Follicular thyroid cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Thyroid cancer was first described by William Stewart Halsted, an American surgeon in the late nineteenth century. Follicular thyroid cancer may be classified according to WHO classification into 2 subtype including minimally invasive follicular thyroid carcinoma, and widely invasive follicular thyroid carcinoma. Follicular thyroid cancer arises from follicular cells of thyroid, which are secretory cells that are normally involved in production and secretion of thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Genes involved in the pathogenesis of follicular thyroid cancer include Ras, PAX8/PPARγ, and PTEN. Follicular thyroid cancer must be differentiated from other diseases that cause neck masses such as goiter, Grave’s disease, Hurthle cell carcinoma, anaplastic thyroid carcinoma, papillary thyroid carcinoma, and medullary thyroid carcinoma. The incidence of follicular thyroid cancer is estimated to be 0.82 per 100 000 person-years. The female to male ratio is approximately 3 to 1. Common risk factors in the development of follicular thyroid cancer are iodine deficiency, family history of thyroid cancer, radiation exposure, and age. MRI may be helpful in the diagnosis of follicular thyroid cancer. MRI may also be performed to detect metastases of follicular thyroid cancer to brain and bones. On biopsy, follicular thyroid cancer is characterized by trabecular, solid, follicular tumor cells that invade tumor capsule or surrounding vascular structures. Surgery is the mainstay of treatment for follicular thyroid cancer.

In 1811, the first thyroid cancer case was reported. Thyroid cancer was first described by William Stewart Halsted, an American surgeon in the late nineteenth century.

Follicular thyroid cancer may be classified according to WHO classification into 2 subtypes including minimally invasive follicular thyroid carcinoma, and widely invasive follicular thyroid carcinoma.

Follicular thyroid cancer arises from follicular cells of thyroid, which are secretory cells that are normally involved in production and secretion of thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Genes involved in the pathogenesis of follicular thyroid cancer include RAS, PAX8/PPARγ, and PTEN.

Follicular thyroid cancer is caused by a mutation in the RAS gene

Follicular thyroid cancer must be differentiated from other diseases that cause neck masses such as goiter, Grave’s disease, Hurthle cell carcinoma, anaplastic thyroid carcinoma, papillary thyroid carcinoma, and medullary thyroid carcinoma.

The incidence of follicular thyroid cancer is estimated to be 0.82 per 100 000 person-years. Females are more commonly affected with follicular thyroid cancer than males. The female to male ratio is approximately 3 to 1. The incidence of follicular thyroid cancer increases with age; the median age at diagnosis is 45 to 50 years.

Common risk factors in the development of follicular thyroid cancer are iodine deficiency, family history of thyroid cancer, radiation exposure, and age.

Depending on the extent of the tumor at the time of diagnosis, the prognosis of follicular thyroid cancer may vary. However, the prognosis is generally regarded as poor. The presence of metastasis is associated with a particularly poor prognosis among patients with follicular thyroid cancer.

According to the American Joint Committee on Cancer (AJCC) there are 4 stages of follicular thyroid cancer based on the clinical features and findings on imaging. Each stage is assigned a letter and a number that designate the tumor size, number of involved lymph node regions, and metastasis.

The hallmark of follicular thyroid cancer is swelling in the neck. A positive history of irradiation of head and neck, rapid growth of the nodule, hoarseness of voice, and family history of follicular carcinoma is suggestive of follicular thyroid cancer. The most common symptoms of follicular thyroid cancer include swelling in the neck, pain in the front of the neck, and hoarseness of voice.

Patients with follicular thyroid cancer usually appear thin and cachectic. Physical examination of patients with follicular thyroid cancer is usually remarkable for thyromegaly, lymphadenopathy and anxiety.

Laboratory findings consistent with the diagnosis of follicular thyroid cancer include elevated T3, elevated T4, and decreased thyroid stimulating hormone.

Chest x-ray may be helpful in the diagnosis of follicular thyroid cancer.

CT scan may be helpful in the diagnosis of diffuse follicular thyroid cancer.

MRI may be helpful in the diagnosis of follicular thyroid cancer. MRI may also be performed to detect metastases of follicular thyroid cancer to brain and bones.

Neck ultrasound may be performed to detect follicular thyroid cancer.

Other diagnostic studies for follicular thyroid cancer include radioiodine scan, which demonstrates increased uptake of radioactive iodine at the areas of metastases and laryngoscopy which demonstrates vocal cord immobility.

On biopsy, follicular thyroid cancer is characterized by trabecular, solid, follicular tumor cells that invade tumor capsule or surrounding vascular structures.

Patients with follicular thyroid cancer are treated with radioactive iodine therapy and targeted medical therapy.

Surgery is the mainstay of treatment for follicular thyroid cancer.

Effective measures for the prevention of follicular thyroid cancer include avoidance of diets low in iodine and avoidance of ultraviolet exposure.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

In 1811, the first thyroid cancer case was reported. Thyroid cancer was first described by William Stewart Halsted, an American surgeon, in the late nineteenth century.

• Cancer of thyroid was the first ever described disease of thyroid.^[1]
• Thyroid cancer was first described by William Stewart Halsted.
• In 1951, head and neck irradiation demonstrated to cause thyroid cancer in children.

• In 1884, thyroidectomies were performed successfully for thyroid disorders.
• Theodore Kocher (1841 – 1917) was considered an expert in thyroidectomies in Switzerland.
• Charles Horace Mayo was considered as an expert in thyroidectomies in the United States.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] Sahar Memar Montazerin, M.D.[3]

Follicular thyroid cancer may be classified according to the degree of invasion into 3 sub-types: minimally invasive follicular thyroid carcinoma, encapsulated angioinvasive follicular thyroid cancer, and widely invasive follicular thyroid carcinoma.

• Follicular thyroid cancer may be classified according to the degree of invasion into:^[1]
  • Minimally invasive follicular thyroid carcinoma: when there is limited capsular and/or vascular invasion
  • Encapsulated angioinvasive follicular thyroid cancer: when there is any evidence of vascular invasion.
  • Widely invasive follicular thyroid carcinoma: when there is widespread infiltration of thyroid tissue and/or vascular invasion.

• It has also been classified into conventional type and oncocytic type according to histologic factors.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Follicular thyroid cancer arises from follicular cells of thyroid, which are secretory cells that are normally involved in production and secretion of thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Genes involved in the pathogenesis of follicular thyroid cancer include RAS, PAX8/PPARγ, and PTEN.

• Follicular thyroid cancer is the second most common type of cancer. It constitutes about 15% of thyroid cancers.

• Follicular thyroid cancer occurs more commonly in women over 50 years of age.
• Thyroglobulin (Tg) can be used as a tumor marker for well-differentiated follicular thyroid cancer.
• Follicular carcinoma tends to metastasize to the lungs and bone via the bloodstream.
• Follicular thyroid cancer metastasizes to lymph nodes late in the course of the disease, with only 5 – 10% of patients having nodal metastases at the time of diagnosis.
• Hematogenous spread is however much more common with 20% of the patients having distant hematogenous metastases at at the time of diagnosis.^[1]
• A Hürthle cell (also known as Askanazy cell) is an oncocytic cell in the thyroid that is often associated with Hashimoto’s thyroiditis as well as follicular thyroid cancer.^[2]

• The Ras oncogene is positive in a significant proportion of individuals.^[3]
• The Ras oncogene acts through the RAF-MEK-MAPK kinase pathway.
• Other genes involved in the pathogenesis of follicular thyroid cancer are:^[4]

• RET/PTC (translocation) associated with MAPK and PI3K–AKT signaling pathways.

• HRAS, KRAS, NRAS (mutation) associated with mitogen-activated protein kinase and PI3K–AKT signaling pathways.

• PAX8/PPARγ (translocation) associated with PAX8-associated nuclear transcription signaling pathways. PAX8 is responsible for the follicular cell differentiation.

• PTEN (mutation) associated with PI3K–AKT signaling pathways.

• PTEN (deletion) associated with PI3K–AKT signaling pathways.

• IDH1 (mutation) assciated with IDH1-associated metabolic pathways signaling pathways.

• Phosphatase and tensin homologue suppressor gene and the phosphatidylinositol 3-kinase pathway are also involved in the pathogenesis of follicular thyroid tumor.
• P53 (protein), c-myc, c-fos, and the thyrotropin (TSH) receptor are some other factors involved in the pathogenesis of follicular thyroid cancer.
• MicroRNAs namely miR-192, miR-197, miR-328, and miR-346 have increased expression in follicular cell carcinoma.

• Cowden disease
• Carney complex, type I

• Encapsulated tumors

• On microscopic examination, trabecular, solid, follicular tumor cells that invade tumor capsule or surrounding vascular structures, are found.

• 
  Metastatic follicular thyroid carcinoma^[5]
• 
  Metastatic follicular thyroid carcinoma^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Follicular thyroid cancer is caused by a mutation in the RAS gene.

• Genetic mutation is suspected to be the main cause of follicular thyroid cancer.^[1][2]
• It is caused by mutation in the RAS gene.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] Sahar Memar Montazerin, M.D.[3]

Follicular thyroid cancer must be differentiated from other diseases that cause neck masses such as goiter, Grave’s disease, Hurthle cell carcinoma, anaplastic thyroid carcinoma, papillary thyroid carcinoma, and medullary thyroid carcinoma.^[1]

Follicular thyroid cancer must be differentiated from other thyroid cancers as well as other disorders such as:

• Goiter
• Follicular adenoma
• Plummer’s disease
• Toxic nodular goiter
• Grave’s disease
• Hurthle cell carcinoma
• Thyroid nodule
• Anaplastic thyroid carcinoma
• Papillary thyroid carcinoma
• Medullary thyroid carcinoma

Disease name	Age of onset	Gender preponderance	Signs/Symptoms	Imaging Feature(s)	Macroscopic feature(s)	Microscopic feature(s)	Laboratory Feature(s)	Other Feature(s)	Microscopic appearance
Follicular Thyroid Cancer[2][3][4]	Peak incidence is 40-60 years of age	More commonly affects women	Asymptomatic thyroid mass or nodule Compressive symptoms such as: Difficulty swallowing/breathing Persistent cough Stridor Vocal chord paralysis Rapid enlarging mass	Ultrasound: solid hypoechoic nodule with a peripheral halo indicating fibrous capsule Irregular margin Imaging features are not characteristic for this cancer	Single encapsulated nodule, Thick and irregular capsule May have cystic or hemorrhage	Invades thyroid capsule and vasculature Uniform follicles	Thyroid function test may be normal Serum thyroglobulin may be used as a tumor marker	RAS mutation may be present PAX8-PPAR-γ translocations
Papillary Thyroid Cancer[5][2][3]	More common in middle aged (30-50 years of age)	More commonly affects women	Asymptomatic thyroid mass or nodule Compressive symptoms such as: Difficulty swallowing/breathing Persistent cough Stridor Vocal chord paralysis Rapid enlarging mass	Ultrasound: solitary mass with an irregular outline, in the subcapsular region and with high vascularity Imaging features are not characteristic for this cancer	Solitary hypoechogenic nodule with lobulated margin which may extend into adjacent tissues Calcification may be present or not	Empty-appearing nuclei with central clearing (Orphan Annie eye) Psammoma bodies	Thyroid function test may be normal Thyroglobulin may be used as a tumor marker	History of radiation in head and neck BRAF and/or RET mutation may be present Most common type of thyroid cancer
Medullary Thyroid Cancer[6][7][8][3]	Incidence increases with age More common in 3rd to 4th decades of life	Both genders affected equally	Solitary thyroid nodule Mostly affects upper lobe of thyroid gland Possible systemic symptoms due to hormonal secretion by the tumor Cervical lymphadenopathy	Ultrasound: solitary hypoechoic nodule with or without calcification Imaging features are not characteristic for this cancer	Single nonencapsulated mass Gray-tan color	Sheets of cells in an amyloid stroma	Secretes calcitonin Normal thyroid function test Carcinoembryonic antigen (CEA) may be used as a tumor marker Rarely negative for calcitonin	May be part of MEN 2A and 2B syndrome May be associated with RET mutation
Anaplastic Thyroid Cancer[9][10][11]	More common among older individuals Mean age at diagnosis is 65 years	More commonly affects women	Rapidly enlarging thyroid mass May manifest with compressive symptoms May present with signs/symptoms of metastasis Constitutional symptoms may be present Hard nodular goiter w/out tenderness	Ultrasound: solid hypoechoic nodule with a peripheral halo indicating fibrous capsule Irregular margin Imaging features are not characteristic for this cancer	Solid tumor with areas of necrosis and hemorrhage Infiltrative pattern	Undifferentiated, devastatingly aggressive variant of Papillary/Follicular thyroid cancer	Normal thyroid function test	Poor prognosis May be associated with TP53 mutation
Follicular Adenoma[12]	More commonly affects individuals older than 50 years of age	More commonly affects women	Asymptomatic or symptoms of hyperthyroidism	Solitary nodule which may show echogenicity or not	Solitary, spherical, and encapsulated lesion Well demarcated from the surrounding parenchyma	Uniform follicles Absence of capsular or vascular invasion	Functional adenoma: Elevated T3, T4 Decreased TSH	May be considered functional or hot May be considered non-functional or cold
Multinodular Goiter[13]	Commonly affects individuals older than 60 years of age	More commonly affects women	Thyroid enlargement Signs/symptoms of hypo/hyperthyroidism	Multiple nodules with different echogenicity Calcification may be present	Multiple thyroid nodules	Variable sized follicles Some may show papillary projections without nuclear characteristics of papillary thyroid cancer	Classified as toxic and non-toxic Toxic => hyperthyroidism Non-toxic => Normal thyroid function test	Benign condition
Thyroid Lymphoma[14] [15][16][17]	Affects adults or elderly	More common among women	Rapidly enlarging mass/ nodule of thyroid Compression symptoms may be present Constitiutional symptoms may be present in 10% P/E:Firm, hard thyroid Fixed to the nearby structure Immobile even during swallowing Cervical or supraclavicular lymphadenopathy may be present	Ultrasound: hypoechogenic appearance difficult to be distinguished from chronic thyroiditis	Thyroid nodule/mass fixing to adjacent tissue with a firm texture	It is of B cell lineage in the majority of cases Dffuse, large B-cell lymphomas is the most common subtype: diffuse infiltrate of B cells destroying thyroid follicles Marginal zone lymphoma is the second most common type	No specific test Some may have hypothyroidism Some may have antibody against thyroid peroxidase or thyroglobulin	Preexisting chronic autoimmune (Hashimoto’s) thyroiditis is a known risk factor for this condition

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

The incidence of follicular thyroid cancer is estimated to be 0.82 per 100,000 individuals. Females are more commonly affected than males. The female to male ratio is approximately 3 to 1. The incidence of follicular thyroid cancer increases with age; the median age at diagnosis is 45 to 50 years.

• The incidence of follicular thyroid cancer in the USA is 0.82 per 100,000 person-years.
• The incidence of follicular thyroid cancer is 1.06 per 100,000 woman-years.
• The incidence of follicular thyroid cancer is 0.59 per 100,000 man-years.^[1]
• The American Cancer Society estimates:
  • Approximately 52,070 new cases of thyroid cancer in the US in the year 2019 with 73% and 27% of these cases in the female and male population, respectively.^[2]

• 9 of every 100 people with thyroid cancer have follicular thyroid cancer.^[3]

• Mortality rate of follicular thyroid cancer ranges from 5% to 15%.
• The American Cancer Society estimates:
  • Approximately 2170 deaths from thyroid cancer in the US in the year 2019 with 53% of these deaths involving women and 47% involving men.^[4]

• The median age at which follicular thyroid cancer is diagnosed is 45 to 50 years.

• Follicular thyroid cancer is 3 times more common in female than in males.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Common risk factors in the development of follicular thyroid cancer are iodine deficiency, family history of thyroid cancer, and radiation exposure.

• Common risk factors in the development of follicular thyroid cancer are:^[1][2]
  • Iodine deficiency
  • Family history of thyroid cancer
  • Radiation exposure
• Less common risk factors in the development of follicular thyroid cancer include:^[3]
  • Occupational and environmental exposures
  • Hepatitis C-related chronic hepatitis
  • Increased parity and late age at first pregnancy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Depending on the extent of the tumor at the time of diagnosis, prognosis of follicular thyroid cancer may vary. However, prognosis is generally regarded as good. The presence of metastasis is associated with a particularly poor prognosis among patients with follicular thyroid cancer.

• Natural history of follicular thyroid cancer is variable.
• Symptoms of follicular thyroid cancer usually develop in the fourth decade of life.
• The condition presents as a slowly enlarging painless mass.
• Without treatment, patients will develop symptoms caused by compression and metastasis, such as hoarseness of voice, difficulty swallowing, and difficulty breathing.^[1]

Common complications of follicular thyroid cancer include:^[2]

• Metastasis
• Hoarseness of voice
• Dysphagia
• Dyspnea

• Prognosis of follicular thyroid cancer is directly related to tumor size.^[3]
  • Good Prognostic Factors:
    • Children
    • Adolescent
    • Women younger than 50
    • Men younger than 40
  • Bad Prognostic Factors:
    • Women older than 50 with follicular carcinoma
    • Men older than 40 with follicular carcinoma
    • Distant metastasis
    • Large tumor size
    • Extensive vascular invasion
    • Extra thyroidal extension
    • Widely invasive tumors
• Stage Related Prognosis
  • The 10-year survival is better for patients with follicular carcinoma without vascular invasion than it is for patients with vascular invasion.
  • Follicular carcinoma invading the cervical tissue has a worse prognosis than tumors confined to the thyroid gland.
  • The presence of vascular invasion is an additional poor prognostic factor.
  • Metastasis to lymph nodes do not worsen the prognosis in patients younger than 45 years.
  • The prognosis for patients with distant metastases is poor.

• 5-year Relative Survival Rate
  • 5-year relative survival rate of follicular thyroid cancer depends on the stage of the disease at the time of diagnosis.
    • Stage 1 has 100% 5-year relative survival rate.
    • Stage 2 has 100% 5-year relative survival rate.
    • Stage 3 has 71% 5-year relative survival rate.
    • Stage 4 has 50% 5-year relative survival rate.