HASHIMOTO THYROIDITIS

Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized by

gradual thyroid failure because of autoimmune destruction of the thyroid gland. The name Hashimoto thyroiditis is derived from the 1912 report by Hashimoto describing patients with

goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa). This disorder is most prevalent between 45 and 65 years of age and is more common in women than in

men, with a female predominance of 10:1 to 20:1. Although it is primarily a disease of older women, it can occur in children and is a major cause of nonendemic goiter in children.

Epidemiologic studies have demonstrated a significant genetic component to Hashimoto thyroiditis, although, as in most other autoimmune disorders, the pattern of inheritance is non-

Mendelian and likely to be influenced by subtle variations in the functions of multiple genes. The concordance rate in monozygotic twins is 30% to 60%, and up to 50% of asymptomatic

first-degree relatives of Hashimoto patients demonstrate circulating antithyroid antibodies.[15] Several chromosomal abnormalities have been associated with thyroid autoimmunity. For

example, adults with Turner syndrome (see Chapter 5 ) have a high prevalence of circulating antithyroid antibodies, and a substantial minority (~20%) develops subclinical or clinical

hypothyroidism that is indistinguishable from Hashimoto thyroiditis. Similarly, adults with trisomy 21 (Down syndrome, see Chapter 5 ) are also at an increased risk for developing

Hashimoto thyroiditis and hypothyroidism. There are reports that polymorphisms in the HLA locus, specifically the HLA-DR3 and HLA-DR5 alleles, are linked to Hashimoto

thyroiditis, but the association is weak. Finally, genomewide linkage analyses in families with Hashimoto thyroiditis have provided evidence for several susceptibility loci, such as on

chromosomes 6p and 12q, that may harbor genes predisposing to this disorder.[16]

Pathogenesis.

Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens. The overriding feature of Hashimoto thyroiditis is progressive

depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to the

death of thyrocytes ( Fig. 24-9 ).[17] [18] Sensitization of autoreactive CD4+ T-helper cells to thyroid antigens appears to be the initiating event. The effector mechanisms for thyrocyte

death include the following:

• CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme granules or

engagement of death receptors, specifically CD95 (also known as Fas) on the target cell ( Chapter 6 ).

• Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines such as IFN-g in the immediate thyrocyte milieu, with resultant recruitment and activation of

macrophages and damage to follicles.

• Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated

cytotoxicity (ADCC) ( Chapter 6 ).

Morphology.

The thyroid is often diffusely enlarged, although more localized enlargement may be seen in some cases. The capsule is intact, and the gland is well demarcated from adjacent structures.

The cut surface is pale, yellow-tan, firm, and somewhat nodular. Microscopic examination reveals extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate

containing small lymphocytes, plasma cells, and well-developed germinal centers( Fig. 24-10 ). The thyroid follicles are atrophic and are lined in many areas by epithelial cells

distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthlecells. This is a metaplastic response of the normally low cuboidal follicular epithelium to

ongoing injury. In fine-needle aspiration biopsies, the presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes is characteristic of Hashimoto thyroiditis.

In "classic" Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant. A fibrous variantis

Figure 24-9Pathogenesis of Hashimoto thyroiditis. Three proposed models for mechanism of thyrocyte destruction in Hashimoto disease. Sensitization of autoreactive CD4+ T cells to

thyroid antigens appears to be the initiating event for all three mechanisms of thyroid cell death. See the text for details.

Figure 24-10Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic

Hürthle cells are also seen.

Figure 24-11Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right).

Figure 24-12Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the

lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid.

Figure 24-13Nodular goiter. The gland is coarsely nodular and contains areas of fibrosis and cystic change.

Figure 24-14Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen.

Figure 24-15Follicular adenoma. The photomicrograph shows well-differentiated follicles resembling normal thyroid parenchyma.

Figure 24-16Hürthle cell tumor. A high-power view showing that the tumor is composed of cells with abundant eosinophilic cytoplasm and small regular nuclei. (Courtesy of Dr. Mary

Sunday, Brigham and Women's Hospital, Boston, MA.)

Figure 24-17Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. This particular example contains

well-formed papillae (B), lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei (C). D, Cells obtained by fine-needle aspiration of a

papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells.

TABLE 24-4-- Thyroid Lesions with a Follicular Architecture

Non-Neoplastic

Hyperplastic nodule in goiter

Neoplastic

Follicular adenoma *

Follicular carcinoma *

Follicular variant of papillary carcinoma †

*Differentiating follicular carcinoma from follicular adenoma requires histologic evidence of capsular or blood vessel invasion, or documented metastasis.

†The diagnosis of papillary carcinoma is rendered on the presence of characteristic nuclear features, irrespective of the presence or absence of papillae.

potential than the ret/PTC observed in usual papillary thyroid cancers. The presence of this genetic abnormality might result in more aggressive behavior.[42] [43]

An unusual diffuse sclerosing variantof papillary carcinoma occurs in younger individuals, including children. These tumors do not present with a mass, but rather with a bilateral

goiter. There is a characteristic "gritty" sensation to the cut surface of the lesion due to the presence of abundant psammoma bodies. The tumor demonstrates a prominent papillary

growth pattern, intermixed with solid areas containing nests of squamous cells (squamous morules). The neoplastic cells exhibit classic nuclear features of a papillary neoplasm. As the

name suggests, there is extensive, diffuse fibrosis throughout the thyroid gland, often associated with a prominent lymphocytic infiltrate, simulating Hashimoto thyroiditis. The

neoplastic cells have a peculiar propensity to invade intrathyroidal lymphatic channels; hence, nodal metastases are present in almost all cases.

Hyalinizing trabecular tumors, a group that includes both adenomas and carcinomas, have recently been reconsidered as a variant of papillary carcinomas, based on the presence of ret/

PTC gene rearrangements in 30% to 60% of these tumors.[44] They are characterized by an "organoid" growth pattern, with nests and trabeculae of elongated tumor cells within a

fibrovascular stroma; at first glance, the tumor may resemble an extra-adrenal paraganglioma (see below). Both intracellular and extracellular hyalinization are prominent and confer a

pink hue on the tumor on low-power microscopic examination. The nuclear features resemble those seen in classic papillary carcinomas, and psammoma bodies may be present.

Hyalinizing trabecular adenomas are well encapsulated, while carcinomas demonstrate capsular and/or vascular invasion.

Clinical Course.

Most papillary carcinomas present as asymptomatic thyroid nodules, but the first manifestation may be a mass in a cervical lymph node. Interestingly, the presence of isolated cervical

nodal metastases does not appear to have a significant influence on the generally good prognosis of these lesions. The carcinoma, which is usually a single nodule, moves freely during

swallowing and is not distinguishable from a benign nodule. Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease. In a minority of patients, hematogenous metastases

are present at the time of diagnosis, most commonly in the lung.

A variety of diagnostic tests have been employed to help separate benign from malignant thyroid nodules, including radionuclide scanning and fine-needle aspiration. Most papillary

lesions are cold masses on scintiscans. Improvements in cytologic analysis have made fine-needle aspiration cytology a reliable test for distinguishing between benign and malignant

nodules. The nuclear features are often nicely demonstrable in aspirated specimens.

Papillary thyroid cancers have an excellent prognosis, with a 10-year survival rate in excess of 95%. Five per cent to 20% of patients have local or regional recurrences, and 10% to 15%

have distant metastases. The prognosis of a patient with papillary thyroid cancers is dependent on several factors including age (in general, the prognosis is less favorable among patients

older than 40 years), the presence of extrathyroidal extension, and presence of distant metastases (stage).

Date: 2016-04-22; view: 659