Thyroid nodule

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In 1500, a renowned artist named Leonardo da Vinci was the first who recognized and drew the thyroid gland. In 1834, Robert Graves was the first who described a syndrome of palpitation, goiter, and exophthalmos. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine for demonstration of a “hot” thyroid nodule. In 1948, T. Templa, J. Aleksandrowicz, and M. Till were the first who described the usage of fine needle thyroid biopsy as a diagnostic method for thyroid nodules. There are various methods for classifying a thyroid nodule. A method has been developed by the National Cancer Institute (NCI) to address terminology and other issues related to thyroid fine-needle aspiration (FNA), called “The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)”. Thyroid nodules may also be classified based on their ultrasound properties according to the TIRAD classification method. The pathogenesis of a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or from inflammation of thyroid tissue. Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. The major causes of thyroid nodule development include, multinodular (sporadic) goiter, Hashimoto’s thyroiditis, cysts, macrofollicular/microfollicular adenomas, childhood radioiodine exposure, familial history, and gene mutations include N&H ras, RET, Gsp, C-MET (α and β subunit), TRK, EGF / EGF-R, and P53 mutation. Neck masses can be mistaken for thyroid nodules. The most important neck masses that can be mistaken with thyroid nodules include, thyroglossal duct cyst, parathyroid cancer, parathyroid cyst, and branchial cleft cyst. While the diagnosis of a thyroid nodule is established, thyroid nodule should be differentiated based on benign or malignant features and the type of nodule. Worldwide, the incidence of thyroid nodule ranges from as low of 40,000 per 100,000 persons to a high of 71,000 per 100,000 persons with an average incidence of 50,000 per 100,000 persons. The incidence of thyroid cancer is estimated to be a total number of 48,288 cases annually in United states. Common risk factors associated with thyroid nodules include, older age, iodine deficiency, previous history of iodine deficiency and hypothyroidism, living in iodine deficient areas, family history of autoimmune diseases, multiparity, and smoking. A solitary thyroid nodule may become symptomatic if it grows rapidly due to hemorrhage or malignancies, invades laryngeal nerves, compressing nearby structures, and secretory nodules that produce TSH. Thyroid nodules may be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness. Without treatment, the patient with benignnodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death. The most common complications of thyroid nodules are hoarseness, horner syndrome, nodule rupture, needle track seeding, hemorrhage/hematoma, dysphagia, upper airway obstruction, pain, skin burn, vasovagal reaction, hypothyroidism, transient thyrotoxicosis, anaphylactic reaction, thromboembolism, and pneumothorax. Physical examination should focus on the thyroid gland and the lateral and central neck and should assess for supraclavicular and submandibular adenopathy. In case of active hot thyroid nodules that produce thyroid hormones, antithyroid drugs should be administered, that include beta-blockers, antithyroid drugs (methimazole,carbimazole,propylthiouracil), radioactive iodine, and thyroidectomy. If the nodule excision treatment (lobectomy, isthmectomy, and total thyroidectomy) is not curative, then treatment with postoperative radioactive iodine (RAI) remnant ablation and recombinant human TSH–mediated therapy is recommended. Surgical management of thyroid nodule is performed in case of non-diagnostic or suspicious biopsy, for removal of primary thyroid cancer or for thyroid cancer staging for radioactive ablation and serum thyroglobulin monitoring. Primary prevention of thyroid nodule is aimed at prevention of thyroid cancer. Avoidance of exposure to radiation and monitoring the population with an increased risk of development of a malignant thyroid nodule play major roles in primary prevention. Secondary prevention of thyroid nodules focuses on prevention of recurrence of nodules. Different prevention strategies may be used depending upon whether the nodule is benign or malignant. In case of a malignant nodule, the major focus is on the prevention of recurrence after removal of a primary nodule. Post-operative periodic monitoring with serum thyroglobulin levels, radioactive iodine scanning, neck ultrasound and thyroid stimulating hormone (TSH) may decrease the chances of recurrence.

In 1500, a renowned artist named Leonardo da Vinci was the first who recognized and drew the thyroid gland. In 1834, Robert Graves was the first who described a syndrome of palpitation, goiter, and exophthalmos. In 1857, Maurice Schiff was the first to perform successful total thyroidectomies in animals. In 1895, Adolf Magnus Levy was the first to describe the influence of the thyroid gland and thyroid hormones on the basal metabolic rate. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine for demonstration of a “hot” thyroid nodule. In 1948, T. Templa, J. Aleksandrowicz, and M. Till were the first who described the usage of fine needle thyroid biopsy as a diagnostic method for thyroid nodules.

There are various methods for classifying a thyroid nodule. A method has been developed by the National Cancer Institute (NCI) to address terminology and other issues related to thyroid fine-needle aspiration (FNA), called “The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)”. The other classification method is the TNM classification (tumor-node-metastasis) method developed by the American Joint Committee on Cancer and the International Union against Cancer focused on prognosis has been established to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers. Thyroid nodules may also be classified based on their ultrasound properties according to the TIRAD classification method, which has been proposed by Horvath et al, with a modified recommendation from Jin Kwak et al, and finally, thyroid nodules may also be classified on the basis of origin.

Thyroid nodules may arise from different cells in the thyroid parenchyma. The pathogenesis of a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or from inflammation of thyroid tissue. Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may exhibit familial inheritance. The most important variety of familial thyroid cancers are caused by genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC). Other important genes related to thyroid nodule formation include, N&H, RAS, RET, Gsp, C-MET, TRK, EGF / EGF-R, and P53.

The major causes of thyroid nodule development include, multinodular (sporadic) goiter, Hashimoto’s thyroiditis, cysts, macrofollicular/microfollicular adenomas, childhood radioiodine exposure, familial history, and gene mutations include N&H ras, RET, Gsp, C-MET (α and β subunit), TRK, EGF / EGF-R, and P53 mutation.

Neck masses can be mistaken for thyroid nodules. The most important neck masses that can be mistaken with thyroid nodules include, thyroglossal duct cyst, parathyroid cancer, parathyroid cyst, and branchial cleft cyst. While the diagnosis of a thyroid nodule is established, thyroid nodule should be differentiated based on benign or malignant features and the type of nodule.

Worldwide, the incidence of thyroid nodule ranges from as low of 40,000 per 100,000 persons to a high of 71,000 per 100,000 persons with an average incidence of 50,000 per 100,000 persons. The incidence of thyroid cancer is estimated to be a total number of 48,288 cases annually in United states. Thyroid nodules are common, their prevalence being largely dependent on the identification method, as sensitivity and specificity of different methods for thyroid nodule diagnosis varies. In United States, the prevalence of thyroid nodule detected by palpation alone ranges from a low of 2,000 per 100,000 persons to a high of 6,000 per 100,000 persons, while the prevalence of thyroid nodule detected by ultrasound ranges from a low of 20,000 per 100,000 persons to a high of 35,000 per 100,000 persons. Worldwide, the prevalence of palpable thyroid nodule is approximately 5,000 per 100,000 in women and 1,000 per 100,000 in men living in iodine-sufficient parts of the world, and the prevalence of ultrasound detected thyroid nodules ranges from as low as 19,000 per 100,000 to as high as 68,000 per 100,000. Thyroid nodules commonly affects individuals younger than 20 and older than 50 years of age. Females are more commonly affected with thyroid nodules than males.

Common risk factors associated with thyroid nodules include, older age, iodine deficiency, previous history of iodine deficiency and hypothyroidism, living in iodine deficient areas, family history of autoimmune diseases, multiparity, and smoking.

According to USPSTF, screening for thyroid cancer is not recommended and there is insufficient evidence to recommend routine screening for thyroid nodule.

A solitary thyroid nodule may become symptomatic if it grows rapidly due to hemorrhage or malignancies, invades laryngeal nerves, compressing nearby structures, and secretory nodules that produce TSH. Thyroid nodules may be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness. Without treatment, the patient with benignnodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death. The most common complications of thyroid nodules are hoarseness, horner syndrome, nodule rupture, needle track seeding, hemorrhage/hematoma, dysphagia, upper airway obstruction, pain, skin burn, vasovagal reaction, hypothyroidism, transient thyrotoxicosis, anaphylactic reaction, thromboembolism, and pneumothorax. Benign thyroid nodules have great prognosis, while prognosis of malignant thyroid nodules may be determined based on their type by scoring system of TNM staging.

There is no definite diagnostic criteria for thyroid nodule. Different diagnostic methods can be used to diagnose thyroid nodules, based on their specific properties. Thyroid function should be assessed in all patients with thyroid nodules as the primary diagnostic step in all patients with a neck mass. The primary evaluation method that should be used in the thyroid nodule evaluation is thyroid ultrasound. Cytology differentiates between malignant and benign lesions. After a suspicion of thyroid malignancy based on ultrasound features, fine needle aspiration biopsy (FNAB) is the most appropriate method for further evaluation. Thyroid scintigraphy is used to determine the functional status of a nodule. Scintigraphy utilizes one of the radioisotopes of iodine (usually I-123) or technetium-99m pertechnetate.

The most important aspects in obtaining a history of a patient presenting with thyroid nodule include, looking for the presence of associated symptoms, change in nodule size, previous head or neck radiation exposure, childhood irradiation associated with high risk of malignancy, family history, history of neck pain, sudden increase in the size of a neck lump, and progressive voice change or hoarseness. The symptomsassociated to thyroid nodule include, dysphagia or anterior neck discomfort, hoarseness, localized pain in the neck, shortness of breath, and prolonged cough.

Physical examination should focus on the thyroid gland and the lateral and central neck and should assess for supraclavicular and submandibular adenopathy. The most important finding in physical examination that need a more attention include assessing the nodule’s size and consistency, localized tenderness in the nodular area, lymphadenopathy, and physical exams coordinated with hypo- or hyperthyroidism.

Laboratory findings in a patient with a thyroid nodule may reveal abnormalities in serum thyrotrophin, serum antithyroperoxidase, free T4, T3, serum thyroglobulin and plasma metanephrines. These findings may vary depending upon whether the nodule is hot or cold.

There are no abnormal electrocardiographic findings associated with thyroid nodule.

There are no indications for X ray in thyroid nodules. Only massive thyroid nodules may be visible on x-ray. The most important findings associated with thyroid nodules are moderately large soft tissue swelling in the neck, that may extent into mediastinum as well.

CT scan has low sensitivity in diagnosing thyroid nodules but it may serve as an alternative imaging modality for the diagnosis of thyroid nodule, in case of large, rapidly growing, retrosternal and invasive tumors.

In case of active hot thyroid nodule that produces thyroid hormones, antithyroid drugs should be administered, that include, beta-blockers, antithyroid drugs (methimazole,carbimazole,propylthiouracil), radioactive iodine, and thyroidectomy. If the nodule excision treatment (lobectomy, isthmectomy, and total thyroidectomy) is not curative, then treatment with postoperative RAI remnant ablation and recombinant human TSH–mediated therapy is recommended.

Thyroid nodules may also be diagnosed via radionuclide thyroid scan, whole-body radioactive iodine scan, positron emission tomography (PET scan) or iodine-131 single photon emission computed tomography (SPECT).

Other diagnostic studies which aid in the diagnosis of thyroid nodule include, fine needle aspiration, molecular markers, genetic evaluation and galectin-3 immunohistochemistry

In case of active hot thyroid nodules that produce thyroid hormones, antithyroid drugs should be administered, that include beta-blockers, antithyroid drugs (methimazole,carbimazole,propylthiouracil), radioactive iodine, and thyroidectomy. If the nodule excision treatment (lobectomy, isthmectomy, and total thyroidectomy) is not curative, then treatment with postoperative radioactive iodine (RAI) remnant ablation and recombinant human TSH–mediated therapy is recommended.

Surgical management of thyroid nodule is performed in case of non-diagnostic or suspicious biopsy, for removal of primary thyroid cancer or for thyroid cancer staging for radioactive ablation and serum thyroglobulin monitoring.

Primary prevention of thyroid nodule is aimed at prevention of thyroid cancer. Avoidance of exposure to radiation and monitoring the population with an increased risk of development of a malignant thyroid nodule play major roles in primary prevention.

Secondary prevention of thyroid nodules focuses on prevention of recurrence of nodules. Different prevention strategies may be used depending upon whether the nodule is benign or malignant. In case of a malignant nodule, the major focus is on the prevention of recurrence after removal of a primary nodule. Post-operative periodic monitoring with serum thyroglobulin levels, radioactive iodine scanning, neck ultrasound and thyroid stimulating hormone (TSH) may decrease the chances of recurrence.

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

In 1500, a renowned artist named Leonardo da Vinci was the first who recognized and drew the thyroid gland. In 1834, Robert Graves was the first who described a syndrome of palpitation, goiter, and exophthalmos. In 1857, Maurice Schiff was the first to perform successful total thyroidectomies in animals. In 1895, Adolf Magnus Levy was the first to describe the influence of the thyroid gland and thyroid hormones on the basal metabolic rate. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine for demonstration of a “hot” thyroid nodule. In 1948, T. Templa, J. Aleksandrowicz, and M. Till were the first who described the usage of fine needle thyroid biopsy as a diagnostic method for thyroid nodules.

The main events associated with thyroid recognition and development are summarized here:[1] In 40 BC, Pliny, Vitruvius, and Juvenal were the first who documented the prevalence of goiter in the Alps. They also used the burnt seaweed for treatment of goiter. In 138, Soranus, a Greek physician, reported a case of neck swelling following pregnancy. In 961, Abul Kasim, a physician in Cordoba, was the first who described thyroidectomy and to perform a needle biopsy. In 1500, Leonardo da Vinci was the first who recognized and drew the thyroid gland. In 1543, Andreas Vesalius was the first who provided the first anatomic description and illustration of the thyroid gland. In 1563, Eustachius was the first who introduced the term “isthmus” to describe tissue connecting the two lobes of the thyroid gland. In 1602, Felix Platter was the first who described cretinism found in Valais region of Switzerland. In 1825, C. Parry was the first who described exophthalmic goiter. In 1834, Robert Graves was the first who described a syndrome of palpitation, goiter, and exophthalmos. In 1857, B. Niepce was the first who described enlargement of sella turcica in cretinism with hypothyroidism in Switzerland. In 1862, A. Trousseau introduced the term “Graves disease” for the disease that was described before by Grave. In 1867, A. von Graefe described lid lag in thyrotoxicosis which later was known as Basedow’s disease. In 1873, Th. Billroth was the first to describe tetany following total thyroidectomy. In 1882, William Ord was the first to describe the term myxedema for a case of a middle-aged woman with cretinism features. In 1888, Rogowitsch was the first to describe the pituitary hyperplasia in rabbits following thyroidectomy. In 1891, Victor Horsley was the first to discover the direct effect of thyroid function deficiency in developing myxedema, cretinism, and post-thyroidectomy cachexia by working on monkeys. In 1895, Adolf Magnus Levy was the first to describe the influence of the thyroid gland and thyroid hormones on the basal metabolic rate. In 1896, B. Riedel was the first to describe chronic fibrous thyroiditis. In 1898, von Notthalt was the first to describe thyrotoxicosis factitia. In 1902, F. de Quervain was the first that described subacute granulomatous thyroiditis. In 1910, Charles H. Mayo was the first who used the term “hyperthyroidism” for explaining the clinical manifestations of primary exophthalmic goiter, toxic adenoma, and adenomatous goiter with hyperthyroidism. In 1931, L. Loeb and R. Bassett were the first who extracted and purified TSH from bovine pituitary. In 1936, Dr. Saul Hertz was the first who described the usage of radioactive iodine for the study of thyroid gland. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine to demonstrate a “hot” thyroid nodule. In 1948, T. Templa, J. Aleksandrowicz, and M. Till were the first who described the usage of fine needle thyroid biopsy as a diagnostic method for thyroid nodules. In 1949, R. G. Hoskins was the first who described negative feedback of thyroid gland on pituitary, a mechanism that he called “servo (feedback) mechanism”. In 1950, J. B. Stanbury was the first who described the genetic abnormality association with thyroid hormone synthesis. In 1959, J. B. Hazard, W. A. Hawk, and G. Crile were the first who described medullary thyroid cancer as a distinct entity. In 1965, S. Berson and R. Yalow were the first who described radioimmunoassay procedure. In 1966, R. F. Rohner, J. T. Prior and J. H. Sipple were the first who described multiple endocrine neoplasia type 2 and reported some cases. In 1970, A. Schally and R. Guillemin were the first who discovered TRH separately from each other.

The main events associated with development of treatment strategies include:^[1]

• In 2700 BC, seaweed was used for the treatment of goiter.
• In 340, Ko-Hung, a Chinese chemist recommended seaweed for treatment of goiter among people living in mountains.
• In 650, Sun Ssu-Mo, another Chinese physician, used dried, powdered mollusca shells and chopped thyroid gland for the treatment of goiter.
• In 1200, Arnaldus de Villanova reported that marine sponges could be used to treat goiters.
• In 1475, Wang Hei, a Chinese physician recommended treat of goiter with minced thyroid gland.
• In 1857, Maurice Schiff was the first to perform successful total thyroidectomies in animals.
• In 1891, G. R. Murray was the first who described the effect of thyroid hormone extract in treating myxedema.
• In 1905, Dr. Robert Abbe was the first who treated Graves disease by implanting radium into the patient’s goiter.
• In 1914, E. C. Kendall was the first to isolate thyroxine.
• In 1917, M. Seymour in Boston was the first who described the use of X ray for treating Graves disease.
• In 1924, H. S. Plummer at the Mayo clinic was the first who described the pre-operative usage of iodine for Graves disease treatment.
• In 1928, Harington and Barger were the first who described the chemical structure of thyroxine and synthesize it.
• In 1946, A. Astwood was the first who used thiourea and thiouracil for medical treatment of Graves disease.
• In 1949, Jones, Kornfeld, McLaughlin, and Anderson were the first to synthesize methimazole.
• In 1831, iodine prophylaxis was proposed as a government-administered public health program, for goiter prevention.
• In 1998, United States scientists were the first that approved clinical usage of recombinant human TSH.

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

There are various methods for classifying a thyroid nodule. A method has been developed by the National Cancer Institute (NCI) to address terminology and other issues related to thyroid fine-needle aspiration (FNA), called “The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)”. The other classification method is the TNM classification (tumor-node-metastasis) method developed by the American Joint Committee on Cancer and the International Union against Cancer focused on prognosis has been established to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers. Thyroid nodules may also be classified based on their ultrasound properties according to the TIRAD classification method, which has been proposed by Horvath et al, with a modified recommendation from Jin Kwak et al, and finally, thyroid nodules may also be classified on the basis of origin.

Thyroid nodule classification

Bethesda classification system

TIRAD classification system

Based on thyroid cytopathology

Based on sonographic features

•Benign •Nondiagnostic or Unsatisfactory •Follicular lesion of undetermined significance •Atypia of undetermined significance •Follicular neoplasm •Suspicious for a follicular neoplasm •Malignant

•TIRADS 1=Normal thyroid gland •TIRADS 2=Benign lesions •TIRADS 3=Probably benign lesions •TIRADS 4= Contain 1-4 suspicious features •TIRADS 5=Contain all five suspicious features •TIRADS 6=Biopsy proven malignancy

Differentiated and anaplastic thyroid carcinoma

TNM staging AJCC UICC 2017

Classification based on their origin

•Primary tumor (T) •Regional lymph nodes (N) •Distant metastasis (M)

Nonmedullary (epithelial) thyroid cancers (NMTCs) •Papillary cell tumors •Follicular tumors •Hurthle cell tumors •Anaplastic tumors

Medullary thyroid cancers

To address terminology and other issues related to thyroid fine-needle aspiration (FNA), the National Cancer Institute (NCI) developed a new classification method called “The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)”.^[1]

Classification	FNA cytology	Predicted risk of malignancy
Benign	Macrofollicular Adenomatoid/hyperplastic nodules Colloid adenomas (most common) Nodular goiter Lymphocytic thyroiditis Granulomatous thyroiditis	0–3 %
Nondiagnostic or unsatisfactory	—	1–4 %
Follicular lesion of undetermined significance	Mixed macro- and microfollicular nodules	5–15 %
Atypia of undetermined significance	Atypical cells
Follicular neoplasm	Microfollicular nodules Hurthle cell lesions	15–30 %
Suspicious for a follicular neoplasm	Suspicious for Hurthle cell neoplasm	60–75 %
Malignant	PTC (most common) MTC Anaplastic carcinoma High-grade metastatic cancers	97–99 %

Abbreviations: PTC– Papillary thyroid carcinoma, MTC– Medullary thyroid carcinoma

The TNM classification (tumor-node-metastasis) was adopted by the American Joint Committee on Cancer and the International Union against Cancer more than 10 years ago. This classification system mainly focuses on prognosis and is developed to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers.^[2]

Papillary, follicular, poorly differentiated, Hurthle cell and anaplastic thyroid carcinoma
Primary tumor (T)					Regional lymph nodes (N)		Distant metastasis (M)
T category	T criteria				N category	N criteria	M category	M criteria
TX	Primary tumor cannot be assessed				NX	Regional lymph nodes cannot be assessed	M0	No distant metastasis
T0	No evidence of primary tumor				N0	No evidence of locoregional lymph node metastasis	M1	Distant metastasis
T1	Tumor ≤2 cm in greatest dimension limited to the thyroid				N0a	One or more cytologically or histologically confirmed benign lymph nodes
T1a	Tumor ≤1 cm in greatest dimension limited to the thyroid				N0b	No radiological or clinical evidence of local regional lymph node metastases
T1b	Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid				N1	Metastasis to regional nodes
T2	Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid				N1a	Metastases to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease
T3	Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles				N1b	Metastasis to unilateral, bilateral, or contralateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes
T3a	Tumor >4 cm limited to the thyroid
T3b	Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size
T4	Includes gross extrathyroidal extension
T4a	Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size
T4b	Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size

A classification system has been proposed by Horvath et al, with a modified recommendation from Jin Kwak et al.^[3]

Ultrasound classification		Features		Risk of Malignancy
TIRADS 1		Normal thyroid gland
TIRADS 2		Benign lesions	Avascular anechoic lesion with echogenic specks (colloid type I) Vascular heteroechoic non-expansile, non-encapsulated nodules with peripheral halo (colloid type II) Isoechoic or heteroechoic, non-encapsulated, expansile vascular nodules (colloid type III)	0% risk of malignancy
TIRADS 3		Probably benign lesions	Nodule property: Hyperechoic, iso-echoic or hypoechoic nodules, with partially formed capsule and peripheral vascularity, usually in the setting of Hashimoto’s thyroiditis	<5% risk of malignancy
TIRADS 4	4a	One suspicious feature	Suspicious lesions: Solid component High stiffness of nodule on elastography if available Markedly hypoechoic nodule Microlobulations or irregular margins Microcalcifications Taller-than-wider shape	5-10% risk of malignancy
	4b	Two suspicious features		10-80% risk of malignancy
	4c	Three/four suspicious features
TIRADS 5		All five suspicious features	Probably malignant lesions (more than 80% risk of malignancy)	>80% risk of malignancy
TIRADS 6		Biopsy proven malignancy

Origin	Prevalence	Origin	Histologic Classification	Subclass
Nonmedullary thyroid cancers (NMTCs)	95% of tumors	Thyroid epithelial cells	Papillary (85%)	Classic variant Tall cell variant Insular variant Columnar variant Hürthle or oxyphilic variant Solid or trabecular variant Clear cell variant Diffuse sclerosing variant Cribriform-morular variant Hobnail variant
			Follicular (11%)	Benign follicular adenoma Minimally invasive follicular carcinoma Widely invasive follicular carcinoma Encapsulated follicular variant of papillary thyroid cancer Infiltrative variant of papillary thyroid cancer
			Hürthle cell (3%)
			Anaplastic (1%)
Medullary thyroid cancers (MTCs)	5% of all thyroid malignancies	Calcitonin-producing parafollicular cells		20% they are familial and occur as part of the multiple endocrine neoplasia (MEN) syndromes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Thyroid nodules may arise from different cells in the thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or frominflammation of thyroid tissue. Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may exhibit familial inheritance. The most important variety of familial thyroid cancers are caused by genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC). Other important genes related to thyroid nodule formation include, N&H ras, RET, Gsp, C-MET, TRK, EGF / EGF-R, and P53.

A summary of thyroid nodule pathophysiology is presented in the slides below: ^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][6][19][20][21][22][23][24][25][26][27][28][29][30][31]}

• Thyroid nodules may arise from different cells in thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign.
• Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or frominflammation of thyroid tissue.

• Hyperplastic nodule pathogenesis seems to start with an increase in thyroid proliferation, which lead to thyroid hyperplasia.
• Rapid thyroid proliferation mainly occur in response to certain stimulants.
• Stimulants mainly act through TSH mediated activity and production. Following the hyperplasia development phase, a new phase may begin, leading to a neoplasia.

• Growth signals in thyroid tissue start by a stimulant, that attaches to the thyroid receptors. The following signals can be transmitted through 3 distinct pathways:
  • Adenylate cyclase/protein kinase A system
  • Phospholipase C pathways
  • Phospholipase A2 system (intracellular metabolism of prostaglandins)

• The most important pathway for thyroid growth is the activation of adenylate cyclase/protein kinase A system. Activation of phospholipase C and phospholipase A2 have only a minor effect on thyroid growth.
• TSH acts as a stimulant by binding to the TSH receptor and leads to activation of both the adenylate cyclase and phospholipase C pathways. As mentioned, the phospholipase C pathway has minor effects, and most of the TSH effect on cell growth is generated by adenylate cyclase pathway. The signal generated by the adenylate cyclase cAMP-dependent pathway is then transduced in the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes. It has been established that TSH has a main mitogenic role, through cAMP, Gs proteins and protein kinase A, which activates the metabolic cascade leading to the stimulation of growth.
• However, to produce hyperplasia, overproduction of cAMP must be continuous, as it occurs in mutations constitutive of the genes which regulate cAMP production.
• Constitutive cAMP overproduction has been demonstrated to be due to point mutation of the TSH receptor or Gs protein.
• Constitutive cAMP overproduction not only stimulates growth but also function.
• Hyperplastic thyroid nodule pathogenesis can be divided into 2 phases:

Thyroid normally has a low proliferative activity, although it can start proliferation rapidly in response to certain stimulants. Stimulants mainly act through TSH mediated activity and production. The following stimulants appear to have the most important role in pathogenesis of hyperplastic nodules:^[32][33]

• Iodine deficiency:
  • Effects directly or indirectly 
  • The most potent stimulator replication of the cells of thyroid gland 
  • Mechanism of action:
    • Acts as an initiator for TSH rise
    • May enhance the effect of other chemicals that induce a rise in TSH by inducing the promotor overactivity
    • The most important reason of high prevalence of thyroid hyperplasia and nodules in iodine-deficient areas
• Industrial chemicals:
  • DDT
  • Polychlorinated biphenyls
  • Pesticides
• Goitrogens:
  • Complex anions and inorganic atoms (iodine, lithium, CLO4–, TcO4–, BF4–)
  • Thiocyanate (SCN–)
  • Goitrin, isolated in plants of the genus Brassica
  • Aniline derivatives (sulfonamides, tolbutamide, sulfaguanidine, sulfamethoxazole, etc.)
  • Phenol derivatives and polyhydroxyphenols
  • Flavonoids:
    • TPO inhibitors
    • Also act on thyroid metabolism by interacting with the nuclear receptor for thyroid hormones
• Antithyroid drugs:
  • Thionamides that are used in the treatment of hyperthyroidism
• Tobacco:
  • May be the reason of high prevalence of thyroid hyperplasia and nodules in iodine-sufficient areas 

• Thyroid stromal cells interact with thyroid follicular cells by cytokines. Inappropriate cytokine activities also seem to be related to TSH overproduction and thyroid hyperplastic nodule formation. The most important cytokines that may lead to differentiation or inhibition of thyroid growth are:
  • TGFβ
  • IFNγ
  • IL-6
  • Somatostatin

• Thyroid cells produce the angiogenic vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) sensitive to TSH stimulation.
• The vascular growth factor induces neovascularization by binding to specific receptors on endothelial cells and stimulating new vessel production.
• In response, endothelial cells produce growth factors that increase thyroid cell proliferation and lead to thyroid hyperplasia.
• Neovascularization in thyroid matrix is accompanied by the production of proteolytic enzymes, which facilitate the expansion of thyroid tissue into the extracellular matrix.

• Each follicle is composed of different clones of cells (polyclonal), but during nodule formation they replicate in a simultaneous and coordinated manner, so each follicle of the nodule reproduces the same heterogeneity of the mother follicle.
• When a neoplasm arises in the nodule, then the neoplastic follicle shows a monoclonal pattern, suggesting that cancer arises from a single cell. 

• Activation of oncogenes is considered the underlying event leading to uncontrolled cell growth.

• Neoplastic nodules development mainly involve the activation of proto-oncogenes as the underlying event leading to uncontrolled cell growth.
• Proto-oncogene activation is associated with thyroid adenoma, hyperplasia, and malignancies.
• Thyroid gland is made up of different follicles, and each follicle is composed of different clones of cells (polyclonal). During nodule formation, cells replicate in a coordinated fashion simultanously, so each follicle of the nodule shares the same heterogenity with other cells.
• Hyperplastic thyroid nodules are considered a risk factor for the development of neoplasia, as these cells may express neoplastic potential during their rapid proliferation phase.
• During neoplasm formation in the nodule, the neoplastic follicle mostly shows a monoclonal pattern. These findings may indicate that neoplasia arises from a single cell genetic mutation. The most important oncogenes related to thyroid neoplasia development are mentioned in the genetic table below.^{[34][35][36][37][38][39]}

• Environmental factors can play an important role in triggering the oncogene mutation. The most important carcinogens involved in the pathogenesis of neoplastic thyroid nodules are:
  • Thioamide compounds
    • Thiourea
    • Methimazole
    • Ethylenethiourea (ETU)
    • Thiouracil
    • Propylthiouracil
  • Aminotriazole: Herbicide
  • Acetylaminofluorene (AAF)
  • Use: Insecticide
  • Oxydianiline (ODA)
  • Use: Azo-Dye
  • Methylene benzenamine
  • Use: Dye intermediate
  • Nitrosamines
  • Nitrosoureas (NMU), (NBU), (ENU)
  • Use: derivatives (BCNU, CCNU, MeCCNU) are drugs against tumors
  • Streptozocin (naturally occurring nitrosourea) is used in the treatment of islet-cell carcinoma of the pancreas

• The most important pathogenic factor involved in developing papillary thyroid cancer is an intracellular signaling pathway called MAPK pathyway (Mitogen-activated protein kinases), also known as ERK pathway (extracellular signal-regulated kinase). After antigen binding to tyrosine receptors, MAPK is translocated into the nucleus. Receptor activation leads to cell division, after phosphorylation by MEK (a serine/threonine kinase).
• Other steps leading to MAPK phosphorylation include phosphorylation of RAS which activates BRAF, a serine/threonine kinase followed by MEK and MAPK phosphorylation.
• In papillary thyroid carcinoma, a somatic mutation may lead to activation of this linear signaling cascade.
• As a result, there will be increased transcription of nuclear proteins, which lead to un-regulated activity and reproduction of cancerous cells. This implies that any single alteration is sufficient to play an early role in tumorigenesis.^[40][41]

Abbrevaitions:

ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase

• The colloid nodules consist of colloid droplets and thyroglobulin vesicles.
• Thyroid gland keeps a balance between colloid and thyroglobulin production by regulating the secretion of thyroglobulin into colloid and reabsorption of colloid into thyroid follicular cells. This regulation is maintained by macro-pinocytosis (pseudopods) and micro-pinocytosis (microvilli).
• Any imbalance between secretion and reabsorption of thyroglobulin leads to a disruption of the equilibrium, and produces a colloid appeared thyroid nodule. These nodules may also be produced as a defect of intraluminal thyroglobulin reabsorption. 

Iodine excess can lead to colloid nodules in thyroid gland, leading to a colloid goitre:

• Endocytosis inhibition: High dosage of iodine may lead to inhibition of the protease activity of thyroid lysosomes thereby inhibiting endocytosis
• Exocytosis inhibition: Iodine reduces the expression of the TSH receptor on the surface of thyroid cells thereby inhibiting and decreasing colloid reabsorption
• Iodine excess in combination with TSH over activity may lead to colloid goitre

Another mechanism that may lead to colloid goitre formation is loss of thyroglobulin packaging ability, that may lead to an enormous enlargement of the follicles and flattening of the epithelium.

Cystic thyroid nodules may be classified into the following types:

• Necrotic cystic nodules:
  • May be due to a relative deficiency of blood supply:
    • Inadequate blood supply for neoplastic growth
    • Imbalance between angiogenesis and cell growth
    • Compression of new vessels due to mass effect, leading to cell damage and necrosis
  • Hyperplastic thyroid nodules may proceed towards necrosis, colliquation, and pseudocyst formation
• Serum-like cystic nodules:
  • May be related to autoimmunity
• Apoptotic cystic nodules:
  • Cysts that may be related to normal cellular apoptosis or neoplastic/infected cellular apoptosis
• Vascular growth factor related cystic nodules:
  • Cyst formation may be the result of an increased concentration of VEGF/VPF inside the cystic area
  • VEGF/VPF lead to stimulation of vascular permeability and promoting the accumulation of fluids in the cysts
  • VEGF/VPF are particularly found in the cystic fluid of rapidly enlarging or recurrent cysts

Nodular lymphocytic thyroiditis almost always present in combination with other thyroiditic diseases. They can also present as a part of infection. It has been shown that the ability of super-antigens (SAgs) to activate the immune system may play a role in the course of autoimmune disorders. In most of these cases, the mechanism of nodular lesion is the same as the mechanism of the main disease, implying that the thyroid nodule is a part of normal disease pattern. Many of these nodules are not identifiable based on physical exam, and are detected during thyroid scintigraphy. The most important thyroiditic diseases that may present as lymphocytic nodular thyroid are:

• Local infections:
  • Pyogenic infection
  • Tuberculosis
  • Parasites
• Subacute de Quervain’s thyroiditis
• Fibrosing (Riedel’s) thyroiditis
• Plasma cell granuloma
• Plasmacytoma
• Primary amyloid tumor and amyloidosis
• Thymoma
• Primary thyroid lymphoma
  • Thyroiditic nodule due to diffuse B-cell infiltration into lymphoma presented areas
• Histiocytosis X
• Medullary carcinoma
• Papillary carcinoma
  • Thyroiditic nodule may be due to an immune response to some abnormal thyroid antigen expressed in the tumor

Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may occur in a familial order. The most important category of familial thyroid cancers are due to genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC), with the following features:

• Rare group of cancers
• Related to other non-medullary tumors
• Inheritance: Autosomal dominant with incomplete penetrance and variable expressivity
• Affected patients in an earlier age
• Associated with:
  • More benign thyroid nodules
  • Multifocal disease
  • A higher rate of locoregional recurrence

Oncogenes and growth factors	Gene mechanism	Mutation effect	Neoplasia
N&H ras	Ras-constitutively bound to GTPase-activating protein (GAP)	Activation of adenylate cyclase and calcium channels	Adenomas Papillary carcinoma Follicular carcinoma Anaplastic carcinoma
RET	Encodes a receptor for glial-derived neurotrophic GF Fusion proteins with constitutive thyrosine kinase activities Dimerization of RET thyrosine kinase receptors (TRK)	Mitogenic through constitutive activation of TKR Increased auto-phosphorylation and alteration of substrate specificity	Papillary carcinoma MEN 2A FMTC MEN 2B
Gsp	Ribosylated GS-α at arginine 201	Impairing of GTPase activity	Hot adenomas
C-MET (α and β subunit)	Increased receptors for HGF/SF	Enhancement of receptor kinase activity	Papillary carcinoma
TRK	Receptor for nerve growth factor	Mitogen activated TK cascade	Papillary carcinoma
EGF / EGF-R	Competence factor in cell cycle	Transition through G0-G1 phase	Anaplastic carcinoma
P53	Lack of activation of p21/Waf l gene expression	Loss of regulation at the critical G1 to S phase	Anaplastic carcinoma Papillary carcinoma Follicular carcinoma

Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with:^[42][43]

• Higher differentiated thyroid cancer stage
• Gross extrathyroidal extension
• Neck node metastases

• On gross pathology, cystic lesions, multiple or a single nodule, and encapsulated lesions are the most important and prevalent characteristic findings of thyroid nodules.
• On gross pathology, follicular thyroid adenoma may present as a big lesion with thick capsule.

Diagnostic speciemen feature: the presence of at least six follicular cell groups, each containing 10–15 cells derived from at least two aspirates of a nodule^{[44][45][46][45]}

Cytology classification		Also referred to as:	Efficient diagnosis		May be seen in:	FNA cytology
			FNA	Surgical biopsy
Follicular lesions	Benign (macrofollicular)	Adenomatoid adenoma Hyperplastic adenoma Colloid adenoma	+		Normal thyroid tissue Sporadic nodular goiter Monoclonal macrofollicular tumors Hyperplastic nodules Colloid adenomas (most common)	May have areas of cystic degeneration with cellular debris and hemosiderin-laden macrophages Cellular characteristics: Small and flat Uniform in size Non-crowded Smeared colloid is seen in the background Follicle size may vary, with a few microfollicles interspersed among the macrofollicles, especially if the sample was obtained from an area close to the capsule of the lesion Colloid: May smear across the slide or occasionally aggregated into droplets due to disruption of follicles during FNA Stains blue on a Papanicolaou stain May be abundant in the background of macrofollicular lesions
	Follicular neoplasm/microfollicular	Cellular adenoma Indeterminate adenoma Trabecular adenoma		+	Follicular adenomas Follicular carcinomas Follicular variant of papillary cancer Occasionally from autonomously functioning thyroid nodules	Well-developed microfollicles Crowding of cells May form clusters and clumps Scant colloid Varying nuclear atypia Varying cellular pleomorphism Follicular carcinoma: Focal microscopic invasion Cellular or trabecular adenomas: Lesions with less definite or no follicle formation May show vascular or capsule invasion
	Follicular lesion of undetermined significance (FLUS)		+		Commonly, especially in nodular goiters	FLUS: The lesion has approximately equal number of macrofollicular fragments and microfollicles AUS: Cells with mild nuclear atypia Mostly due to compromised speciemens: Poor fixation or obscuring blood (FLUS)
	Atypia of undetermined significance (AUS)
	Hürthle cells	Oncocytes Askanazy cells Oxyphil cells	+		Focal Hürthle-cell change: Degenerating macrofollicular lesions Hashimoto’s thyroiditis	Large polyclonal cells Oxyphil cytoplasm Considered benign if there is no evidence of vascular or capsular invasion Considered malignant if invasion is present Hürthle-cell cancer Follicular cancer Oxyphil cell type cancer
Papillary cancer		The follicular variant of papillary cancer		+	Epithelioid giant cells Papillary cancer Degenerating areas of macrofollicular nodules Subacute granulomatous thyroiditis Psammoma bodies Papillary carcinoma Benign thyroid lesions	Large cells and nuclei  Ground glass appearance of cytoplasm  Nuclei appearance: Clefts  Grooves  Holes  Intranuclear cytoplasmic inclusions = Orphan Annie eye Small nucleoli  Psammoma bodies Small laminated calcifications Sticky colloid Colloid “stick” to debris and cell clusters, instead of smearing across the slide Epithelioid giant cells Can also be seen in: Degenerating areas of macrofollicular nodules Subacute granulomatous thyroiditis
Medullary cancer				+	Medullary cancer	Spindle-shaped cells Frequently pleomorphic cells without follicle development Supporting stroma may frequently stains for amyloid Red cytoplasmic granules Eccentrically placed nuclei Slightly granular cytoplasm that may be configured as a tear drop or cytoplasmic tail
Anaplastic thyroid cancer			+		Anaplastic thyroid cancer	Spindle cells Pleomorphic giant cell Squamoid Mitosis Numerous mitotic figures Atypical mitoses Extensive necrosis

• Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign
• The diagnosis of follicular cancer can not be made based on FNA, because vascular or capsular invasion is required to make the diagnosis of follicular cancer. 8420446

Neoplasm	Subclass	Features
Follicular thyroid lesions	Minimally invasive follicular carcinoma	Only invasion of the capsule of the tumor without vascular invasion
	Widely invasive follicular carcinoma	Extensive invasion of the tumor capsule A multinodular tumor without a well-defined capsule invading the normal thyroid surrounding the tumor Extensive vascular invasion (>4 foci of angioinvasion)
	Encapsulated follicular variant of papillary thyroid cancer	Minor vascular invasion (≤4 foci of angioinvasion within the tumor or capsule of the tumor) with or without capsular invasion
	Infiltrative variant of papillary thyroid cancer
Papillary thyroid cancer	Tall cell variant	Tumor cells with eosinophilic cytoplasm that are twice as tall as they are wide The primary tumors tend to be large  Often invasive, that many patients have both local and distant metastases at the time of diagnosis
	Insular varient	Solid nests of tumor, often separated by fibrous bands, but the tumor cell nuclei have the same characteristics as do the nuclei of classical papillary cancers
	Columnar variant	Elongated cells with palisading nuclei
	Hürthle or oxyphilic variant	Cellular features of Hürthle cell carcinomas but cells that are arranged in papillary formations.
	Clear cell variant	Clear cell view with clear cytoplasm Must be distinguished from clear cell carcinomas of other organs such as the kidney or colon that have metastasized to the thyroid
	Diffuse sclerosing variant	Diffuse involvement of the thyroid Stromal fibrosis Prominent lymphocytic infiltration
	Cribriform morular variant	Prominent cribriform pattern with solid and spindle cell areas as well as squamous morules Often associated with familial adenomatous polyposis
	Hobnail variant	Multifocal with variably sized complex papillary structures lined by cells Cells with increased nuclear to cytoplasmatic ratios Apically placed nuclei that lead to a surface bulge (hobnail appearance) 19956062

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

The major causes of thyroid nodule development include, multinodular (sporadic) goiter, Hashimoto’s thyroiditis, cysts, macrofollicular/microfollicular adenomas, childhood radioiodine exposure, familial history, and gene mutations include N&H ras, RET, Gsp, C-MET (α and β subunit), TRK, EGF / EGF-R, and P53 mutation.

The most important causes of thyroid nodule development include:^[1][2][3]

• Causes of benign thyroid nodule:
  • Multinodular (sporadic) goiter (“colloid adenoma”)
  • Hashimoto’s (chronic lymphocytic) thyroiditis
  • Cysts (colloid, simple, or hemorrhagic)
  • Follicular adenomas
  • Macrofollicular adenomas
  • Microfollicular or cellular adenomas
  • Hürthle cell (oxyphil cell) adenomas
  • Macro- or microfollicular patterns
• Causes of malignant nodule mutations:
  • Childhood radioiodine exposure
  • Familial history

The most important genes which can lead to thyroid cancer include:^[1][2][3]

• N&H ras
• RET
• Gsp
• C-MET (α and β subunit)
• TRK
• EGF / EGF-R
• P53

Template:WH Template:WS

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

Neck masses can be mistaken with thyroid nodules. The most important neck masses that can be mistaken with thyroid nodules include: Thyroglossal duct cyst, parathyroid cancer, parathyroid cyst, and branchial cleft cyst. While the diagnosis of a thyroid nodule is established, thyroid nodule should be differentiated based on benign or malignant features and the type of nodule.

Neck masses can be mistaken with thyroid nodules. While the diagnosis of a thyroid nodule is established, thyroid nodule should be differentiated based on benign or malignant features and the type of nodule:

Disease	Manifestation	Spread	Nodular growth	Laboratory		Imaging	Pathology	Associated findings
				TSH	FT4/T3
Colloid adenoma	Benign Noncancerous enlargement of thyroid tissue May be painful	−	Intermediate Slow	NL	NL	Iso- to hypoechoic May have internal cystic or heterogeneous change May have calcification Multiple echogenic foci (of inspissated colloid) with comet tail artifact	Hyperplasia of colloid parenchyma of thyroid gland	May progress to carcinoma
Hashimoto’s thyroiditis	Benign Rarely painful May be accompanied with fever	−	Rapid Intermediate	↓↓	↓	Hypoechoic micronodules (1-6 mm) with surrounding echogenic septations	Massive infiltration of the thyroid gland by lymphocytes and plasma cells Germinal centers Thyroid follicles are usually absent and the few remaining follicles are devoid of colloid Hurthle cells	HLA-A HLA-B Autoimmune disease of thyroid gland
Cysts nodule	Benign Most common cause of painful neck lesion	−	Rapid Intermediate	NL	NL	Cystic non-calcified nodules	Follicular cells Macrophages RBC Colloid	Mostly due to degenerating thyroid adenomas
Disease	Manifestation	Spread	Nodular growth	TSH	FT4/T3	Imaging	Pathology	Associated findings
Follicular adenoma	Benign Rarely painful	−	Intermediate Slow	↓↓	↑	Thin peripheral halo Predominantly cystic or mixed cystic and solid lesions Isoechoic or predominantly anechoic	Depends on type	PAX8-PPAR gamma 1
Hyperplastic nodule	Benign Rarely painful	−	Rapid Intermediate	↓↓	↑
Macrofollicular adenoma	Benign Rarely painful	−	Intermediate Slow	↓↓	↑
Microfollicular or cellular adenoma	Benign Rarely painful	−	Intermediate Slow	↓↓	↑
Hürthle cell adenoma	Benign Rarely painful	−	Intermediate Slow	↑↓	↑↓
Disease	Manifestation	Spread	Nodular growth	TSH	FT4/T3	Imaging	Pathology	Associated findings
Papillary carcinoma	Malignant Fixed Painless	Spread to lymph nodes and vessels Metastases to: Lung Skeleton	Intermediate Slow	NL	NL	Solitary mass usually with an irregular outline, located in the subcapsular region Small punctate regions of echogenicity representing microcalcifications (psammoma bodies)	Unencapsulated and may be partially cystic Papillae consisting of one or two layers of tumor cells surrounding a well-defined fibrovascular core Large, oval, and appear crowded and overlapping nuclei May contain hypodense powdery chromatin, cytoplasmic pseudoinclusions due to a redundant nuclear membrane, or nuclear grooves	RET/PTC NTRK1 RAS BRAF
Follicular carcinoma	Malignant Fixed Painless Most common thyroid cancer in iodine deficient areas	Spread to lymph nodes and vessels Metastases to: Bone Lung	Intermediate Slow	↑↓	↑↓	Lesions are typically hypoechoic Usually lacks cystic change	FLUS Tumor capsule Vascular invasion	RAS mutations PAX8-PPAR gamma 1
Medullary carcinoma	Malignant Mainly manifest paraneoplastic symptoms: Diarrhea Itching Flushing	Spread to lymph nodes May spread to vessels Metastasis locally to neck Can metastasize to all body organ systems	Intermediate Slow	NL	NL	Unifocal May present as multifocal	Hypoechoic Microcalcifications	May be associated with other co-existing diseases Associated with high levels of calcitonin
Disease	Manifestation	Spread	Nodular growth	TSH	FT4/T3	Imaging	Pathology	Associated findings
Anaplastic carcinoma	Very malignant, always considered as stage IV Dyspnea Dysphagia Vocal cord paralysis Hoarseness of voice	Spread to lymph nodes and vessels Very aggressive Invade directly into adjacent organs, such as the trachea, larynx, esophagus, blood vessel and muscle	Slow	↓	↑	Microcalcifications Infiltrative lesion	Cytologically malignant: Huge nuclear-cytoplasmic ratio Mitosis Presence or absence of necrosis	P53 BRAF
Primary thyroid lymphoma	Malignant Vocal cord paralysis Dyspnea Dysphagia	Spread to lymph nodes MALT lymphoma less aggressive Diffuse large cell lymphomas more aggressive	Intermediate Slow	NL	NL	Nodular (hypoechoic mass), diffuse (mixed echotexture) or mixed Calcifications uncommon	Lymphoepithelial lesion Plasma cells Thyroid parenchyma displaced by lymphocytes	BRAF NRAS MAPK Hashimoto’s thyroiditis
Metastatic carcinoma	Malignant Thyroid and extra thyroid manifestations	Spread to lymph nodes and vessels Metastases	Intermediate Slow	↑↓	↑↓	−	−	Malignant melanoma Lung cancer breast cancer Renal cancer Gastrointestinal cancer
Thyroglossal duct cyst[1]	Mostly midline Can be painful if get infected	−	−	NL	NL	Cyst in subhyoid portion or lateral tip of the hyoid bone	−	NA
Disease	Manifestation	Spread	Nodular growth	TSH	FT4/T3	Imaging	Pathology	Associated findings
Branchial cleft cyst[2]	Cystic mass that develops under the skin in the neck between the sternocleidomastoid muscle and the pharynx	May adhere to great vessels at the mandibular angle	−	NL	NL	Cyst between sternocleidomastoid and pharynx	−	NA
Neck abscess[3]	Painful mass in the neck, may be accompanied with erythema	Spread to lymph nodes	Rapid	NL	NL	Cyst with hyperechoic debris containing pus	−	NA
Parathyroid cyst[4]	Painless mass	−	Rapid Intermediate	NL	NL	Cystic lesion that is uniformly anechoic	−	NA
Parathyroid cancer[5]	Lymphadenopathy Palpable lump in the neck	Spread to lymph nodes and vessels Rarely distant metastases, mainly thyroid gland, overlying strap muscles, recurrent laryngeal nerve, trachea, or esophagus	Slow Intermediate	NL	NL	Normal thyroid size with a complex echogenic structure May contain hyperechoic solid part and several centrally located anechoic cavities	Tumor cells form branching cord surrounded by fat cells with areas of fibrosis and chronic inflammatory cells or abundant granular eosinophilic cytoplasm	FIHP MEN1
Disease	Manifestation	Spread	Nodular growth	TSH	FT4/T3	Imaging	Pathology	Associated findings

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

Worldwide, the incidence of thyroid nodule ranges from as low of 40,000 per 100,000 persons to a high of 71,000 per 100,000 persons with an average incidence of 50,000 per 100,000 persons. The incidence of thyroid cancer is estimated to be a total number of 48,288 cases annually in United states. Thyroid nodules are common, their prevalence being largely dependent on the identification method, as sensitivity and specificity of different methods for thyroid nodule diagnosis varies. In United States, the prevalence of thyroid nodule detected by palpation alone ranges from a low of 2,000 per 100,000 persons to a high of 6,000 per 100,000 persons, while the prevalence of thyroid nodule detected by ultrasound ranges from a low of 20,000 per 100,000 persons to a high of 35,000 per 100,000 persons. Worldwide, the prevalence of palpable thyroid nodule is approximately 5,000 per 100,000 in women and 1,000 per 100,000 in men living in iodine-sufficient parts of the world, and the prevalence of ultrasound detected thyroid nodules ranges from as low as 19,000 per 100,000 to as high as 68,000 per 100,000. Thyroid nodules commonly affects individuals younger than 20 and older than 50 years of age. Females are more commonly affected with thyroid nodules than males.

• Worldwide, the incidence of thyroid nodule ranges from as low of 40,000 per 100,000 persons to a high of 71,000 per 100,000 persons with an average incidence of 50,000 per 100,000 persons.^[1][2]
• The risk for malignancy in asymptomatic nodules found in non-irradiated glands is 0.45% to 13% (mean +/- SD = 3.9% +/- 4.1%), which means the incidence of malignant thyroid nodule ranges from as low as 250 per 100,000 persons to as high as 7000 per 100,000 persons approximately.^[1][2]
• The incidence of thyroid cancer is estimated to be a total number of 48,288 cases annually in United states.
• There is a large increase worldwide in the incidence of thyroid cancers. It is likely to be due to:^[1][2]

• • The use of head and neck external beam radiation, commonly used to treat benign childhood conditions between 1910 and 1960.
  • The increased detection of small papillary cancers secondary to more widespread use of neck ultrasound and fine-needle aspiration (FNA) of very small thyroid nodules.

Thyroid nodules are common, their prevalence being largely dependent on the identification method, as sensitivity and specificity of different methods for thyroid nodule diagnosis varies.^[3]

• In United States, the prevalence of thyroid nodule detected by palpation alone ranges from a low of 2,000 per 100,000 persons to a high of 6,000 per 100,000 persons, while the prevalence of thyroid nodule detected by ultrasound ranges from a low of 20,000 per 100,000 persons to a high of 35,000 per 100,000 persons.^[4]
• In United States, the prevalence of thyroid nodule detected by surgery or autopsy ranges from a low of 50,000 per 100,000 persons to a high of 65,000 per 100,000 persons, that correlate more with the prevalence detected by ultrasound.^[5]
• In the United States, 4 to 7 percent of the adult population have a palpable thyroid nodule.^[6][5]

Worldwide, the prevalence of palpable thyroid nodule is approximately 5,000 per 100,000 in women and 1,000 per 100,000 in men living in iodine-sufficient parts of the world, and the prevalence of ultrasound detected thyroid nodules ranges from as low as 19,000 per 100,000 to as high as 68,000 per 100,000. ^[5][6]

• There is a large increase worldwide in the incidence of thyroid cancers. The largest increase in thyroid cancer incidence has been observed in South Korea:^[7]

• • In 1993-1997, the incidence of thyroid cancer was estimated to be 12.2 cases per 100,000 individuals, while in 2003-2007, the incidence of thyroid cancer increased and was estimated to be 59.9 cases per 100,000 individuals.
  • Thyroid cancer is recognized as the most common cancer among women in South Korea.

• Thyroid nodules commonly affects individuals younger than 20 and older than 50 years of age.^[2]
• There is no association between the thyroid cancer development in a previous patient with the thyroid nodule and the age. ^[8][9]

• Females are more commonly affected with thyroid nodules than males.^[10]
• The female to male ratio is approximately 5 to 1.^[11]
• Males are more commonly affected with aggressive thyroid neoplasms and have a more fatality rate than women.^[12]
• Females are more commonly affected with follicular thyroid lesions than males.^[12]

• Although goiter is more prevalent in iodine deficient and developing countries, there are insufficient data regarding association of thyroid nodules and the country of residence.^[10][11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Common risk factors in the development of thyroid nodules include: older age, iodine deficiency, previous history of iodine deficiency and hypothyroidism, living in iodine deficient areas, family history of autoimmune diseases, multiparity, and smoking.

Common risk factors in the development of thyroid nodules include:^{[1][2][3][4][5][6][7][8][9]}

• Hard nodule
• Nodule that stuck to nearby structures
• Family history of thyroid cancer
• Younger than 20 or older than 70 years
  • As thyroid nodularity increases with age, presence of thyroid nodule in a children is twice more likely to be a cancer than in adults
• History of radiation exposure to the head or neck
• Either externally from therapeutic X-radiation or internally through treatment with radioactive iodine (131I) and possibly radioactive fallout (131I)
  • As an example, ground nuclear bomb testing in Nevada in the 1950s led to a meaningful increase in thyroid cancer incidence
• History of radiation treatment to the head and neck region, for example for treatment purposes is associated with an increased incidence of thyroid nodularity and cancer:
  • To treat acne
  • To treat inflammation of the tonsils or adenoids
  • To treat thymic enlargement
• Male gender
  • The risk of benign thyroid nodule development in women is more but the rate of cancer is twice as high in men than women (8 versus 4 percent)
• Smoking
• Alcohol consumption
• Insulin-like growth factor 1 (IGF-1) levels
• Increased parity and late age at first pregnancy
• Hepatitis C-related chronic hepatitis (odds ratio 12.2 in one report)
• Decreased serum TSH levels in women

• Uterine fibroids

• Less common risk factors in the development of thyroid nodules include:^{[10][11][12][13]}
  • Oral contraceptive use
  • Use of statins
    • Associated with a reduced risk of nodules on ultrasound
    • Reduced prevalence, number and volume of thyroid nodules
  • A history of papillary thyroid cancer in at least one first-degree family member is associated with an increased risk of a nodule being malignant
  • Hematopoietic stem cell transplantation increases the relative risk (RR) for thyroid cancer to 3.26; if transplantation occurred prior to age 10, the RR was 24.6.

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

According to USPSTF, screening for thyroid cancer is not recommended and there is insufficient evidence to recommend routine screening for thyroid nodule.

• According to the USPSTF, there is insufficient evidence to recommend routine screening for thyroid nodule in United States.^[1]
• Most countries do not recommend routine screening for thyroid nodules, however in Japan’s Fukushima Prefecture, a new intensive screening program was adopted in 2014 for children and adolescents group, in response to the 2011 nuclear accident.

• The result showed an approxiamtely 30 times thyroid cancer incidence as high as the national average among the screened children and adolescents. ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

A solitary thyroid nodule can become symptomatic if it grows rapidly due to hemorrhage or malignancies, invades laryngeal nerves, compressing nearby structures, and secretory nodules that produce TSH. Thyroid nodules may be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness. Without treatment, the patient with benign nodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death. The most common complications of thyroid nodules are hoarseness, horner syndrome, nodule rupture, needle track seeding, hemorrhage/hematoma, dysphagia, upper airway obstruction, pain, skin burn, vasovagal reaction, hypothyroidism, transient thyrotoxicosis, anaphylactic reaction, thromboembolism, and pneumothorax. Benign thyroid nodules have great prognosis, while prognosis of malignant thyroid nodules may be determined based on their type by scoring system of TNM staging.

• Thyroid nodules are mostly asymptomatic. A solitary thyroid nodule can become symptomatic if:
  • Grows rapidly due to hemorrhage or malignancies
  • Invades laryngeal nerves
  • Compress nearby structures including:
    • Trachea: Dyspnea
    • Esophagus: Dysphagia
    • Carotid artery: Lightheadedness
    • Vagus nerve: Vasovagal syncope
  • Secretory nodules that produce TSH

A simple thyroid nodule without any complication usually remain asymptomatic, may resolve spontaneously or may progress to other malignant diseases. Thyroid nodules can be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness.

Without treatment, the patient with benign nodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death.

• Noncancerous thyroid nodules are not life threatening. Many do not require treatment. Follow-up exams are enough. On the other hand, cancerous thyroid nodules can lead to a different variety of complications, depending on the type of cancer.
• Common complications of thyroid nodules include:^[1]

Complication	Features	Cause	Treatment
Hoarseness	Usually transient Patients with recurrent thyroid cancers have a greater risk of permanent hoarseness	Invasion of the laryngeal nerves that controls the vocal cords Radiofrequency ablation (RFA)-induced thermal injury of the recurrent laryngeal nerve or vagus nerve Trauma: Laryngoscopic evaluation Stretching of the nerve over a hematoma Lidocaine injection Post hemorrhage inflammation Fibrosis around the nerve	Usually resolve spontaneously Prednisone may shorten the duration
Horner syndrome	Ocular discomfort Conjunctivitis Ptosis Miosis Anhidrosis of the face	Subsequent thermal injury to middle cervical sympathetic ganglion due to RAI to a nearby ganglion	Usually resolve spontaneously Prednisone may shorten the duration
Nodule rupture	Breakdown of the thyroid capsule and a leak of the fluid from intra-thyroidal lesions toward extra-thyroidal lesions Sudden neck swelling and pain	Spontaneous tearing of the tumor wall and thyroid capsule at a weak point Post radiofrequency ablation massage Strong movement of the neck Delayed bleeding caused by micro vessel leakage within the nodule, leading to delayed volume expansion and rupture	May resolve spotanously May need antibiotic therapy May need incision and drainage
Needle track seeding	Rare Implantation of tumor cells by contamination when instruments like biopsy needles are used to examine, excise or ablate a tumor Spread of the tumor to nearby structures	After RFA or FNA of thyroid carcinoma	—
Hemorrhage/hematoma	Usually asymptomatic A rapidly expanding hypo/anechoic signal within the nodular tissue, resulting in gradual enlargement Can be detected by real-time ultrasound	May cause hemorrhage in the following structures: Perithyroidal capsule Subcapsular region Intranodular during needle insertion May be due to the sudden reduction of intranodular pressure due to fluid evacuation especially in multinodular or complex nodular structures	Drainage if indicated
Dysphagia	May be associated with odinophagia	Mass effect of thyroid nodule on the esophagus	Tumor resection
Upper airway obstruction	Dyspnea	Mass effect of thyroid nodule on the trachea	Tumor resection
Pain/sensation of heat	Pain located generally in the neck Occasionally radiating around toward the head, gonial angle, ear, shoulder, or teeth	During the raioactive iodine(RAI) procedure mostly due to thyroid capsule thermal damage Due to parenchymal edema	Mostly self-limited
Skin burn	First-grade skin burns, which presented with skin color changes and mild pain and discomfort	Due to radioiodine frequency ablation	Topical corticosteroids
Vasovagal reaction	Bradycardia Hypotension Vomiting	Due to vagus nerve stimulation in nodules adjacent to the common carotid artery and the internal jugular vein	Symptoms usually last a few minutes
Hypothyroidism	Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain	Due to radio-iodine therapy Due to antibody formation prior to any treatment	Levothyroxine
Transient thyrotoxicosis	Thyroid hormone increase TSH decrease	An inflammatory process following needle aspiration of a thyroid cyst Cause thyroiditis and thyrotoxicosis that triggers the release of thyroid hormones	Temporary anti thyroid drugs
Anaphylactic reaction	Rare Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence)	Mostly due to: Local anesthetics Rupture of a parasitic cyst, mistaken for a simple cystic thyroid nodule	Epinephrine
Thromboembolism	Rare Mostly present with TIA or stroke	Mostly in elderly especially if known carotid artery atherosclerosis coincides	Anticoagulants
Pneumothorax	Rare Mostly asymptomatic Mostly a self limited situation that resolves spontanously	May cause pneumothorax due to apical pleural injury in: Supraclavicular thyroid nodules Deep-seated thyroid nodules Substernal multinodular goiter	Prednisone

The American Joint Committee on Cancer (AJCC) introduced the TNM staging system for evaluating thyroid cancer prognosis.

T categories for thyroid cancer (other than anaplastic thyroid cancer)
TX		Primary tumor cannot be assessed.
T0		No evidence of primary tumor.
T1	T1a	The tumor is 1 cm (less than half an inch) across or smaller and has not grown outside the thyroid.
	T1b	The tumor is larger than 1 cm but not larger than 2 cm across and has not grown outside of the thyroid.
T2		The tumor is more than 2 cm but not larger than 4 cm (slightly less than 2 inches) across and has not grown out of the thyroid.
T3		The tumor is larger than 4 cm across, or it has just begun to grow into nearby tissues outside the thyroid.
T4	T4a	The tumor is any size and has grown extensively beyond the thyroid gland into nearby tissues of the neck, such as the larynx (voice box), trachea (windpipe), esophagus (tube connecting the throat to the stomach), or the nerve to the larynx. This is also called moderately advanced disease.
	T4b	The tumor is any size and has grown either back toward the spine or into nearby large blood vessels. This is also called very advanced disease.
T categories for anaplastic thyroid cancer
T4	T4a	The tumor is still within the thyroid.
	T4b	The tumor has grown outside the thyroid.
N categories for thyroid cancer
NX		Regional (nearby) lymph nodes cannot be assessed.
N1	N0	The cancer has not spread to nearby lymph nodes.
	N1a	The cancer has spread to lymph nodes around the thyroid in the neck (called pretracheal, paratracheal, and prelaryngeal lymph nodes).
N1b		The cancer has spread to other lymph nodes in the neck (called cervical) or to lymph nodes behind the throat (retropharyngeal) or in the upper chest (superior mediastinal).
M categories for thyroid cancer
MX		Distant metastasis cannot be assessed.
M0		There is no distant metastasis.
M1		The cancer has spread to other parts of the body, such as distant lymph nodes, internal organs, bones, etc.

Once thyroid cancer diagnosis is made, the values for T, N, and M should be determined to be combined into stages. Unlike most other cancers, thyroid cancer staging system considers cancer subtype and the patient’s age for determining the prognosis.

Staging of thyroid tumors is the most valid way to determine cancer’s prognosis. The best prognostic factor considering thyroid cancer is 5 year survival rate since the diagnosis date. The latest survival statistics were provided by AJCC, based on the staging of thyroid cancer during initial diagnosis phase. These statistics were published in 2010 in the 7th edition of AJCC Cancer Staging Manual.^[2][3][4][5]

Cancer type	Stage	Definition	5 year survival rate
Papillary or follicular (differentiated) thyroid cancer in patients younger than 55	Stage I (Any T, Any N, M0)	The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0).	100%
	Stage II (Any T, Any N, M1)	The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Papillary or follicular (differentiated) thyroid cancer in patients 55 years and older	Stage I (T1, N0, M0)	The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0).	100%
	Stage II (T2, N0, M0)	The tumor is more than 2 cm but not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0).
	Stage III	One of the following applies: T3, N0, M0: The tumor is larger than 4 cm across or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0). T1 to T3, N1a, M0: The tumor is any size and may have grown slightly outside the thyroid (T1 to T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to other lymph nodes or to distant sites (M0).	93%
	Stage IVA	One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It might or might not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1 to T3, N1b, M0: The tumor is any size and might have grown slightly outside the thyroid gland (T1 to T3). It has spread to certain lymph nodes in the neck (cervical nodes) or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b), but it has not spread to distant sites (M0).	51%
	Stage IVB (T4b, Any N, M0)	The tumor is any size and has grown either back toward the spine or into nearby large blood vessels (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor is any size and might or might not have grown outside the thyroid (any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Medullary thyroid cancer	Stage I (T1, N0, M0)	The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0).	100%
	Stage II	One of the following applies: T2, N0, M0: The tumor is more than 2 cm but is not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0). T3, N0, M0: The tumor is larger than 4 cm or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0).	98%
	Stage III (T1 to T3, N1a, M0)	The tumor is any size and might have grown slightly outside the thyroid(T1 to T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to other lymph nodes or to distant sites (M0).	81%
	Stage IVA	One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It might or might not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1 to T3, N1b, M0: The tumor is any size and might have grown slightly outside the thyroid gland (T1 to T3). It has spread to certain lymph nodes in the neck (cervical nodes) or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b), but it has not spread to distant sites (M0).	28%
	Stage IVB (T4b, Any N, M0)	The tumor is any size and has grown either back toward the spine or into nearby large blood vessels (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor is any size and might or might not have grown outside the thyroid(any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Anaplastic (undifferentiated) thyroid cancer	Stage IVA (T4a, Any N, M0)	The tumor is still within the thyroid (T4a). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).	7%
	Stage IVB (T4b, Any N, M0)	The tumor has grown outside the thyroid (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor might or might not have grown outside of the thyroid (any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).

There is no evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers.^[6]

Recent large prospective studies have confirmed the ability of genetic markers (BRAF, Ras, RET=PTC) and protein markers (galectin-3) to improve preoperative diagnostic accuracy for patients with indeterminate thyroid nodules.^[7][8] Thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5% with FNA.^[9][10] False negative diagnosis may be even higher with nodules>4 cm.^[11] While benign nodules may decrease in size, malignant tumors often increase in size, albeit slowly.^[12] Morbidity and mortality are increased in patients with distant metastases, but individual prognosis depends upon factors including histology of the primary tumor, distribution and number of sites of metastases (e.g., brain, bone, lung), tumor burden, age at diagnosis of metastases, and 18FDG and radio-active iodine avidity.^{[13] [14]} Improved survival is associated with responsiveness to surgery and or radio-active iodine. The rate of survival in patients with distant metastases is variable, depending upon the site of metastases. Among patients with small pulmonary metastases but no other metastases outside of the neck, the 10-year survival rate is 30 to 50 percent; even higher survival rates have been reported in patients whose pulmonary metastases were detected only by radio-iodine imaging.^[15]

Overall predictive value of thyroid nodule malignancies is low. The most important related clinical features that can be associated with a more accurate malignancy diagnosis include:

• Male sex
• Nodule size (>4 cm)
• Oder patient age
• Cytologic features such as presence of atypia can improve the diagnostic accuracy for malignancy in patients with indeterminate cytology, overall predictive values are still low^[16][17][18]

Comparison of carcinomas

Thyroid cancer type

Follicular carcinoma

Papillary thyroid carcinoma

• Peak incidence between ages 40 and 60 years • Presence of local clinical symptoms and infiltration into neighboring structures as the main predictive factors[19] • Rates of disease-free patients are 71% at 5 years and 58% at 10 years • Gender specificity, with an approximate prevalence of three times more in women than in men

• Peak incidence between the ages of 30 to 50 yearsm • Cancer-related mortality in patients without metastases at presentation who underwent total thyroidectomy, with a median follow-up of 16 years, is around 6 percent  [20] • Mortality increases progressively with advancing age without a specific age cutoff that stratifies mortality risk • Persistent or recurrent disease associated with:[21] •• Nonincidental cancer •• Lymph node metastases at presentation •• Bilateral tumor

• Low-risk patients have the following characteristics:^[22][23]
  • No local or distant metastases
  • Complete resection of all macroscopic tumor
  • Lack of tumor invasion to loco-regional tissues or structures
  • Non-aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma)
  • Lack of vascular invasion
  • No 131-iodine uptake outside the thyroid bed on the first post treatment whole-body RAI scan
• Intermediate-risk patients have any of the following:^[24][25][26]
  • Microscopic invasion of tumor into the peri-thyroidal soft tissues at initial surgery
  • Cervical lymph node metastases
  • 131 iodine uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation
  • Tumor with aggressive cell type
  • Vascular invasion

• High-risk patients have:^[27]
  • Macroscopic tumor invasion
  • Incomplete tumor resection
  • Distant metastases
  • Thyroglobulinemia out of proportion to what is seen on the post treatment scan

Other factors associated with a minor increase in the risk of either recurrence or death include:^[28][29]

• Multi-centricity of intrathyroidal tumor

• Bilateral or mediastinal lymph node involvement
• Greater than 10 nodal metastases
• Nodal metastases with extranodal extension
• Male sex
• Delay in primary surgical therapy of more than one year after detection of a thyroid nodule

5–20% of patients with distant metastases die from progressive cervical disease. That is the reason why treatment of a specific metastatic area must be considered in light of the patient’s performance status and other sites of disease.^[30]

• Poorer prognosis in patients who have large tumors
• Increase in the risk of death of five fold in case of soft-tissue invasion
• Substantial morbidity if there is involvement of the trachea, esophagus, recurrent laryngeal nerves, or the spinal cord
• Poorer prognosis for specific sub-types of papillary thyroid cancers, including:^[31][32]
  • Tall cell varient
  • Insular varient
  • Hobnail variant

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