Excerpt from Thyroid Nodules

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Background

Thyroid nodules are common, perhaps existing in almost half the population, as determined using ultrasonography (US). Only 4-7% of thyroid nodules detected with US are palpable in the adult population in the United States, with women affected more frequently than men. Although the thyroid is the most common endocrine organ to undergo malignant degeneration, thyroid carcinoma accounts for only 1% of diagnosed neoplasms in the United States each year (McNeil, 2006; Wiersinga, 2001). Thyroid cancer is rare; the annual detection rate of clinically significant thyroid cancer in the general population is only 0.004%. Only 5-10% of thyroid cancers are clinically palpable (Bruneton et al, 1994; Nabriski et al, 2003).

Palpable nodules can be visualized as areas of increased (hot) or decreased (cold) tracer activity. However, terms such as hot nodules and cold nodules are misleading unless the nodule can be clearly delineated in several projections. A nonfunctioning (cold) nodule placed in the center of a lobe with functioning normal tissue superficial to it may appear as warm on scans because of integrated activity with depth. Unless oblique views are imaged, the presence of activity concentration cannot be definitively determined. Therefore, nodules should be identified as being functioning (hot), nonfunctioning (cold), or photon deficient. Hot nodules (which are typically adenomas) are more often benign than cold lesions are.

Traditionally, radionuclide imaging was performed to assess possible malignancy. On radionuclide images, 4% of hot nodules are shown to contain tumor, compared with 16% of photon-deficient (cold) nodules (Daumerie et al, 1998). However, radionuclide imaging is not reliable in excluding or confirming the presence of tumor. The classification of thyroid neoplasms has been significantly revised in the last 20 years, and the changes reflect an increased understanding of both the prognosis and histologic characteristics of the tumors. Among asymptomatic patients, 7-21% have palpable nodules found on routine clinical examination. US can be used to identify many more nonpalpable nodules, and it can depict thyroid cysts as small as 2 mm and solid nodules as small as 3 mm (Mandel 2004; Miki et al, 1993).

Sonograms in 40% of the general adult population demonstrate single or multiple nodules. In an autopsy series, 49% of patients who had had clinically normal thyroid glands were found to have one or more grossly visible nodules, whereas the incidence of malignancy in the same autopsy series was 2-4% (Brander et al, 1989; Cannon, 1986).

At examination, the challenge is to differentiate the few clinically significant nodules from the many benign ones. Thyroid nodules are usually clearly identified by using US. No single US criterion is reliable for differentiating all benign thyroid nodules from malignant ones, but many US features may aid in predicting the benign or malignant nature of a given nodule.

For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

Pathophysiology

Pathology

Most thyroid nodules are not true neoplasms but are benign growths caused by cycles of hyperplasia and involution of underlying thyroid tissue. This process results in the fusion of regions of colloid-filled follicles and parenchyma, forming adenomatous or colloid nodules. The classification of thyroid neoplasms has been significantly revised in the last 20 years, and the changes reflect an increased understanding of both the prognosis and the histologic characteristics of the tumors.

Thyroid cysts

Thyroid cysts account for 15-25% of all thyroid nodules. True thyroid cysts lined with epithelium are rare. Most thyroid cysts are macronodules, which undergo degeneration, with the accumulation of serous fluid, colloid substance, or blood.

Inflammatory nodules

• Inflammatory nodules represented by focal chronic thyroiditis and thyroid abscesses are usually symptomatic, but they are rare.
• Hashimoto thyroiditis is much more diffuse and involves the entire thyroid.
• de Quervain thyroiditis is a diffuse disease, although in rare cases, a solitary cold area or multiple ones may be seen on scintigrams.
• Painless thyroiditis is a rare, diffuse disease.
• Acute suppurative thyroiditis may demonstrate diffuse or focal hypofunction on scintigrams, and it may be diffuse or focally hypoechoic.

Thyroid adenoma

Most thyroid nodules (42-77%) represent adenomatous nodules. Most are multiple, and multiplicity is demonstrated at US, scintigraphy, and surgery. The nodules are usually nonfunctioning, although a few may be hyperfunctioning at scintigraphy. When solid, the nodules are poorly encapsulated and not well defined, and they merge into the surrounding tissue. Cystic adenomatous nodules are hemorrhagic, with irregular internal walls and particulate fluid content. Intratumoral calcification is occasionally seen.

Follicular adenomas (15-40%) arise from follicular epithelium and are usually single, well-encapsulated lesions. They may be functioning toxic adenomas (hot on scintigrams), or they may represent a hyperfunctioning adenoma in a multinodular goiter. A nonfunctioning adenoma is cold at scintigraphy. On sonograms, adenomas may be hyperechoic or hypoechoic solid nodules with a regular hypoechoic area surrounding ring called the halo sign. Rarely, a parathyroid adenoma has an ectopic intrathyroid location.

Whether solitary adenomas transform into follicular carcinoma is uncertain. In particular, whether aneuploid cells, which are present in approximately 25% of follicular adenomas, represent carcinoma in situ is unclear.

Thyroid cancer

The incidence of thyroid cancer is 10,000 cases per year, one third of which are clinically silent and are found during surgery or autopsy (Weber et al, 2006). Most commonly, thyroid cancer involves patients under 30 years of age, with a female preponderance. In 20% of cases, other abnormalities in the thyroid gland are associated with thyroid cancer; these include adenomatous hyperplasia, follicular adenoma, colloid nodules, and thyroiditis. Thyroid cancer may be radiation induced, with the incidence increasing with higher doses of radiation. Peak incidence occurs 5-30 years after irradiation.

The presentation is varied, but it involves a rapidly growing, stone-hard thyroid nodule that is usually hypoechoic and has ill-defined borders without a halo; these findings are highly suggestive. Usually, no signs of hemorrhage or liquefaction necrosis are noted.

Papillary carcinoma

Papillary carcinomas represent the most common type of thyroid cancer, accounting for 50-81% of cases (Weber). Similar to all thyroid neoplasms, they are more prevalent in women, with a reported female-to-male ratio of 2-4:1. Although the cancer occurs in any age group, it is especially prevalent in patients aged 20-40 years. The most common clinically silent thyroid cancers are papillary carcinomas, which are usually smaller than 1 cm.

Once the patient with papillary carcinoma has symptoms, a thyroid mass is the most typical complaint. Histologically, tumors are nonencapsulated and well differentiated, and they may be purely papillary or mixed with follicular elements. The latter pattern is more common in patients younger than 40 years. Approximately 22% of lesions are pseudoencapsulated. Malignant cells have large nuclei with nuclear grooves and areas devoid of significant chromatin, which produce an appearance of Orphan Annie eyes. These nuclei are identified in 83% of cells. Psammoma bodies, seen in 50% of specimens, represent calcified, dead papillae.

Adenopathy may be found in a significant minority of patients. Reportedly, nodal involvement occurs in 50% of patients at the time of diagnosis and does not appear to affect prognosis. Although recurrence occurs in 15-25% of patients, the long-term outcome is believed to be exceedingly good, with a survival rate higher than 90% after 20 years. The prognosis is poorer in patients who are older at initial diagnosis, who are male, or who have a large tumor. Extracapsular spread is associated with a poorer prognosis. Metastatic spread to the regional nodes occurs in as many as 40% of the patients, with an approximately doubled incidence in children. Hematogenous spread occurs in 5-10% of patients, with a propensity for the lung and bones. Treatment usually involves surgical resection. Suppressive hormonal therapy has been advocated, although its effectiveness has not been confirmed.

Follicular carcinoma

Follicular carcinoma of the thyroid also is considered a well-differentiated neoplasm. Incidence is 5% of thyroid neoplasms if adequate iodine is ingested; however, the incidence can be as high as 40% of malignancies in iodine-deficient populations. Women are affected 2-3 times more often than men. Compared with other lesions, follicular carcinoma occurs in a slightly older age group, commonly in patients aged 40-50 years. Although the neoplasm may be detected as a result of mass effect, it is more likely to be clinically silent at initial presentation.

Nodal disease occurs in approximately 10% of patients with follicular carcinoma. Hematogenously spread metastatic disease in the lung, brain, and bone occurs in fewer than 5%. On pathologic examination, the neoplasm appears as an expansive, encapsulated mass. Differentiating follicular carcinoma from benign follicular adenoma can be difficult. The diagnosis of malignancy relies on the demonstration of vascular invasion or full-thickness capsule invasion.

Histologically, follicular carcinomas are considered to be well or moderately differentiated. Poor prognostic indicators include less-differentiated lesions, larger lesions, extrathyroidal spread, nodal disease, and advanced patient age at the time of initial diagnosis. Treatment involves surgical resection (possibly total thyroidectomy) or the administration of radioactive iodine. Thyroid hormone suppression has been shown to be useful in treating the well-differentiated varieties of follicular carcinoma because they are dependent on thyroid-stimulating hormone.

Medullary carcinoma

Medullary carcinoma, which represents 3-10% of thyroid malignancies, is derived from parafollicular cells (C cells). Calcitonin levels may be increased; the levels are reported to be correlated with the tumor load. Although more common in women than in men, medullary carcinoma is less sex specific than other thyroid malignancies. A familial basis is found in 10-20% of patients, with an autosomal dominant inheritance pattern. Medullary carcinoma is a component of multiple endocrine neoplasia (MEN) syndrome types IIA and IIB and is associated with pheochromocytoma and parathyroid adenoma or parathyroid hyperplasia (Brauckhoff et al, 2004; Weber).

The neoplasms are typically seen as masses, possibly associated with a sensation of pressure or dysphagia, as felt by the patient. Regional lymph node spread is present in 50% of patients at the time of diagnosis. Hematogenous spread to the liver, bone, and lung may occur. The reported 5-year survival rates vary from less than 65% to 80%. A poor prognosis is associated with MEN syndrome type IIB, pleomorphic necrosis, and increased mitotic activity.

Anaplastic carcinoma

Anaplastic thyroid carcinomas are extremely aggressive tumors and represent 8-16% of thyroid neoplasms. These cancers are prevalent in regions in which goiter is endemic. Typically seen in patients aged 60-80 years, they occur slightly later in life, compared with other thyroid neoplasms. A strong female predominance is noted, with a female-to-male ratio of approximately 3:1 (Weber).

Most patients are symptomatic and have a rapidly enlarging neck mass. Neck pain, dysphonia, dysphagia, and dyspnea are common initial complaints. Regional nodal disease and distant metastases are seen in 50-69% of patients at the time of diagnosis. The cause of the tumors is somewhat speculative. Transformation from other thyroid neoplasms is recognized, although this is an uncommon cause. Despite reports suggesting a relationship with prior irradiation, this hypothesis is considered controversial. Unlike other thyroid neoplasms, no effective treatment is available for anaplastic carcinoma, and most patients die within the first year.

Thyroid lymphoma

Thyroid lymphomas are almost always non-Hodgkin lymphomas, and they account for 4-10% of thyroid malignancies. Principally, women older than 50 years are affected, typically in association with Hashimoto thyroiditis. Patients usually present with a rapidly growing neck mass, which may cause symptoms of obstruction, such as dyspnea and dysphagia. In 70-80% of patients, thyroid lymphoma arises in a preexisting chronic thyroiditis with subclinical or overt hypothyroidism. The prognosis depends on the stage of the disease at diagnosis. The 5-year survival rate ranges from 89% in early disease to only 5% in disseminated disease. Signs of cervical invasion in the late stages are also similar to those of an undifferentiated thyroid carcinoma.

Percutaneous needle aspiration remains the key procedure for the diagnosis of thyroid lymphoma; however, thyroid lymphoma's differentiation from thyroiditis occasionally can be difficult. Currently, the most accurate imaging method for staging thyroid lymphoma is computed tomography (CT) scanning. Lymph node involvement is depicted equally well by using magnetic resonance imaging (MRI) or CT scanning, and both are superior to US. Tumor invasion of the esophagus also is depicted well on MRIs and CT scans but not on sonograms. Accordingly, the diagnosis of thyroid lymphoma by using US-guided fine-needle aspiration (FNA) is recommended. Subsequently, MRI is used to stage the disease and to assess adenopathy and esophageal involvement. Gallium-67 scintigraphy is a useful adjunct to imaging, because thyroid lymphoma is the only thyroid malignancy in which uptake of the radionuclide is reported.

Thyroid metastases

Thyroid metastases are rare and are usually a late manifestation of primary cancer located elsewhere. By far, most metastases are derived from disseminated disease in the liver, bones, lungs, and, invariably, cervical lymph nodes. The incidence of known primary cancer in these patients is 2-17%. Common primary sites include the skin (melanoma, 39%), breast (21%), and kidney (renal cell carcinoma, 10%) (Untch and Olson, 2006).

Frequency

United States

Thyroid nodules are common. In the United States, palpable thyroid nodules are found in 4-7% of the adult population, with women affected more frequently than men. US-detectable thyroid nodules are found in almost half the population. A proportion of nodules discovered with palpation or US are malignant. Thyroid carcinoma is rare and accounts for 1% of neoplasms diagnosed annually; these represent approximately 10,000 cases per year. The annual detection rate of clinically significant thyroid cancer in the general population is only 0.004%. About 40% of the general adult population has a single nodule or multiple ones, as shown on sonograms. In an autopsy series, 49% of patients with clinically normal thyroid glands had one or more grossly visible nodules, whereas the incidence of malignancy was 2-4%. Most thyroid nodules are benign (Papini, Simeone).

International

Thyroid nodules are more common in hilly regions of the world, where the incidence of multinodular goiter thyroid carcinomas is increased. Hashimoto thyroiditis and thyroid lymphoma are more frequently found in Japan than in the rest of the world.

Mortality/Morbidity

Mortality and morbidity depend on the nature of the thyroid nodule. Patients with thyroid cysts and adenomas have a normal life expectancy and are usually asymptomatic. In thyroid cancer, mortality and morbidity rates vary.

• For papillary carcinoma, the 10-year survival rate is 90% with occult cancers and 60% with extrathyroidal disease. The prognosis worsens with advancing age.
• For follicular carcinoma, the 10-year survival rate is 90% with minor vascular invasion, but the rate decreases to 35% with moderate to marked vascular invasion.
• For medullary carcinoma, the 10-year survival rate is 90% without nodal metastases, decreasing to 42% with nodal metastases.
• For anaplastic carcinoma, the prognosis is poor, with a 5-year survival rate of 5% and an average survival of 6-12 months.
• For thyroid lymphomas, the 5-year-survival rate ranges from 89% early in the disease to 5% when the disease is disseminated.

Sex

• Papillary carcinoma is more common in females than in males.
• Follicular carcinoma is more common in females than in males, with a male-to-female ratio of 1:2-3.
• Medullary carcinoma is slightly more common in females, but it is less sex specific than other forms of cancer.
• Anaplastic carcinoma is more common in females than in males, with a male-to-female ratio of 1:3.
• Thyroid lymphoma is more common in females than in males.

Age

• The incidence of papillary carcinoma peaks in those aged 40-50 years.
• The incidence of follicular carcinoma peaks in those aged 40-50 years.
• The mean age of patients with medullary carcinoma is 60 years in sporadic cases. However, in association with MEN types IIA and IIB, the tumor occurs in adolescence.
• The average age of patients with anaplastic carcinoma is 50-70 years.
• Thyroid lymphoma occurs principally after 50 years of age.

Anatomy

The thyroid gland lies in the infrahyoid compartment of the neck, which is outlined by the strap muscles anteriorly and by the parathyroids, larynx, trachea, and esophagus posteriorly. The carotid vessels and the jugular veins constitute the lateral boundaries. The mature thyroid gland comprises a right lobe and left lobe anterior to thyroid cartilage. Each lobe is approximately 5 cm long, 2 cm wide, and as much as 3 cm deep. The lobes are connected by a narrow isthmus.

A pyramidal lobe arising from the isthmus is present in approximately 50% of the population. The pyramidal lobe is seen more frequently on scintigraphy in patients with thyrotoxia. The thyroid gland is slightly larger in women than in men. Embryologically, the thyroid gland descends from the floor of the pharynx. The line of descent is represented by the thyroglossal duct; aberrant thyroid tissue may present anywhere along the path of embryonic migration. Aberrant thyroid tissue is well delineated with scintigraphy.

Clinical Details

Most patients with thyroid nodules are asymptomatic, and most nodules are found on clinical examination or self-palpation. Acute suppurative thyroiditis usually affects children and causes swelling, fever, and pain on swallowing. Neck pain, fever, and lethargy are caused by de Quervain subacute thyroiditis, soon after an upper respiratory infection or a viral illness. A hemorrhagic cyst may present with a sudden onset of pain and swelling in the neck. The presentation of thyroid cancer is variable and depends on the histologic type, causing neck pain resulting from local invasion, with dysphasia or symptoms of distant metastases. Many nodules are identified with US, CT, or MRI performed to stage lymphomas and other head and neck cancers.

Clinicians disagree considerably about the treatment for solitary thyroid nodules after they are discovered. Some clinicians are proponents of scintigraphy for diagnosis, whereas others promote US as the most important diagnostic tool for detection and characterization of thyroid nodules. However, most clinicians agree that the differentiation of functioning toxic nodules and thyroid metastases from follicular and papillary carcinomas is performed best by using iodine-123 uptake studies. Gallium-67 can be useful in the diagnosis of thyroid lymphoma. US is the most useful modality available for the detection and characterization of most thyroid nodules.

CT and MRI are useful in the detection of local and mediastinal cancer extension and regional lymphadenopathy. FNA is used because of the inability of imaging to precisely define the nature of the thyroid nodule. For palpable nodules, FNA can be performed with palpation. Guided FNA provides specimens for cytologic studies. The procedure is safe and inexpensive and provides direct information. Although the sensitivity and specificity of scintigraphy are 100% and 5.5%, respectively, these can be considerably improved with FNA to 100% and 91.2%, respectively.

Preferred Examination

Usually, US is the first modality used to investigate a palpable thyroid nodule and in searching for a primary lesion in a patient with systemic metastases. US may be the only examination required in cases of hemorrhagic cyst and multinodular goiter. Doppler US is an extension of US and provides valuable information regarding the vascularity of nodules. Most intervention in the thyroid, such as FNA and guided thyroid ablation, are performed under US guidance.

Currently, scintigraphy is reserved for characterizing functioning nodules and for staging follicular and papillary carcinomas. Lymphoma of the thyroid is the only gallium-67–avid thyroid nodule.

Plain radiographs are used to detect retrosternal thyroid extension, thyroid calcification, bony or mediastinal lymph nodes, and lung metastases.

CT is an effective method for detecting regional and distant metastasis from thyroid cancer.

At the present time, MRI has a limited role in characterizing thyroid nodules, although it appears to be effective in the diagnosis of cervical lymph node metastasis.

Percutaneous needle aspiration remains the key procedure in the diagnosis of thyroid lymphoma; however, thyroid lymphoma's differentiation from thyroiditis occasionally can be difficult. US helps in diagnosing thyroid lymphoma most accurately, and CT helps in staging the disease most accurately. However, MRI also can be useful in staging the lymphoma. A tissue-specific diagnosis of a lymphoma can be achieved by using US-guided FNA.

Limitations of Techniques

In the past, radionuclide imaging was performed to differentiate malignant from benign lesions. On radionuclide imaging, 4% of hot nodules are shown to contain tumor, compared with 16% of cold nodules. Thus, radionuclide imaging is unreliable in excluding or confirming the presence of cancer. Technetium-99m pertechnetate, an inexpensive and readily available isotope, delivers a low dose of radiation because of its 6-hour half-life; it has a favorable decay scheme without particulate emission. A gamma camera using a 140-keV photon is ideal for imaging. The disadvantages of technetium-99m pertechnetate studies are that they can delineate only the trapping function and not organification, and 3-dimensional distortion occurs with pinhole imaging and decreased sensitivity in the mediastinum.

Currently, iodine-123 is the radioisotope of choice. The 13.3-hour half-life, the 159-keV principal photon, and the absence of particulate emission allow for good imaging with modest patient exposure. However, this isotope is cyclotron produced and relatively expensive, and the short half-life necessitates frequent shipments from the producer. Metastatic cancer is imaged well with iodine-123 because one half of papillary carcinomas and two thirds of follicular carcinomas are sufficiently iodine avid to allow their visualization.

US is an alternative method and can be used to evaluate local tumor recurrence because, unlike iodine-123 scintigraphy, it does not require the cessation of thyroid hormone therapy for as long as 5-6 weeks.

Gallium-67 has not enabled sufficient differentiation between the degree of uptake in malignant lesions and that of benign lesions to warrant its routine use, but it appears to be useful when thyroid lymphoma is suspected. US is the most sensitive method for diagnosing intrathyroid lesions; it can depict 2-mm cystic lesions and 3-cm solid intrathyroid lesions. The challenge is to differentiate a few malignant nodules from common benign nodules, because no single US criterion can be used to reliably differentiate all benign thyroid nodules from malignant ones. However, many US features may aid in predicting the benign or malignant nature of a given nodule.

Similarly to MRI, CT is not sensitive in the prediction of intrathyroid lesions; however, it is useful for evaluating lymphadenopathy, local tumor extension, and extension into the mediastinum or retrotracheal region. Guided FNA provides specimens for cytologic studies. The procedure is safe and inexpensive and provides direct information.

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