Thyroid nodule overview

# Overview
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 ( and  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 TSHmediated 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.

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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.

# Causes
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 ( and  subunit), TRK, EGF / EGF-R, and P53 mutation.

# Differentiating Thyroid Nodule From Other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

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

# Natural History, Complications and Prognosis
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.

# Diagnosis

## Diagnostic criteria
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.

## History and Symptoms
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
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
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.

## Electrocardiogram
There are no abnormal electrocardiographic findings associated with thyroid nodule.

## Chest X-ray
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
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.

## MRI
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 TSHmediated therapy is recommended.

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

# Treatment

## Medical Therapy
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 TSHmediated therapy is recommended.

## Surgery
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
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
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.