7.1 Introduction

Benign thyroid diseases comprise both nodular diseases and inflammatory thyroid conditions. Nodular diseases can be categorized as solitary thyroid nodules and multinodular goiters. The term goiter is used to describe a pathological enlargement of the thyroid gland. Goiters can be classified as diffuse or nodular, toxic or nontoxic. Toxic conditions of the thyroid are thoroughly reviewed in Chapter 8. Inflammatory thyroid conditions include autoimmune thyroiditis, subacute thyroiditis, and Riedel’s thyroiditis.

The prevalence of clinically evident thyroid nodules is approximately 5%, depending on age, sex, and geography. ¹ In autopsy series the prevalence of solitary nodules is approximately 10%, and of thyroid nodularity it is as high as 50%. ² In recent years imaging modalities have become more ubiquitous and sensitive in medicine, resulting in serendipitous discovery of asymptomatic unexpected thyroid nodules, referred to as incidentalomas. With the routine use of imaging modalities, such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), the incidence of thyroid incidentalomas will likely be similar to the prevalence of nodules found on autopsy. US can detect thyroid nodules in 19 to 68% of randomly selected individuals. ^{3 , 4} The incidence of malignancy in a solitary nodule ranges from 10 to 40%, depending on the age, sex, characteristics of the nodule, selective criteria for surgery, and presence of risk factors. ^{5 , 6 ,; 7 , 8} In evaluating a thyroid nodule, a complete history should be elicited regarding factors that may predict the risk of malignancy, such as voice change, hemoptysis, rapid growth, history of childhood head and neck irradiation, total body irradiation for bone marrow transplantation, exposure to ionizing radiation in childhood or adolescence, and thyroid malignancy in first-degree relatives. ^{5 , 7 , 8 , 9 , 10} Radiation exposure can be from prior head and neck irradiation for lymphoma or benign conditions (acne, thymus, enlarged adenoids, tinea capitis), ^{11 , 12} total body irradiation for bone marrow transplantation, ^{13 , 14} and exposure to fallout, such as from the Chernobyl incidents, particularly in those under 15 years of age. ^{15 , 16 , 17}

A review of the patient’s family history is important for assessing the risk factor for thyroid cancer. The probability of a patient with a thyroid nodule having a malignancy is estimated to be approximately 38% when two first-degree family members are affected, and is even higher when three or more are affected. ¹⁸ It is also important to be aware that nodular thyroid diseases may be associated with various hereditary syndromes, particularly when present at a younger age. Familial adenomatous polyposis is an autosomal dominant disease caused by mutation of the APC gene and is characterized by polyposis of the colon, epidermoid cysts of the skin, desmoid tumors of the abdominal wall, retinal pigmented epithelium, and thyroid carcinoma. A small subset of these patients present with osteomas, referred to as Gardner’s syndrome. Thyroid carcinomas occur in 1 to 2% of these patients and are usually papillary carcinoma. ^{19 , 20} Cowden’s disease is an autosomal dominant disease characterized by tumors of the thyroid, breast, colon, endometrium, and brain, and hamartomas and tumors of the skin. The thyroid abnormalities may present in childhood as multinodular goiters, multifocal follicular adenomas, and adenomatous nodules. ^{20 , 21} Carney’s complex is an autosomal dominant multiple neoplasia syndrome due to mutation in the PRKAR1A gene consisting of spotty skin pigmentation, myxomas, endocrine tumors, and schwannomas. ²² Multiple endocrine organs are affected, resulting in thyroid tumors; primary pigmented nodular adrenocortical disease, which can result in Cushing’s syndrome; prolactin-producing pituitary tumors; testicular tumors causing precocious puberty; and ovarian tumors. ²² Up to 75% of patients with Carney’s complex have multiple thyroid nodules, and some may also present with thyroid malignancy. ²² Skin manifestations include spotty pigmented skin lesions, blue nevi, and café au lait spots. The myxomas can involve the heart, breast, and skin. ²² Pendred syndrome is an autosomal recessive disease manifesting as a combination of goiter and congenital deafness. Goiters may be present from childhood to early adolescent years. The genetic defect with this disease has been shown to be a mutation of the PDS (SLC26A4) gene on chromosome 7q22–31.1. ²³

In the evaluation of nodular thyroid disease, the head and neck examination should include the characteristics of the thyroid gland and an assessment for lymphadenopathy and cranial nerve function, particularly vocal cord mobility. A thyroid nodule associated with ipsilateral vocal cord paralysis is highly suspicious for a malignancy. In the rare patient who may also have hemoptysis, flexible laryngoscopy should be performed to assess laryngeal pathology and to examine the upper trachea for presence of tracheal invasion from a thyroid malignancy.

7.2 Evaluation and Management of Solitary Thyroid Nodules

The natural course of thyroid nodules is not fully understood. One long-term study showed that 23% of thyroid nodules ultimately increased in size. ²⁴ The most important goal in the diagnostic evaluation of a thyroid nodule is to exclude malignancy. Because thyroid nodules are quite prevalent, including nonpalpable ones found incidentally, the challenge for the clinician is in deciding which nodules need to be biopsied or surgically excised and which ones can be observed. Serum thyroid-stimulating hormone (TSH) should be the initial first test in the evaluation of nodular thyroid disease. ⁵ US is also an important initial test. It is excellent for detection and characterization of thyroid nodules and thus is an adjunct to the physical examination. ^{5 , 25 , 26 , 27} Thyroid sonography provides very useful management information that includes accurate measurement of the size of the nodule; whether the nodule is purely cystic, solid, or mixed; whether other nonpalpable nodules are present; and whether there are findings indicating a malignancy, such as microcalcifications and irregular margins, intranodular hypervascularity, and marked hypoechogenicity. ^{27 , 28 , 29} A thyroid uptake scan for solitary nodules is not particularly useful unless the TSH level is suppressed (i.e., below normal range). In which case, a thyroid uptake scan can be obtained to see if the nodule is hyperfunctioning, indicative of a toxic single adenomatous nodule. Fine-needle aspiration (FNA) is a very important and useful tool in the diagnostic evaluation of solitary nodules. ^{7 , 30}

In general, a solitary nodule requires histological evaluation, either by FNA or surgical excision, when associated with risk factors for malignancy. These factors include rapid enlargement, associated lymphadenopathy, associated vocal cord paralysis, prior radiation exposure, age over 60 or under 20, and a family history of thyroid cancer in a first-degree relative. The incidence of malignancy in a solitary nodule in childhood is greater than that in adults and has been reported to be as high as 50%. ^{11 , 31 , 32 , 33} Therefore, serious consideration should also be given to biopsy or surgical excision of thyroid nodules detected during childhood, particularly if they are > 1.5 cm and solid. Solid thyroid nodules in patients over 65 years of age have a higher risk of being malignant. Furthermore a higher percentage of the malignancies in this age group tend to be of the more aggressive type. ^{6 , 34 , 35} In a study of 21,748 patients with thyroid nodules who underwent US-guided FNA and surgical pathological correlation in 3,629 patients, 37% of the nodules occurring in those over age 65 were found to be malignant, and up to 36% of the malignancies were diagnosed as anaplastic or metastatic. ⁶ Therefore, a cytological or pathological diagnosis is warranted in elderly patients who present with a new thyroid nodule, particularly if it is rapidly growing. Sonographic evaluation of the anterior cervical lymph node (central and bilateral) compartments should be performed whenever thyroid nodules are detected. ⁷ If US detects cervical lymph nodes that are sonographically suspicious for thyroid cancer, FNA of the suspicious lymph node should be performed. Incidentalomas pose a management dilemma. Nodules with sonographic findings suspicious for malignancy as discussed earlier should be biopsied. ^{28 , 36} It has been suggested by several authors as well as the American Thyroid Association (ATA) Task Force on Thyroid Nodules and Differentiated Thyroid Cancer that, in the absence of clinical risk factors for malignancy, risk stratification of a thyroid nodule base on a constellation of US findings would help triage which nodules should be biopsied and which should not. ^{7 , 36 , 37 , 38 , 39} The 2014 ATA guidelines recommend characterizing the pattern of US findings and stratifying the nodules into benign or suspicious. ⁷ Purely cystic nodules are considered benign and do not require a biopsy. Suspicious findings are risk stratified into high, intermediate, low, and very low suspicion categories based on whether they are solid or cystic, their echogenicity, and the presence of one or more of the following worrisome features: microcalcifications, a taller than wide shape, rim calcifications with a small extrusive soft tissue component, and extrathyroidal extension. Hypoechoic solid nodules with or without a cystic component exhibiting one or more of these worrisome features are considered high risk (70–90% risk of malignancy) and should be biopsied if > 1 cm. Hypoechoic solid nodules without these worrisome features carry a much lower risk of malignancy (10–20%); biopsy of such lesions should be considered if they are > 1 cm. Nodules that are isoechoic, hyperechoic, or partially cystic with eccentric solid areas that do not exhibit any of the worrisome features are considered low risk (5–10% risk of malignancy), and thus biopsy can be considered when the nodules are > 1.5 cm. Mixed cystic solid nodules with a spongiform appearance strongly correlate with benignity, and FNA can be withheld until they are > 2 cm.

Other laboratory tests considered in the evaluation of a thyroid nodule include serum calcitonin and thyroglobulin levels. A serum calcitonin level should be obtained if there is a family history of medullary thyroid carcinoma, or if the FNA of the nodule reveals atypical small round cells or spindle cells, which are not typical of cells derived from a follicular origin. Serum thyroglobulin is not very helpful as a diagnostic tool. An elevated thyroglobulin level itself is not indicative of a thyroid malignancy because benign conditions, such as an adenomatous nodule or a recent FNA, can cause elevation of serum thyroglobulin. However, should the nodule turn out to be a follicular cell–derived thyroid carcinoma, a normal preoperative level obtained prior to FNA may be indicative of a nonthyroglobulin-secreting tumor, which may guide the methodology of subsequent cancer surveillance.

Thyroid FNA cytological findings are generally reported using the Bethesda System for Reporting Thyroid Cytopathology. ^{40 , 41} The Bethesda System recognizes six diagnostic categories: (I) nondiagnostic/unsatisfactory; (II) benign; (III) atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); (IV) follicular neoplasm/suspicious for follicular neoplasm (FN), a category that also encompasses the diagnosis of Hürthle cell neoplasm/suspicious for Hürthle cell neoplasm; (V) suspicious for malignancy (SUSP), and (VI) malignant.

A nondiagnostic FNA results from poor preservation of the specimen or low cellularity obtained from the aspiration, which can occur for several reasons, including small nodules, densely fibrotic or calcified nodules, cystic nodules, and operator inexperience. The diagnostic yield of FNA can be improved when performed under US guidance. ^{42 , 43} Furthermore, with US guidance, small, nonpalpable nodules can be biopsied with high yield. The rate of nondiagnostic aspiration can be further reduced to < 2% when the biopsy is performed under US guidance with on-site cytological preparation where cytotechnologists or cytopathologists can provide immediate feedback on whether or not the aspirate is sufficiently cellular. ^{6 , 44 , 45}

Thyroidectomy should be recommended if the FNA cytology is consistent with or suspicious for a malignancy. The risk of malignancy in an indeterminate nodule (Bethesda classifications III and IV) ranges from 20 to 30%. ^{46 , 47 , 48} With indeterminate cytology, the options are surgical excision for definitive diagnosis, or testing the FNA with the Afirma Gene Expression Classifier (GEC), which evaluates mRNA expression of 167 genes. ⁴⁹ The GEC has been shown in a multi-institutional study to have a negative predictive value of 95%, and a 37% positive predictive value. This means that if the GEC is nonsuspicious, the risk of malignancy is 5%; however, if it is suspicious, the risk of malignancy is only 37%; thus it is considered a rule-out test.

The decision is not as straightforward when the FNA cytology is nondiagnostic. Repeat FNA or surgery should be recommended if the cytologically nondiagnostic nodule is solid, depending on the clinical and US suspicious features. The patient’s age and underlying medical condition also need to be factored into the decision making. In young patients with large nodules, particularly if they are solid or demonstrate some atypia, surgical excision for definitive diagnosis and long-term treatment is preferred over observation. In elderly patients with this scenario, if the patient has little or no anesthetic risks, surgical excision should be considered. However, in those with significant comorbidities, it would be appropriate to repeat the FNA and closely observe the nodule. ⁵⁰

Cystic nodules are diagnostically challenging because aspiration of the fluid usually yields a hypocellular specimen. The risk of malignancy in cystic thyroid nodules among adults ranges from approximately 15 to 30%, similar to that of solid nodules, and the risk a of false-negative aspirate is high. ^{51 , 52 , 53} The recommendation formulated by the ATA is that cystic nodules which repeatedly yield nondiagnostic aspirates need surgical excision or close observation with fastidious follow-up and repeat FNA. ⁷ A cystic nodule containing a large solid component, particularly with microcalcifications, or with an irregular and fingerlike pedunculated mass extending into the lumen, is suspicious for a cystic papillary carcinoma. ^{54 , 55} If the initial FNA of a cystic nodule with these US characteristics is nondiagnostic, either the FNA should be repeated with US guidance and on-site cytologic evaluation, or surgery should be recommended. When performing FNA on a cystic nodule, the diagnostic yield can be improved by first aspirating the fluid content and then reaspirating under US guidance the remaining cyst wall or solid component. ^{55 , 56 , 57} A cystic thyroid nodule associated with cystic lymphadenopathy in the paratracheal region is strongly suggestive of cystic papillary thyroid carcinoma and should be treated as such until proven otherwise. FNA of the thyroid nodule and cystic node, particularly if performed under US and cytological guidance, should confirm the diagnosis. A cystic thyroid nodule associated with cystic lymphadenopathy in the lateral neck is more challenging in terms of establishing a cytological diagnosis because the aspirate from the lymph node can be hypocellular or can mimic lesions of nonthyroid origin, such as a branchial cleft cyst. ^{52 , 58} In that setting, the fluid from the lymph node aspiration can be sent for a thyroglobulin level; if elevated, it would be diagnostic of cystic papillary carcinoma; however, a normal level does not exclude malignancy. Measuring the thyroglobulin level in the fluid obtained from FNA of a cystic thyroid nodule is generally not helpful because it can also be elevated in a benign nodule. If FNA of a thyroid nodule associated with cystic cervical lymphadenopathy cannot establish a diagnosis, surgery with frozen section is warranted.

7.3 Nodular Goiters

Nodular goiters encompass several different pathological conditions, including hyperthyroidism, hypothyroidism, autoimmune thyroiditis, and malignancy. In the absence of such conditions, it constitutes an entity described as simple nodular goiter, often interchangeably termed multinodular goiter. Multinodular goiter is the most common endocrine disorder worldwide. Goiters can occur endemically and sporadically. An endemic goiter is one that occurs in a region, such as the Andes and Pyrenees, where its prevalence in children 6 to 12 years of age is > 5%. ⁵⁹ Sporadic goiter is one that occurs in a nonendemic region in a euthyroid individual.

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