1. THYROID PATHOLOGY

2. Thyroid gland Normal anatomy Congenital abnormalities Thyroiditis
Hyperplasia
Tumors

3. 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

7. Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 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 (cAMP)-mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 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.
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8. 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,lingual,prelaringeal,substernal

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

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

11. Granulomatous(de Ouervain’s) Thyroditis
Ages: ,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 T4 and T3 levels and low serum TSH levels.

12. 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.

13. 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.

14. Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right).
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16. Other granulomatous inflammations
Palpation thyroiditis
Tuberculosis
Sarcoidosis
Mycoses
Postoperattive necrotizing granulomas

17. 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.

18. 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

19. 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-DR3 and HLA-DR5 alleles, are linked to Hashimoto thyroiditis

20. 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

21. CD8+ 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

22. Pathogenesis of Hashimoto thyroiditis
Pathogenesis 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.
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23. 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.

25. Hashimoto thyroiditis
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.
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27. 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.

28. 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

29. 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.

30. 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 T4 and T3 and depressed levels of TSH.

31. 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

32. 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

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

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

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

36. 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

37. Pathogenesis Ages of 20 and 40, F/M:7/1 HLA-B8 and -DR3
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.

38. 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

39. Diffusely hyperplastic thyroid in a case of Graves disease
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.
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41. 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 T4 and T3 levels
Depressed TSH levels.
Radioactive iodine uptake is increased, and radioiodine scans show a diffuse uptake of iodine.

42. 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.

43. 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

44. 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.

45. 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.

46. 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 T3 and T4 levels are normal, the serum TSH is usually elevated or at the upper range of normal

47. 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

48. 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.

49. 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.

52. Nodular goiter. The gland is coarsely nodular and contains areas of fibrosis and cystic change.
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54. 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 colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular epithelial hypertrophy and hyperplasia, accompanied by the degenerative changes noted previously.

55. 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

56. 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

57. 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

58. 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.

59. 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 cAMP, 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

60. 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.

61. 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.

62. 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.

63. Follicular adenoma of the thyroid
Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen.
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65. Follicular adenoma. The photomicrograph shows well-differentiated follicles resembling normal thyroid parenchyma.
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66. 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.)
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67. 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

68. 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.

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

70. 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)

71. 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.

72. 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 NTRK1 (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

73. 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.

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

75. 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

76. Papillary carcinoma of the thyroid
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
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78. 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.

79. Papillary carcinoma of the thyroid
Papillary carcinoma of the thyroid. This particular example contains well-formed papillae (B), lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei
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82. Papillary carcinoma of the thyroid
Papillary carcinoma of the thyroid. lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei (C).
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83. Papillary carcinoma of the thyroid
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.
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84. 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.

85. 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,

86. 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.

87. 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.
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88. 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

89. Capsular integrity in follicular neoplasms
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 (top of the panel).
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91. 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.

92. 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 2A or 2B or as familial tumors without an associated MEN syndrome

93. 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.

94. 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 cells-immunohistochemical methods.

96. 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).

97. 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.

98. 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.

99. 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.