THYROID PATHOLOGY Thyroid gland Normal anatomy Congenital abnormalities

THYROID PATHOLOGY

Thyroid gland Normal anatomy Congenital abnormalities Thyroiditis Hyperplasia Tumors

THYROID-ANATOMY Butterfly-two lateral lobes-isthmus 15 -20 g A thin fibrous capsule Red-brown Follicle Round oval-single layer of epithelial cells (Flattened-cuboidal-columnar)-on basement membrane C-cells-NE cells-calcitonin Lumen of the follicle-kolloid

Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T 3 and T 4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T 3 and T 4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T 3 and T 4 levels to rise. Elevated T 3 and T 4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (c. AMP)-mediated synthesis and release of thyroid hormones (T 3 and T 4). In the periphery, T 3 and T 4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor complex that translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes initiating transcription. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Congenital abnormalities Thyroglossal duct anomalies Localized-persistence of the throglossal duct Thyroglossal duct cyst Midline of the neck Mic: cyst: Pseudostratified-squamous epitelium Heterotopic thyroid tissue Tongue, sublingual, prelaringeal, substernal

Thyroiditis Acute thyroiditis Granulomatous (de Ouervain’s) Thyroditis Other granulomatous inflammations Autoimmune (lymphocytic and Hashimoto’s) thyroiditis Riedel’s Thyroiditis

Acute thyroiditis Infectious nature-pharyngitis, tonsillitis St. Haemolyticus, Staph aureus, Pneumoccus Mic: neutrophilic infiltration, tissue necrosis

Granulomatous(de Ouervain’s) Thyroditis Ages: 30 - 50 , F/M: 3: 1 to 5: 1 Clinical Course The presentation of subacute thyroiditis may be sudden or gradual. It is characterized by pain in the neck, which may radiate to the upper neck, jaw, throat, or ears, particularly when swallowing Nearly all patients have high serum T 4 and T 3 levels and low serum TSH levels.

Pathogenesis Subacute thyroiditis- viral infection or a postviral inflammatory process- a history of an upper respiratory infection A viral infection that provides an antigen, either viral or a thyroid antigen that is released secondary to virus-induced host tissue damage. This antigen stimulates cytotoxic T lymphocytes, which then damage thyroid follicular cells.

Morphology The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule. On cut section, the involved areas are firm and yellow-white and stand out from the more rubbery, normal brown thyroid substance. Histologically. Early in the active inflammatory phase, scattered follicles- replaced by neutrophils forming microabscesses. Later, aggregations of lymphocytes, histiocytes, and plasma cells about collapsed and damaged thyroid follicles. Multinucleate giant cells enclose naked pools or fragments of colloid , hence the designation granulomatous thyroiditis.

Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right). Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Other granulomatous inflammations Palpation thyroiditis Tuberculosis Sarcoidosis Mycoses Postoperattive necrotizing granulomas

Autoimmune (lymphocytic and Hashimoto’s) thyroiditis Some authors use terms lymphocytic and Hashimoto thyroiditis synonymously Another autoimmune -Graves’ disease Mechanism: Humoral and cellular nature Circulating autoab-TG-follicular cell Ag-TSH receptor Follicle epithelial cell- ag Morphological common finding autoimmune thyroiditis: extensive lymphocytic infiltration with gland associated-germinal center formation.

Lymphocytic thyroiditis Children Juvenil form lymphocytic thyroiditis Silent-painless thyroiditis with hyperthyroidism Grossly: Diffusely enlarged-nodular, white, nodular cut surface. Mic: lymphocytic nodules with germinal centers, follicles

Hashimoto’s thyroiditis Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world in 45 and 65 years of age A female predominance of 10: 1 to 20: 1 Epidemiologic studies have demonstrated a significant genetic component to Hashimoto thyroiditis Specifically the HLA-DR 3 and HLA-DR 5 alleles, are linked to Hashimoto thyroiditis

Pathogenesis Hashimoto thyroiditis is an autoimmune disease. The overriding feature of Hashimoto thyroiditis is progressive depletion of thyroid epithelial cells (thyrocytes)gradually replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to the death of thyrocytes

CD 8+ cytotoxic T cell-mediated cell death Cytokine-mediated cell death Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity

Pathogenesis of Hashimoto thyroiditis. Three proposed models for mechanism of thyrocyte destruction in Hashimoto disease. Sensitization of autoreactive CD 4+ T cells to thyroid antigens appears to be the initiating event for all three mechanisms of thyroid cell death. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Morphology The thyroid is often diffusely enlarged The capsule is intact, and the gland is well demarcated from adjacent structures. The cut surface is pale, yellow-tan, firm, and somewhat nodular. Mic: extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers The thyroid follicles are atrophic - lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hurthle cells- metaplastic cells.

Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hurthle cells are also seen. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Clinical Course Hypothyroidism develops gradually. It may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones ("hashitoxicosis"). Patients with Hashimoto thyroiditis are at increased risk for developing other concomitant autoimmune diseases, both endocrine (type 1 diabetes, autoimmune adrenalitis), and nonendocrine (systemic lupus erythematosus, myasthenia gravis, and Sjögren syndrome *Increased risk for the development of B-cell non-Hodgkin lymphomas.

SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS Subacute lymphocytic thyroiditis, which is also referred to as painless thyroiditis or silent thyroiditis, is an uncommon cause of hyperthyroidism. Middle-aged adults and is more common in women, especially during the postpartum period (postpartum thyroiditis), than in men The pathogenesis of this disorder is unknown. An autoimmune basis has been suggested because some patients have elevated levels of antibodies to thyroglobulin and thyroid peroxidase or a family history of thyroid autoimmune disease

Morphology Mild symmetric enlargement, the thyroid appears normal on gross inspection. The most specific histologic features consist of lymphocytic infiltration with hyperplastic germinal centers within the thyroid parenchyma and patch disruption and collapse of thyroid follicles.

Clinical Course The principal clinical manifestation of painless thyroiditis is hyperthyroidism. Symptoms usually develop over 1 to 2 weeks and last from 2 to 8 weeks Laboratory findings during periods of thyrotoxicosis include elevated levels of T 4 and T 3 and depressed levels of TSH.

Riedel thyroiditis A rare disorder of unknown etiology characterized by extensive fibrosis involving the thyroid and contiguous neck structures. The presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma. Grossly: asymmetric-stony hard Mic: Fibrous tissue involves gland Inflammatory fibrosclerosis-idiopathic disorders

Palpation thyroiditis, caused by vigorous clinical palpation of the thyroid gland, results in multifocal follicular disruption associated with chronic inflammatory cells and occasional giant cell formation. Unlike De Quervain thyroiditis, abnormalities of thyroid function are not present

Hyperplasia Dyshormonogenetic goiter Graves’ Disease(Diffuse toxic goiter) Diffuse nontoxic goiter Multinodular-goiter-Nodular hyperplasia

Name Mechanism Dyshormono genetic goiter Graves’ disease Nodular – difuse hyperplasia -Endemic goiter Sporadic goiter Genetically Pathology Nodular or less diffuse hyperplasia Autoimmune Diffuse hyperplasia Iodine Nodular deficiency hyperplasia Unknown Nodular hyperplasia Functional status Hypotyhroid Hyperthyroid Usually eutyroid; sometimes hypothyroid Usually euthyroid: sometimes hyper or hypo

Dyshormonogenetic goiter Enzyme defects in hormone synthesis Genetic mutations Grossly: enlarged-multinodular Mic: Hyperplastic follicles are lined by marked nuclear pleomorphism, fibrosis.

Graves’ Disease (Diffuse toxic goiter) Graves disease is the most common cause of endogenous hyperthyroidism. It is characterized by a triad of clinical findings: Hyperthyroidism owing to hyperfunctional, diffuse enlargement of the thyroid Infiltrative ophthalmopathy with resultant exophthalmos Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patients

Ages of 20 and 40, F/M: 7/1 HLA-B 8 and -DR 3 Pathogenesis Graves disease is an autoimmune disorder in which a variety of antibodies may be present in the serum, including antibodies to the TSH receptor, thyroid peroxisomes, and thyroglobulin. Thyroid-stimulating immunoglobulin (TSI): Almost 50 years ago, serum from patients with Graves disease was found to contain a long-acting thyroid stimulator (LATS) Thyroid growth-stimulating immunoglobulins (TGI): TSH-binding inhibitor immunoglobulins (TBII): These anti. TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroid epithelial cells resulting in the stimulation of thyroid epithelial cell activity.

Morphology Symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. Cut surface: meaty appearance resembling normal muscle. Histologically, too many cells. The follicular epithelial cells in untreated cases are tall and more crowded than usual. The formation of small papillae, Lymphoid infiltrates, consisting predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common

Diffusely 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. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Clinical Course The clinical findings in Graves disease include changes referable to thyrotoxicosis as well as those associated uniquely with Graves disease: diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy. Laboratory findings: Elevated free T 4 and T 3 levels Depressed TSH levels. Radioactive iodine uptake is increased, and radioiodine scans show a diffuse uptake of iodine.

Diffuse non-toxic Goiter This disorder occurs in both an endemic and a sporadic distribution. Endemic goiter -occurs in geographic areas where the soil, water, and food supply contain only low levels of iodine. The lack of iodine leads to decreased synthesis of thyroid hormone and a compensatory increase in TSH, leading to follicular cell hypertrophy and hyperplasia and goitrous enlargement-diffuse or nodular colloid goiter.

Sporadic goiter Occurs less frequently than does endemic goiter. There is a striking female preponderance and a peak incidence at puberty or in young adult life. Mild dietary deficiency of iodine Slight impairment of hormone synthesis Increased iodide clearance by kidneys

Morphology Two phases can be identified in the evolution of diffuse non-toxic goiter: the hyperplastic phase and the phase of colloid involution. Diffusely and symmetrically enlarged, although the increase is usually modest, and the gland rarely exceeds 100 to 150 gm. The follicles are lined by crowded columnar cells, which may pile up and form projections similar to those seen in Graves disease. The accumulation is not uniform throughout the gland, and some follicles are hugely distended, whereas others remain small.

If dietary iodine subsequently increases or if the demand for thyroid hormone decreases, the stimulated follicular epithelium involutes to form an enlarged, colloid-rich gland (colloid goiter). In these cases, the cut surface of the thyroid is usually brown, somewhat glassy, and translucent. Histologically, the follicular epithelium is flattened and cuboidal, and colloid is abundant during periods of involution.

Clinical Course The vast majority of patients with simple goiters are clinically euthyroid. The clinical manifestations are primarily related to mass effects from the enlarged thyroid gland Serum T 3 and T 4 levels are normal, the serum TSH is usually elevated or at the upper range of normal

MULTINODULAR GOITER – Nodular hyperplasia Recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter. -Nodular hyperplasia They may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter). Multinodular goiters produce the most extreme thyroid enlargements - mistaken for neoplastic involvement

Multinodal goiters may arise because of variations among follicular cells in responses to external stimuli, such as trophic hormones. If some cells in a follicle have a growth advantage, perhaps because of intrinsic genetic abnormalities similar to those that give rise to adenomas, those cells will develop into clones of proliferating cells. This may result in the formation of a nodule whose continued growth could even be autonomous, without the external stimulus.

Morphology Multinodular goiters are multilobulated, asymmetrically enlarged glands that can achieve a weight of more than 2000 gm. The pattern of enlargement is quite unpredictable and may involve one lobe far more than the other, producing lateral pressure on midline structures, such as the trachea and esophagus. The goiter grows behind the sternum and clavicles to produce the so-called intrathoracic or plunging goiter.

Nodular goiter. The gland is coarsely nodular and contains areas of fibrosis and cystic change. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

One nodule may so stand out as to impart the clinical appearance of a solitary nodule. On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid are present. Regressive changes occur frequently, particularly in older lesions, and include areas of hemorrhage, fibrosis, calcification, and cystic change. The microscopic appearance includes colloidrich follicles lined by flattened, inactive epithelium and areas of follicular epithelial hypertrophy and hyperplasia, accompanied by the degenerative changes noted previously.

Clinical Course The dominant clinical features of goiter are those caused by the mass effects of the enlarged gland. Cosmetic effects of a large neck mass, goiters may cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax. Most patients are euthyroid, but in a substantial minority of patients, a hyperfunctioning nodule may develop within a long-standing goiter, resulting in hyperthyroidism (toxic multinodular goiter). Hyperfunctioning nodules concentrate radioiodine and appear "hot. “ Goiters are also of clinical significance because of their ability to mask or to mimic neoplastic diseases arising in the thyroid

Thyroid Tumors Epithelial Tumors-specific types A-Follicular adenoma -Hyalinizing trabecular adenoma and related lesions B-Papillary carcinoma C-Follicular carcinoma D-Clear cell tumors E-Squmaous cell, mucinous, and related tumors F-Poorly differentiated carcinoma G-Undiferentiated carcinoma H-Medullary carcinoma and related NE lesions Lymphoid tumors and tumorlike conditions Mesencymal tumors Other primary tumors and tumorlike conditions Metastatic tumors

Neoplasms of the Thyroid Several clinical criteria might provide a clue to the nature of a given thyroid nodule: 1 -Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules. 2 -Nodules in younger patients are more likely to be neoplastic than are those in older patients. 3 -Nodules in males are more likely to be neoplastic than are those in females. 4 -A history of radiation treatment to the head and neck region is associated with an increased incidence of thyroid malignancy. 5 -Nodules that take up radioactive iodine in imaging studies (hot nodules) are more likely to be benign than malignant

ADENOMAS Adenomas of the thyroid are typically discrete, solitary masses Most of these benign tumors are nonfunctional Simple colloid adenomas (macrofollicular adenomas), a common form, resemble normal thyroid tissue; Others recapitulate stages in the embryogenesis of the normal thyroid (fetal or microfollicular, embryonal or trabecular). Hormone production in functional adenomas ("toxic adenomas") occurs independent of TSH stimulation and represents another example of thyroid autonomy, analogous to toxic multinodular goiters.

Pathogenesis. The TSH receptor signaling pathway plays an important role in the pathogenesis of toxic adenomas. Activating ("gain of function") somatic mutations in one of two components of this signaling system-most often the TSH receptor itself or the α-subunit of Gs-cause chronic overproduction of c. AMP, generating cells that acquire a growth advantage This results in clonal expansion of follicular epithelial cells that can autonomously produce thyroid hormone and cause symptoms of thyroid excess

Morphology The typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is well demarcated from the surrounding thyroid parenchyma. Follicular adenomas average about 3 cm in diameter, but some are smaller and others are much larger (up to 10 cm in diameter). The neoplastic cells are demarcated from the adjacent parenchyma by a well-defined, intact capsule. These features are important in making the distinction from multinodular goiters, Areas of hemorrhage, fibrosis, calcification, and cystic change, similar to those encountered in multinodular goiters, are common in follicular adenomas, particularly within larger lesions.

Microscopically The follicular growth pattern within the adenoma is usually quite distinct from the adjacent non-neoplastic thyroid. The epithelial cells composing the follicular adenoma reveal little variation in cell and nuclear morphology. Mitotic figures are rare, and extensive mitotic activity warrants careful examination of the capsule to exclude follicular carcinoma.

Similar to endocrine tumors at other anatomic sites, even benign follicular adenomas may, on occasion, exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli (endocrine atypia); this by itself does not constitute a feature of malignancy.

Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Follicular adenoma. The photomicrograph shows well-differentiated follicles resembling normal thyroid parenchyma. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Follicular adenoma. 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. ) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Atypical follicular adenomas: Increased cellularity, more extensive variation in cellular size and nuclear morphology, and even mitotic activity. The hallmark of all follicular adenomas is the presence of an intact, well-formed capsule encircling the tumor. Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas , which demonstrate capsular and/or vascular invasion

Clinical Features unilateral painless mass, cold nodules relative to the adjacent thyroid tissue Owing to the need for evaluating capsular integrity, the definitive diagnosis of adenomas can be made only after careful histologic examination of the resected specimen. Suspected adenomas of the thyroid are therefore removed surgically to exclude malignancy. Thyroid adenomas, including atypical adenomas, have an excellent prognosis and do not recur or metastasize.

OTHER BENIGN TUMORS Additional benign lesions include dermoid cysts, lipomas, hemangiomas, and teratomas (seen mainly in infants).

CARCINOMAS 1. 5% of all cancers(in United States) Most cases occur in adults, although some forms, particularly papillary carcinomas, may present in childhood. A female predominance The major subtypes of thyroid carcinoma: Papillary carcinoma (75% to 85% of cases) Follicular carcinoma (10% to 20% of cases) Medullary carcinoma (5% of cases) Anaplastic carcinoma (<5% of cases)

Most thyroid carcinomas are derived from the follicular epithelium, except for medullary carcinomas; the latter are derived from the parafollicular or C cells Pathogenesis There are several factors, genetic and environmental, implicated in the pathogenesis of thyroid cancers.

Pathogenesis Genetic Follicular Thyroid Carcinomas -Approximately half of follicular thyroid carcinomas harbor mutations in the RAS family of oncogenes (HRAS, NRAS, and KRAS Papillary Thyroid Carcinomas- One pathway involves rearrangements of the tyrosine kinase receptors RET or NTRK 1 (neurotrophic tyrosine kinase receptor 1) and another involves activating mutations in the BRAF oncogene. A third pathway involves RAS mutations (10% to 20% of papillary carcinomas), suggesting that some of these cancers are related to follicular adenomas

Environmental Factors The major risk factor-ionizing radiation, particularly during the first two decades of life. In the past, radiation therapy was liberally employed in the treatment of a number of head and neck lesions in infants and children, including reactive tonsillar enlargement, acne, and tinea capitis. Up to 9% of people-thyroid malignancies Long-standing multinodular goiter-areas with iodine deficiency-related endemic goiter have a higher prevalence of follicular carcinomas Thyroid lymphomas may arise from pre-existing Hashimoto thyroiditis.

Papillary Carcinoma Papillary carcinomas are the most common form of thyroid cancer Young-middle age adults.

Morphology Papillary carcinomas are solitary or multifocal lesions. Well-circumscribed and even encapsulated; others may infiltrate the adjacent parenchyma with ill-defined margins. The lesions may contain areas of fibrosis and calcification and are often cystic. On the cut surface, they may appear granular and may sometimes contain grossly discernible papillary foci. The definitive diagnosis of papillary carcinoma can be made only after microscopic examination

Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. This particular example contains well-formed papillae Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Microscopic examination Papillary carcinomas can contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells. The nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground glass or Orphan Annie eye nuclei. intranuclear inclusions ("pseudo-inclusions") or intranuclear grooves. Concentrically calcified structures termed psammoma bodies are often present within the lesion, usually within the cores of papillae. Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon, particularly in smaller lesions. Metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases.

Papillary carcinoma of the thyroid. This particular example contains wellformed papillae (B), lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Papillary carcinoma of the thyroid. lined by cells with characteristic emptyappearing nuclei, sometimes termed "Orphan Annie eye" nuclei (C). Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Papillary carcinoma of the thyroid. D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Clinical Course Most papillary carcinomas present as asymptomatic thyroid nodules, but the first manifestation may be a mass in a cervical lymph node. In a minority of patients, hematogenous metastases are present at the time of diagnosis, most commonly in the lung. Most papillary lesions are cold masses on scintiscans. 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.

Follicular Carcinoma The second most common form of thyroid cancer, accounting for 10% to 20% of all thyroid cancers. They tend to present in women, and at an older age than do papillary carcinomas, with a peak incidence in the forties and fifties. The incidence of follicular carcinoma is increased in areas of dietary iodine deficiency,

Morphology Follicular carcinomas are single nodules well circumscribed or widely infiltrative Sharply demarcated lesions may be exceedingly difficult to distinguish from follicular adenomas by gross examination. Degenerative changes, such as central fibrosis and foci of calcification, are sometimes present.

Follicular carcinoma. Cut surface of a follicular carcinoma with substantial replacement of the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Microscopically Most follicular carcinomas are composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid The nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not present. Distinction from follicular adenomas requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular invasion

Capsular integrity in follicular neoplasms. Evaluating the integrity of the capsule is critical in distinguishing follicular adenomas from follicular carcinomas. In adenomas (A), a fibrous capsule, usually thin but occasionally more prominent, circumferentially surrounds the neoplastic follicles and no capsular invasion is seen (arrowheads); compressed normal thyroid parenchyma is usually present external to the capsule Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) (top of the panel). © 2007 Elsevier

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 February 2007 05: 41 PM) © 2007 Elsevier

Clinical Course Follicular carcinomas present as slowly enlarging painless nodules. Most frequently, they are cold nodules on scintigrams Vascular invasion is common, with spread to bone, lungs, liver, and elsewhere The prognosis is largely dependent on the extent of invasion and stage at presentation. Most follicular carcinomas are treated with total thyroidectomy followed by the administration of radioactive iodine.

Medullary Carcinoma Medullary carcinomas of the thyroid are neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid The cells of medullary carcinomas, similar to normal C cells, secrete calcitonin, In some instances, the tumor cells elaborate other polypeptide hormones, such as somatostatin, serotonin, and vasoactive intestinal peptide (VIP). The tumors arise sporadically in about 80% of cases. The remainder occurs in the setting of MEN syndrome 2 A or 2 B or as familial tumors without an associated MEN syndrome

Morphology Medullary carcinomas can arise as a solitary nodule or may present as multiple lesions involving both lobes of the thyroid. The sporadic neoplasms tend to originate in one lobe Bilaterality and multicentricity are common in familial cases. The tumor tissue is firm, pale gray to tan, and infiltrative.

Microscopically Medullary carcinomas are composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles. Small, more anaplastic cells are present in some tumors and may be the predominant cell type. Acellular amyloid deposits, derived from altered calcitonin molecules, are present in the adjacent stroma in many cases. Calcitonin is readily demonstrable within the cytoplasm of the tumor cellsimmunohistochemical methods.

Clinical Course Sporadic cases of medullary carcinoma come to medical attention most often as a mass in the neck In some instances, the initial manifestations are those of a paraneoplastic syndrome, caused by the secretion of a peptide hormone (e. g. , diarrhea owing to the secretion of VIP).

Anaplastic Carcinoma Anaplastic carcinomas of the thyroid are undifferentiated tumors of the thyroid follicular epithelium Anaplastic carcinomas are aggressive tumors, with a mortality rate approaching 100%. Patients with anaplastic carcinoma are older than those with other types of thyroid cancer, with a mean age of 65 years.

Morphology Microscopically, these neoplasms are composed of highly anaplastic cells, which may take one of several histologic patterns: (1) large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells; (2) spindle cells with a sarcomatous appearance; (3) mixed spindle and giant cells; and (4) small cells resembling those seen in small cell carcinomas arising at other sites.

Clinical Course Anaplastic carcinomas usually present as a rapidly enlarging bulky neck mass. In most cases, spread beyond the thyroid capsule into adjacent neck structures or has metastasized to the lungs at the time of presentation. Compression and invasion symptoms, such as dyspnea, dysphagia, hoarseness, and cough, are common. There is no effective therapy for anaplastic thyroid carcinoma, and the disease is almost uniformly fatal.