Nodular goiter (NG) is a nodular enlargement of the thyroid gland characterized by excessive hyperplasia of the thyroid tissue and structural and functional changes in one or more areas of normal thyroid tissue. In cases where thyroid insufficiency, autoimmune thyroid disease, thyroiditis and thyroid tumors are excluded, it may be referred to as simple nodular goiter (SNG).
The pathological changes depend on the severity and duration of the disease. In the early stages of the disease, hyperplastic, dilated follicles are distributed more evenly throughout the gland, forming a diffuse goiter; as the lesion persists or worsens repeatedly, the dilated follicles accumulate into multiple nodules of varying size, forming a nodular goiter. When some nodules degenerate due to poor blood supply, they may also cause cysts, internal bleeding, fibrosis and calcification. Heterogeneity of thyroid structure and function and a certain degree of functional autonomy are characteristic of the later stages of the disease.
Environmental iodine deficiency is the main environmental factor causing goiter simplex. Insufficient iodine intake prevents the synthesis of sufficient thyroid hormones, which in turn feedback causes increased TSH secretion from the pituitary gland and stimulates thyroid hyperplasia and compensatory enlargement. Other environmental factors include: high iodine, smoking, naturally occurring goitrogens, emotional stress, medications and infections.
Some adolescents during puberty, pregnancy or menopause can cause mild diffuse goiter, called physiological goiter, due to an increased need for thyroxine.
Studies on goiter-causing genes (TG, MNG-1, TSHR, NIS, etc.) have not yielded conclusive results.
Females are more susceptible, and the ratio of female to male incidence in non-endemic goiter areas can be 5 to 10:1.
Regional and family history.
1. Most commonly seen in endemic goiter areas with iodine deficiency.
2. Family history of benign thyroid disease: Nodular goiter has some familial aggregation, but classical genetic analysis has not shown a single pattern of transmission.
Clinical presentation.
There is no direct link between the patient’s chief complaint and the size, morphology and function of the nodular goiter. Most patients are asymptomatic clinically, and some may present with.
1: Slowly growing pre-cervical goiter: In the early stage of the disease, the thyroid gland is symmetrically and diffusely enlarged with a smooth gland surface and soft or tough texture; as the lesion progresses single or multiple nodules may be found on one or both sides of the gland.
2: Rapidly enlarging anterior cervical thyroid mass: Rarely, rapid enlargement of the thyroid mass and sudden short-term pain may occur when there is internal bleeding in the goiter; rapid enlargement of the thyroid mass may also occur in normal pregnancy.
Physical examination: single or multiple nodules can be found in the thyroid area, soft or tough in texture, moving up and down with swallowing, and harder when the mass has been growing for a long time or is accompanied by obvious calcification, and the lymph nodes in the neck are usually not enlarged. Note that the examination area should include both the thyroid gland and the lymph nodes in the neck.
4. There is no obvious discomfort in the early stage, but as the nodules of nodular goiter increase in size, the symptoms of pressure on the adjacent organs and tissues may include
(1) Tracheal compression: Tracheal compression can cause bending, displacement and narrowing of the trachea affecting breathing. At first, shortness of breath and coughing only after activity, but after aggravation, there can be dyspnea even in the resting state, collapse of the trachea, degeneration and softening of cartilage.
(2) Compression of the esophagus: A giant goiter growing backward compresses the esophagus and causes progressive dysphagia, mostly caused by a giant goiter in the chest.
(3) Pressure on the recurrent laryngeal nerve: A goiter may excessively pull or compress the recurrent laryngeal nerve resulting in hoarseness, which may be temporary or permanent.
(4) Compression of the sympathetic nerve chain: leads to Horner’s sign (sunken eyes, narrow pupils, drooping eyelids and absence of sweating on the ipsilateral side); phrenic nerve palsy is rare.
(5) Compression of the internal jugular vein or superior vena cava: causes angry chest wall veins, skin bruising or pulmonary atelectasis; can also cause superior vena cava occlusion syndrome (unilateral head, facial or upper extremity edema), often caused by retrosternal or ectopic goiter.
(6) Compression at the thoracic inlet: due to compression or thrombosis of the internal jugular vein, subclavian vein, and superior vena cava, the thoracic venous outflow tract is obstructed, resulting in Pemberton’s sign (when the affected upper arm is raised, it can cause shortness of breath, wheezing, jugular vein anger, and facial congestion due to the goiter being stuck at the thoracic inlet after being elevated).
5. Secondary hyperthyroidism symptoms: Mostly manifested as subclinical hyperthyroidism, which is less common. It usually occurs in patients who have had nodular goiter for many years, and the symptoms of hyperthyroidism appear at the age of 40 or above.
The relationship between nodular goiter and thyroid cancer is still difficult to be sure. A certain percentage of surgical specimens of nodular goiter can be accompanied by thyroid cancer, and most of them are papillary carcinoma.
Laboratory tests
Thyroid function tests: TSH, T3, T4, TPO, TG and calcitonin. Serum TSH, T3 and T4 are basically normal. If the patient has iodine deficiency, serum TG concentration will increase; when there is secondary hyperthyroidism, serum T3 and T4 will increase and basal TSH will decrease.
Imaging examination
1. Ultrasonography: The popularity of ultrasonography has significantly increased the detection rate of thyroid nodules in the population, which is one of the main reasons for the current increase in the incidence of nodular goiter. Ultrasound is ① convenient, fast and inexpensive; ② accurate morphology and volume assessment of the mass; ③ dynamic assessment; ④ Doppler flow detection; ⑤ no radioactivity; ⑥ effective differentiation of benign and malignant thyroid tumors (malignant tumors have unclear borders, rich blood flow and multiple microcalcifications); ⑦ ultrasound guidance can improve the accuracy of fine needle aspiration cytology examination, etc. It is the preferred clinical examination method.
2.CT and MRI examination: They can provide high-resolution, three-dimensional imaging data and have the advantages of (1) good evaluation of mass morphology and volume; (2) evaluation of adjacent important structures and cervical lymph nodes; (3) evaluation of retrosternal goiter; and (4) better resolution of local soft tissue by MRI. However, it is inferior to ultrasonography in describing the intrinsic structure of the mass and identifying the benignity and malignancy of the tumor.
3.Nuclear examination: The advantages include: (1) functional examination, which can detect whether there are autonomous functional nodules in the thyroid tissue; (2) assessment of iodine intake in the thyroid gland; (3) assessment of the feasibility of I131 treatment; and (4) detection of ectopic goiter. From the viewpoint of clinical practice, it has obvious limitations in the identification of benign and malignant thyroid tumors.
4.PET-CT examination: The advantages include: ① is a functional examination, which can reflect the metabolic status of the thyroid gland; ② has good effect on the evaluation of benign and malignant thyroid tumors, but most of the thyroid masses are found incidentally during PET examination, and the high cost limits its clinical application.
Fine-needle aspiration cytology (FNAB)
Fine needle aspiration cytology has the advantages of simple operation, few complications and low price, and the clinical diagnostic accuracy can reach 80%, which is one of the most accurate examination methods at present [26]. More than 70% of patients with nodular goiter in Europe and the United States are diagnosed by FNAB, which can significantly reduce unnecessary surgical treatment (about 50%) [27], which has not been popularized in China because of the insufficient level of cytopathological diagnosis. FNAB by ultrasound-guided examination of major or suspicious nodules in goiter can increase the diagnostic accuracy to more than 90%; combined detection of tumor-related immunological indices (TPO, glectin-3, CD44v6, etc.) can further improve the diagnostic value of FNAB.
For patients with nodular goiter, commonly used ancillary tests are recommended: a thyroid function (including TSH, T3, T4, TPO, TG and calcitonin); b: thyroid ultrasonography; c: fine needle aspiration cytology.
【Treatment】.
The main treatment methods include: iodine supplementation therapy, conservative therapy, surgical therapy, radioactive I131 therapy, etc.
1. Iodine supplementation therapy.
For physiological goiter, appropriate iodine supplementation or more iodine-rich foods such as kelp and nori can be used; for non-physiological nodular goiter, iodine supplementation is not recommended because it may induce hyperthyroidism and increase the incidence of lymphocytic thyroiditis and papillary thyroid cancer.
2. L-T4 suppression therapy.
For patients with diffuse goiter under 20 years old, small doses of thyroxine can be given to alleviate hyperplasia or hypertrophy of the thyroid gland through feedback inhibition of TSH secretion in the anterior pituitary gland. The commonly used dose is levothyroxine: 50-100ug/d or thyroid tablets: 40-120mg/d for 3-6 months as a course of treatment. L-T4 suppression therapy is also feasible for patients with nodular goiter who have mild lesions and are unwilling or unable to tolerate surgery. The effectiveness of L-T4 suppression therapy depends on the extent to which TSH is suppressed, and the ideal dose of oral L-T4 is currently more widely accepted: TSH is controlled at 0.1 to 0.3 mU/L, and T3 and T4 are controlled within the high limit of normal values. However, it should be noted that in three clinical trials, the results showed that only a small number of patients with nodular goiter were effective for L-T4 suppression therapy; in addition, there is a risk of subclinical hyperthyroidism, osteoporosis, induced atrial fibrillation, and menstrual disorders during long-term L-T4 administration, so the selection of indications and duration of L-T4 suppression therapy should be carefully, especially for postmenopausal women.
3.Surgical therapy.
Surgical treatment has the advantages of rapidly reducing the symptoms of compression, normalizing the volume of the enlarged thyroid gland, and clarifying the pathological diagnosis.
Indications for surgery
(1) Nodular goiter with compression symptoms: some of the compression symptoms caused by nodular goiter are reversible, such as: narrowing of the trachea by compression, compression of the esophagus, compression of the internal jugular vein and superior vena cava, once the compression is relieved, the above symptoms will be rapidly relieved or disappear; some of the symptoms are irreversible, such as the nerves of the recurrent laryngeal nerve, sympathetic nerve chain or phrenic nerve have degenerated due to prolonged compression, even if the compression Some symptoms are irreversible. Clinically, patients with nodular goiter with peripheral organ compression or a tendency to grow towards the posterior sternum or superior mediastinum should be treated with surgery in a timely manner to avoid unnecessary emergency tracheal intubation or emergency surgery.
(2) Retrosternal goiter with compression symptoms: Retrosternal goiter is a goiter in which more than 50% of the volume is located below the entrance to the thorax, and surgical treatment is the only effective method. There are generally three types: Type I is incomplete retrosternal goiter; Type II is complete retrosternal goiter; and Type III is intrathoracic vagal goiter, whose blood supply is related to the intrathoracic vessels. Types I and II are due to the combined effect of the goiter’s own gravity, swallowing activity and negative pressure in the thoracic cavity, causing it to fall down into the thoracic cavity along the anterior tracheal space, and its blood supply still comes from the superior and inferior thyroid arteries and their branches. Because the left side of the retrosternal sternum is blocked by the aortic arch and the left common carotid artery, a right-sided retrosternal goiter is more common in clinical practice. The majority of type I and II retrosternal goiters can be removed through a cervical surgical approach; type III can be removed through a combined cervicothoracic approach.
(3) Secondary hyperthyroidism: Simple goiter (5%-8%) may show symptoms of hyperthyroidism, also known as toxic multinodular goiter, which starts slowly, mostly in the elderly or those taking large amounts of iodine, often with prominent cardiovascular symptoms, such as arrhythmia, heart failure, etc., and significant wasting and weakness, which may be accompanied by anorexia. The surgical treatment should be performed in strict accordance with the preoperative preparation of hyperthyroidism, and total thyroidectomy or near-total thyroidectomy is appropriate. Surgery has been gradually replaced by radioactive I131 therapy to reduce the risk of surgery and postoperative complications.
(4) Nodular goiter with suspected malignancy: There is no conclusive evidence that nodular goiter is pre-cancerous, but 4% to 17% of surgically removed nodular goiter specimens are associated with thyroid cancer. Patients with nodular goiter should be highly suspected of having thyroid cancer if they have: (1) a family history of medullary thyroid cancer or multiple endocrine adenoma syndrome; (2) a rapidly growing mass (especially during L-T4 treatment); (3) a fixed mass; (4) adhesions to surrounding tissues; (5) vocal cord paralysis; (6) enlarged adjacent lymph nodes; and (7) distant metastases (lung or bone). Moderate suspicion of thyroid cancer includes: (i) age less than 20 years or more than 60 years; (ii) male; (iii) isolated nodule; (iv) history of head and neck radiation; (v) hard texture; (vi) pressure symptoms: dysphagia, dysphonia, hoarseness, dyspnea and cough.
(5) Nodular goiter affecting appearance: superficially located nodular goiter protruding from the anterior cervical region, especially in the isthmus, affecting appearance, and patients urgently requesting surgery.
Mode of surgery.
The choice of surgical approach should be determined by the number, size and distribution of nodules. For single nodular goiter, removal of the mass, partial lobectomy or total unilateral lobectomy is feasible; for multiple nodular goiters, subtotal thyroidectomy and total thyroidectomy are also feasible. The specific procedures are.
(1) Total thyroidectomy: It is currently the main surgical procedure recommended by general surgery and surgical oncology in Europe and the United States. Although this procedure can effectively avoid intraoperative mass omission and postoperative recurrence, it also has its disadvantages: a permanent hypothyroidism; b hypoparathyroidism due to intraoperative parathyroid gland miscutting; c serious complications such as increased probability of laryngeal nerve injury. Therefore, the indications should be strictly controlled: (1) bilateral nodular goiter with suspected bilateral thyroid cancer; (2) bilateral nodular goiter with intraoperative finding that normal thyroid tissue cannot be preserved; (3) nodular goiter with secondary hyperthyroidism.
(2) Lobectomy of thyroid gland: The indications for surgery are (1) nodular goiter mainly located in one lobe and normal gland cannot be preserved on the affected side; (2) nodular goiter located in one gland and thyroid cancer is suspected on the affected side.
(3) Subtotal thyroidectomy: if the nodular goiter lesion is located in the thyroid gland bilaterally and some normal thyroid tissue can be preserved.
(4) Mass excision of thyroid gland: Mass excision is feasible for solitary nodular goiter, and attention should be paid to the exploration of the gland surrounding the mass and the contralateral thyroid gland during surgery.
Once thyroid cancer is found, it should be treated as thyroid cancer: excision of the ipsilateral gland, isthmus and removal of lymph nodes in the central area to avoid secondary surgery.
Principles of postoperative follow-up.
To avoid recurrence, a small oral dose of L-T4 (50-100ug) is recommended after surgery, with follow-up every 3-6 months (including physical examination, thyroid and neck ultrasound, and thyroid function). To reduce unnecessary side effects, the L-T4 dose should be adjusted according to thyroid function during the follow-up. If malignancy is clinically considered as a possibility, CT examination of the neck (plain scan + enhancement) should be added.
4. Radioactive I131 therapy.
Indications for treatment: For patients with postoperative recurrence of nodular goiter and still needing further treatment, radioactive I131 therapy can be switched to avoid serious surgical complications. Radioactive I131 therapy is also an option for patients with large nodular goiters or nodular goiters with hyperthyroidism who do not want to undergo surgery or cannot tolerate surgery.
Patients who have relapsed after surgery and still need further treatment may be switched to radioactive I131 therapy to avoid serious surgical complications. Radiation I131 therapy may also be chosen for patients with large nodular goiter or nodular goiter with hyperthyroidism who do not want to undergo surgery or cannot tolerate surgery.