Chronic Lymphocytic Thyroiditis (Hashimoto’s or Autoimmune Thyroiditis)

Chronic lymphocytic thyroiditis (CLT), alternatively known as Hashimoto’s thyroiditis or autoimmune thyroiditis, is an autoimmune disorder and the most common clinically significant form of thyroiditis. It is characterized by destruction of follicular cells, which, over time, can result in hypothyroidism. The pathogenesis of CLT is incompletely understood, but both cell-mediated and humoral mechanisms appear to be involved, probably induced by the interaction of genetic and environmental factors. ⁴

CLT is typically associated with diffuse thyroid enlargement, generally, two to four times normal size. Thyroid tissue is usually paler than its normal red-brown color due to lymphocytic infiltration and loss of follicular tissue. Glands may show accentuated lobulation. Histologically, the most characteristic feature is infiltration by lymphocytes and plasma cells (Fig. 5.1). The lymphoplasmacytic infiltration is diffuse but variable in its intensity and effacement of the follicles. Lymphoid germinal centers are another characteristic feature.

Variable numbers of follicular epithelial cells exhibit enlargement and abundant, finely granular eosinophilic cytoplasm, known as oncocytic or Hürthle cell metaplasia. This appearance is caused by abundant cytoplasmic mitochondria. Oncocytic follicular cells may also show nuclear enlargement and prominent nucleoli.

Variants of CLT include fibrous, fibrous atrophy, toxic (hashitoxicosis), and juvenile, though most cases of CLT have slight to moderate fibrosis. The fibrous variant usually exhibits some degree of thyroid enlargement associated with marked deposition of dense fibrous tissue and follicular atrophy. Fibrosis is limited to the thyroid, in contrast to the extrathyroidal fibrosis of invasive fibrous (Riedel’s) thyroiditis. Squamous metaplasia is more common and prominent compared to classic CLT. Some cases may represent immunoglobulin G4 (IgG4)-related sclerosing disease involving the thyroid. ⁵ The fibrous atrophy variant is histologically similar to the fibrous variant but is distinguished by the small size of the thyroid. Whether the fibrous atrophy variant represents progression of the fibrous variant and/or classic form of CLT or has a distinct pathogenic mechanism is unclear at this time.

CLT may be associated with hyperthyroidism, a condition referred to as hashitoxicosis. Thyroids with this condition generally exhibit classical changes of CLT with variable degrees of follicular epithelial hyperplasia. ⁶

Subacute Granulomatous Thyroiditis (Subacute or de Quervain’s Thyroiditis)

Subacute granulomatous thyroiditis (SGT) is characterized by the presence of epithelioid macrophages (histiocytes) and variable numbers of multinucleated giant cells. This condition has a variety of alternate names, including de Quervain’s, subacute, painful subacute, postviral, and giant cell thyroiditis. SGT appears to be the result of a systemic illness, with viral infection being the leading suspect, although conclusive evidence is lacking at this time.

The thyroid gland is usually enlarged to about twice its normal size. The enlargement may be asymmetric, and a small percentage of cases present as a solitary nodule. ⁷ During the early, usually hyperthyroid, stage of disease the thyroid shows follicular damage with loss of epithelium and colloid. Acute and chronic inflammatory cells are present within residual follicles and interfollicular areas. Over time granulomatous and chronic inflammation with variable degrees of fibrosis predominate. ⁸ Distinct granulomata or lymphoid follicles are usually not seen; instead giant cells are found around disrupted follicles. The inflammatory and repair process may be heterogeneous with areas of active inflammation coexisting with areas of fibrosis.

Acute Thyroiditis

Acute, or suppurative, thyroiditis is characterized by a predominantly neutrophilic inflammatory infiltrate. This is a rare form of thyroiditis, usually caused by bacterial infection arising elsewhere in the neck and secondarily involving the thyroid. In children, acute thyroiditis is usually associated with a pyriform sinus fistula. ⁹

Invasive Fibrous Thyroiditis (Riedel’s Thyroiditis)

Invasive fibrous thyroiditis (IFT), also known as Riedel’s, fibrosing, or sclerosing thyroiditis, is a rare disease characterized by progressive fibrosis of the thyroid. Affected glands are extremely firm and adherent to perithyroidal tissues due to fibrosis extending beyond the thyroid. The thyroid parenchyma is effaced by chronic inflammation and fibrosis, with absence or marked atrophy of follicles. Lymphocytes and plasma cells are the predominant inflammatory cells. Occlusive vasculitis of small- to medium-sized veins is a distinctive feature. FNA is almost always nondiagnostic due to acellular or paucicellular specimens. The presence of IgG4-positive plasma cells and association with other fibroinflammatory disorders suggest that IFT may be a manifestation of IgG4-related sclerosing disease. ¹⁰

Multinodular Goiter (Nodular Hyperplasia)

Multinodular goiter (MNG) is a common condition characterized by enlargement of the thyroid gland with variable amounts of nodularity. MNG is also known as nodular hyperplasia, nodular goiter, colloid goiter or nodule, adenomatoid nodule or hyperplasia, and other combinations of these terms. The term nodular hyperplasia reflects histopathologic changes seen in this condition and is often used in the pathological description and diagnosis.

Sporadic and endemic MNG have comparable pathological features. Endemic goiter is usually due to dietary iodine deficiency. ¹¹ Sporadic cases have a number of possible pathogenic mechanisms, including individual dietary iodine deficiency, excessive ingestion of goitrogenic foods, medications, increased thyroid-stimulating hormone (TSH) secretion, and constitutive activation of follicular cells due to somatic mutations of the TSH receptor gene. ¹² Identifying a specific cause may be difficult, if not impossible, because most cases of MNG appear to be due to complex interaction between multiple genes and various environmental factors. Congenital defects in the pathways of thyroid hormone synthesis and release can result in dyshormonogenetic goiter and associated hypothyroidism.

MNG is characterized by thyroid enlargement that can range from mild to massive. Most cases have multiple nodules evident grossly, although early cases may lack distinct nodularity or only have a single macroscopic nodule. Thyroid enlargement may be symmetric or asymmetric. The sectioned surfaces typically have a nodular, heterogeneous appearance. Some areas have a semitranslucent appearance due to abundant colloid, whereas other foci exhibit hemorrhage, fibrosis, cystic degeneration, and/or calcification. Nodules may appear partially encapsulated by fibrous tissue.

Microscopically, follicles exhibit variable sizes and shapes, ranging from small with minimal colloid to very large with abundant colloid (Fig. 5.2). Some pathologists use the term adenomatous nodule to refer to a nodule with high cellularity due to a microfollicular or solid growth pattern, and the term colloid nodule for a nodule with abundant colloid and a low density of follicular cells. The follicular epithelium varies from flattened to cuboidal or columnar and focally may exhibit oncocytic or clear cell features. Follicles may contain papillary-like infolding of epithelium, sometimes raising concern for papillary carcinoma. Foci of hemorrhage and fibrosis are common and may be associated with dystrophic calcification.

FNA typically yields a mixture of colloid and benign-appearing follicular cells. Follicular cells are usually arranged in evenly spaced monolayer sheets. Macrophages are commonly seen and may contain hemosiderin.

Endemic Goiter

Endemic goiter refers to thyroid enlargement that occurs in a significant portion of a region or population. A common criterion is 5% or more of children aged 6 to 12 having thyroid enlargement. ¹³ The pathological features of endemic goiter are comparable to those of MNG.

Dyshormonogenetic Goiter

Dyshormonogenetic goiter results from a genetic defect that interrupts any one of the steps of thyroid hormone synthesis. Excess TSH, released to try to correct the primary hypothyroidism, leads to enlargement of the thyroid gland. Dyshormonogenetic goiter is grossly indistinguishable from MNG, and their microscopic features overlap. A feature favoring dyshormonogenetic goiter is pronounced hyperplasia with a predominantly solid or microfollicular pattern throughout the entire gland, not just the nodules. ¹⁴ Colloid is usually absent or minimal, and follicular cells frequently show marked nuclear atypia. These findings in the thyroid of a child or young adult are suspicious for dyshormonogenetic goiter, but definitive diagnosis will depend on clinicopathologic correlation and confirmatory ancillary studies.

Toxic (Hyperfunctioning) Multinodular Goiter

Toxic MNG is a complication of MNG in which one or more nodular collections of follicular cells secrete an excessive amount of thyroid hormone. Affected glands are grossly comparable to nontoxic MNG. Microscopically, one or more nodules may show features of hyperfunction, including tall follicular cells, papillary-like infoldings, and scant, watery colloid with peripheral scalloping. Definitive diagnosis depends on clinical and laboratory findings of hyperthyroidism.

Diffuse Toxic Hyperplasia (Graves’ Disease)

Diffuse toxic hyperplasia (DTH), also known as Graves’ disease or diffuse toxic goiter, is an autoimmune disorder characterized by excessive production of thyroid hormone and diffuse hyperplasia with enlargement of the thyroid. DTH is associated with extrathyroidal lesions, including inflammation of the orbital tissues, known as Graves’ ophthalmopathy, and excessive accumulation of glycosaminoglycans in the skin, known as myxedema.

DTH is caused by autoantibodies attaching to the TSH receptor (TSHR) on follicular cells. The autoantibodies activate the receptor and stimulate thyroid hormone synthesis and secretion in addition to proliferation of the follicular epithelium. A combination of genetic susceptibility and one or more environmental triggers appears to result in this autoimmune disorder. ⁴

Thyroid glands are mild to moderately enlarged, usually in a symmetrical manner. Untreated cases have a dark red appearance due to high vascularity, whereas treated cases appear lighter and more similar to normal thyroid due to decreased vascularity and the presence of more colloid. The classic microscopic appearance is diffuse hyperplasia, with follicles lined by tall columnar cells that exhibit papillary-like infolding into the central space (Fig. 5.3). Untreated cases contain very little colloid.

Some form of therapy precedes resection of most cases, resulting in reduction of the hyperplastic changes and an increase in the amount of colloid. The regression of hyperplastic changes is typically incomplete, with scattered areas of follicular hyperplasia still present. Variable numbers of lymphocytes are seen in the interfollicular stroma. Radioiodine may cause nuclear atypia that, in some cases, suggests papillary carcinoma.

A case of treated DTH may be interpreted as MNG or CLT by a pathologist unaware of the clinical diagnosis and prior treatment. Nodular lesions are found in 10 to 25% of thyroids with DTH, and most are benign with features of follicular hyperplasia or colloid nodule. However, about 10 to 20% of nodules are found to have carcinoma, usually papillary carcinoma, and the overall incidence of carcinoma associated with DTH is in the 1 to 9% range. ^{15 , 16}

Papillary Thyroid Carcinoma

PTC is a well-differentiated malignant tumor of thyroid follicular cells defined by characteristic nuclear features. A papillary growth pattern is frequently seen but is not required for the diagnosis. PTC is the most common type of thyroid cancer, accounting for 85 to 90% of cases in the United States. ¹⁸

The vast majority of tumors are sporadic cases, with only a small portion being due to germline mutations. ¹⁹ Preexisting solitary thyroid nodules and/or adenomas and multinodular goiter are risk factors for PTC, possibly due to an increased cell proliferation rate in adenomas and hyperplastic nodules and RAS gene mutations in follicular adenomas that may predispose to malignant transformation. ²⁰

Grossly, most PTCs appear as a discrete but ill-defined nodule with irregular borders. A capsule is typically absent, but some tumors may be well demarcated or encapsulated, with the exception of the follicular variant. Tumors range in appearance from tan-brown to gray-white and from firm and solid to more friable with cystic spaces. Irregularly shaped areas of fibrosis are frequent. Spontaneous necrosis and hemorrhage are rare but may be seen after FNA. Multifocal tumors are fairly common.

PTC can exhibit a variety of patterns. Microscopically, most PTCs show a papillary growth pattern characterized by fine, fingerlike strands of fibrovascular stroma covered by neoplastic epithelial cells, usually forming a single layer. This pattern is commonly admixed with a variable proportion of neoplastic follicles. Approximately two-thirds of tumors have this predominantly papillary growth, whereas about one-third exhibit a predominantly follicular architecture (Fig. 5.4). ²¹ Papillary carcinomas can have other growth patterns, including solid and trabecular, but these rarely predominate.

Despite these histological findings, the diagnosis of PTC is dependent on characteristic nuclear features, not growth pattern. These features include nuclear enlargement, overlapping, hypochromasia, irregular contours, grooves, and pseudoinclusions (Fig. 5.5). In some PTCs all of the nuclear features are readily identifiable. Others exhibit most, but not all, of these features, or they are found focally. There is no consensus on how many nuclear features are sufficient for the diagnosis and how widespread they should be, but most exhibit at least four. None of these features are pathognomonic for PTC, and a single feature may be seen in a variety of benign lesions. True nuclear pseudoinclusions have a relatively high specificity, but they are the least common feature and absent in a significant proportion of PTCs.

Psammoma bodies are distinctive laminated calcifications that are found in about half of all PTCs. ^{21 , 22} Psammoma bodies are particularly abundant in the diffuse sclerosing variant of PTC, and true psammoma bodies are exceedingly rare in lesions other than PTC.

PTC FNA specimens contain follicular cells arranged in papillae and/or monolayers. The cells exhibit the characteristic nuclear features already noted (Fig. 5.6). The amount of colloid is variable, and sometimes psammoma bodies are seen.

Multifocal disease may represent either multiple independent primary tumors or intraglandular dissemination from a single primary tumor. Lymphatic invasion is frequently seen, whereas blood vessel invasion is very uncommon.

Extrathyroidal extension of tumor may be minimal or extensive. Minimal extrathyroidal extension includes infiltration of perithyroidal skeletal muscle or the areas surrounding sizable vascular structures or nerves. ²³ Whether a minimal presence in perithyroidal adipose tissue qualifies as extrathyroidal extension is somewhat controversial. Extensive extrathyroidal extension is defined as involvement of the adjacent viscera (larynx, trachea, and/or esophagus), recurrent laryngeal nerve, carotid artery, mediastinal blood vessels, or subcutaneous soft tissues, and some authors also include involvement of adjacent skeletal muscle in this category. Extensive extrathyroidal invasion may be associated with a poorer prognosis. ²⁴