thyroid cancer. The bone metastases in FTC are osteolytic. Older patients have an increased risk of developing bone and lung metastases.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms, with prompt completion of thyroidectomy if invasive FTC is found on the final histologic section. Therapeutic neck dissection of involved compartments is recommended for clinically apparent/biopsy-proven disease. The NCCN recommends total thyroidectomy as the initial procedure only if invasive cancer or metastatic disease is apparent at the time of surgery, or if the patient wishes to avoid a second, completion thyroidectomy should the pathologic review reveal cancer. [1]

If all gross disease cannot be resected, or if residual disease is not avid for radioactive iodine, radiation therapy is often employed for locally advanced disease. Similarly, radiation therapy is indicated for unresectable disease extending into adjacent structures. Chemotherapy may be considered in symptomatic patients with recurrent or progressive disease. It could improve quality of life in patients with bone metastases.

For patient education information, see the Thyroid Cancer Directory. Patient education information on thyroid cancer is also available on the American Cancer Society Web site.

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Pathophysiology

The molecular pathogenesis of follicular thyroid carcinoma (FTC) is thought to be initiated by point mutations that result in dysregulation of the phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathway. Dysregulation of PI3K/AKT can be triggered by activating mutations in a variety of genes, including RAS, PIK3CA, and AKT1, as well as by inactivation of PTEN. [2]

Activating point mutations in RAS oncogenes are well known in follicular adenoma and carcinoma, [3, 4, 5] especially in poorly differentiated (55%) and anaplastic carcinoma (52%). Mutations in NRAS have been reported in 17% to 57% of FTCs; mutations in KRAS and HRAS are less often found. PAX8/PPARG gene fusion, which results in production of a PAX8-PPARγ fusion protein, has been identified in approximately one-third of FTC cases (range, 12% to 53%). Activating mutations in TERT, which encodes telomerase reverse transcriptase, have been described in about 15% of FTCs and are associated with the worst clinical features and prognosis. TSH receptor mutations have been found in 10.3% of FTC cases; these appear to be mutually exclusive with RAS mutations. [2]

A study of differential gene expression profiling of aggressive and nonaggressive follicular carcinomas identified 94 genes that distinguish follicular carcinomas from follicular adenomas (including PBP and CKS2) and 4 genes that distinguish aggressive follicular carcinomas from nonaggressive follicular carcinomas (NID2, TM7SF2, TRIM2, and GLTSCR2). [6]

Some molecules that physiologically regulate the growth of thyrocytes, such as interleukins (IL-1 and IL-8) or other cytokines (IGF1, TGF-beta, EGF) could play a role in the pathogenesis of FTC.

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Etiology

The thyroid is particularly sensitive to the effects of ionizing radiation. Exposure to ionizing radiation results in a 30% risk for thyroid cancer.

A history of exposure of the head and neck to x-ray beams, especially during childhood, has been recognized as an important contributing factor to the development of thyroid cancer.

Seven percent of the individuals exposed to the atomic bomb blasts in Japan developed thyroid cancers. However, exposure to fallout from the Chernobyl nuclear accident was asssociated with increases in papillary rather than follicular thyroid carcinoma. [7, 8]

From the 1920s to the 1960s, irradiation was used to treat tumors and benign conditions, such as acne; excessive facial hair; tuberculosis in the neck; fungal diseases of the scalp; sore throats; chronic coughs; and enlargement of the thymus, tonsils, and adenoids. About 10% of individuals who were treated with irradiation developed thyroid cancer after a latency period of 30 years.

Patients who receive radiotherapy for certain types of cancer of the head and neck area also may have an increased risk of developing thyroid cancer.

Exposure to diagnostic x-rays does not increase the risk of developing thyroid cancer.

Although follicular cancer is frequently present in goitrous thyroids, the relationship between prolonged elevation of thyroid-stimulating hormone (TSH) and follicular carcinoma is not known. Several reports have shown a relationship between iodine deficiency and the incidence of thyroid carcinoma, and rates of FTC decreased in geographic areas of endemic goiter after iodized salt was introduced.

 

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Epidemiology

Frequency

United States

The American Cancer Society (ACS) estimates that 52,890 new thyroid cancers will occur in 2020, 12,720 in men and 40,170 in women; the ACS estimates that 2180 deaths from thyroid cancer will occur in 2020, 1040 in men and 1140 in women. In women, thyroid cancer is the fifth most common cancer, accounting for approximately 4% of all new cases. [9] In the United States, about 10-15% of all thyroid cancers are follicular.

International

Thyroid cancers account for 1.5% of all cancers in adults and 3% in children. The European Network of Cancer Registries reports that the incidence varies from country to country: Lithuania reported the highest age-standardized rate per 100,000 population (15.5), followed by Italy (13.5), Austria (12.4), Croatia (11.4), and Luxembourg (11.1). [10] ​ The highest incidence of thyroid carcinomas in the world is among female Chinese residents of Hawaii. In Hawaii, the incidence of FTC ranges from 10-3 new cases a year per million inhabitants.

In recent years, the frequency of FTC has appeared to increase; however, this increase is related to improvement in diagnostic techniques and a successful campaign of information about this carcinoma. [10]

Of all thyroid cancers, 17-20% are follicular. According to world epidemiologic data, follicular carcinoma is the second most common thyroid neoplasm; in some geographic areas, however, FTC is the most common thyroid tumor. The relative incidence of follicular carcinoma is higher in areas of endemic goiter.

Race-, sex-, and age-related demographics

FTC occurs more frequently in whites than in blacks. The incidence is higher in women than men by a factor of 2-3 or more. The ratio varies by patient age:

  • In patients younger than 19 years, the female-to-male ratio is 4:1
  • In patients aged 20-45 years, the female-to-male ratio is 3:1
  • In patients older than 45 years, the female-to-male ratio is 4:1

In postmenopausal women, a weak positive association (relative risk < 1.20) has been found between increased body mass index and thyroid cancer. [11]

Thyroid carcinoma occurs in all age groups, but is most  diagnosed in persons aged 45–54 years. Median age at diagnosis is 51 years. [12] In older adults, FTC tends to occur more often than papillary thyroid carcinoma.

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Prognosis

In contrast to other cancers, thyroid cancer is almost always curable. In fact, most FTCs are slow growing and are associated with a very favorable prognosis. Mean mortality rates are 1.5% in females and 1.4% in males.  FTC prognosis is related to age, sex, and staging. In general, if the cancer does not extend beyond the capsule of the gland, life expectancy is minimally affected. Prognosis is better in female patients and in patients younger than 40 years. The 5-year relative survival rate for 2010-2016 was 98.3%. [12]

Current World Health Organization classification proposes three subtypes of FTC: minimally invasive, encapsulated angioinvasive, and widely invasive. [13] O'Neill et al reported that disease‐free survival rates at 40 months in patients with those three subtypes were 97%, 81%, and 46%, respectively. [14]

Mean survival rate after 10 years is 60%. Metastases are still rare and are due to angioinvasion and hematogenous spread. Lymphatic involvement is even more rare, occurring in less than 10% of cases. In some patients, however, metastases are found at diagnosis.

In a Spanish study of FTC in 66 patients, with follow-up of 99 ± 38 months, disease-related mortality was 3%; disease-free survival rates were 71% at 5 years and 58% at 10 years. The main predictive factors for recurrence were the presence of local clinical symptoms and infiltration into neighboring structures. [15]

A relatively large prospective study by Sugino et al demonstrates that age and primary tumor size may result in poorer outcome for patients with distant metastases. Authors recommend conservative management for younger patients with minimally invasive follicular thyroid carcinoma with small tumors. [16]

Unlike medullary thyroid carcinoma, FTC is not part of a multiple endocrine neoplasia (MEN) syndrome.

 

 

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