Thyroid Pathology

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normal thyroid anatomy

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*most superficial endocrine gland
*15 to 20g when you have normal I levels

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thyroid development:

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*b/t pouches 1 and 2
*thyroglossal duct attaches to pharynx; may remain as pyramidal lobe.

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Thyroid development--pouches:

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*foramen cecum is point where thyroid began to develop

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Lingual Thyroid
Thyroid tissue remnants may be present in the adult along the course of descent of the thyroglossal duct.

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Thyroglossal Duct Cyst
*Commonest congenital thyroid anomaly

*Midline location

*Most common in children but can present in adults

*Squamous or respiratory epithelium-lined cysts/chronic inflammation and thyroid tissue in wall

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Thyroglossal Duct Cyst:

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*Commonest congenital thyroid anomaly

*Midline location

*Most common in children but can present in adults

*Squamous or respiratory epithelium-lined cysts/chronic inflammation and thyroid tissue in wall

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Thyroglossal duct cyst

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Discuss 1˚ and 2˚ HYPOTHYROIDISM:

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*Primary:
Developmental (aplasia, hypoplasia; homeobox gene mutations--> cretinism)
Radiation injury
Surgical removal of gland
Hashimoto’s thyroiditis
Inherited biosynthetic disorders
Iodine deficiency
Drugs (lithium)

*Secondary:
Associated with decreased TSH or TRH

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CONGENITAL HYPOTHYROIDISM:

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*Cretinism = hypothyroidism in infancy or early childhood

*Impaired development of skeletal system leading to dwarfism

*Impaired development of CNS leading to mental retardation

*Coarse facial features, protruding tongue and umbilical hernia

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*DYSHORMONOGENETIC GOITER DUE TO ENZYMATIC DEFECT IN THYROID HORMONE BIOSYNTHESIS

*The brothers had severe mental retardation in addition to goiter and short stature

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DYSHORMONOGENETIC GOITER

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DYSHORMONOGENETIC GOITER:

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Patients with dyshormonogenetic goiters typically have massive enlargement of the gland with multiple hyperplastic nodules. Can lead to dyspnea.

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HASHIMOTO DISEASE: general info--

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Most common cause of hypothyroidism in which there is sufficient dietary iodine

Predominates in middle aged women

Concordance in identical twins is 40-60%

Most cases associated with HLA-DR5 with a smaller number associated with HLA-DR3 (don't memorize)

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HASHIMOTO DISEASE- genetic components:

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Polymorphism in multiple immunoregulatory genes: cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and protein tyrosine phosphatase-22 (PTPN-22)

Breakdown in self-tolerance to thyroid autoantigens

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HASHIMOTO DISEASE
The gland on cross-sections appears tan-white due to the presence of lymphoid hyperplasia

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HASHIMOTO DISEASE--histologic info:

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*Extensive lymphocytic and plasmacytic infiltrates

*Lymphoid follicles with germinal centers

*Atrophic thyroid follicles

*Thyroid follicles lined by Hürthle cells (also known as oxyphil cells or oncocytes)

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*HASHIMOTO DISEASE
*Characterized by lymphoid infiltrates with germinal centers and associated with eosinophilic (Hurthle cell) change of the follicular epithelium.
Arrows = Hurthle cells; LF = lymphoid follicle

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Pathogenesis of Hashimoto Thyroiditis:

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Sensitization of autoreactive CD4+ helper T cells to thyroid antigens seems to be the initiating event for all proposed mechanisms of thyroid cell death. Sensitized CD4+ helper T cells then either differentiate into TH1 cells with resulting delayed-type hypersensitivity reaction, or stimulate cytotoxic T-cell responses and help B cells (not shown) to develop into antibody-secreting plasma cells.

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OTHER TYPES OF THYROIDITIS-- 4

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Acute (usually related to bacteria)

Subacute (granulomatous/ De Quervain)

Subacute lymphocytic (painless)

Riedel’s

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SUBACUTE (GRANULOMATOUS/ DE QUERVAIN) thyroiditis:

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Self limited inflammatory disorder

Related to systemic viral infection (mumps, influenza, Coxsackie)

Pain in thyroid region with radiation to ear

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SUBACUTE/GRANULOMATOUS THYROIDITIS
Arrows = Giant Cells

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RIEDEL THYROIDITIS:

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Very, very uncommon

Fibroinflammatory disorder

Associated with retroperitoneal fibrosis, sclerosing mediastinitis, sclerosing cholangitis, orbital pseudotumor

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RIEDEL THYROIDITIS

-lymphocytes, plasma cells; no thyroid cells present.

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CAUSES OF THYROTOXICOSIS:

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Graves’ disease
Toxic multinodular goiter
Toxic adenoma (Plummer’s disease)
Trophoblastic tumor*
Increased TSH secretion

*hCG can bind to TSH receptor

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GRAVES DISEASE:

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*Most common cause of hyperthyroidism in patients less than 40

*Female predominance (F:M=10:1)

*Prevalence = 2.7%

*Incidence = 1 case per 1000 per year

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GRAVES’ DISEASE
DIFFUSE enlargement of the thyroid in a patient with Graves’ disease
*hyperplastic pyramidal lobe present

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Photomicrograph of a diffusely hyperplastic gland in a case of Graves disease. The follicles are lined by tall columnar epithelial cells that 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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GRAVES DISEASE--genetic components:

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*Genetic susceptibility linked to CTLA-4 and PTPN-22; HLA-DR3

*Breakdown in self-tolerance to thyroid autoantigens (TSH receptor)
-Thyroid stimulating immunoglobulin
-Thyroid growth-stimulating immunoglobulins
-TSH-binding inhibitor immunoglobulins

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Single vs. Multiple Thyroid Nodules:

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Occurrence of thyroid nodules by age:

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~5-7% occurrence around 50-60 years of age

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NON-TOXIC NODULAR GOITER:

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Enlargement of thyroid in absence of hyper – or hypo-thyroidism

Most common form of goiter in U.S.

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NON-TOXIC GOITER

The gland is markedly enlarged with the formation of multiple nodules

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ADENOMATOUS NODULE
*like an adenoma (hyperplastic), but NOT an adenoma.
*seen in non-toxic multinodular goiter

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NON-TOXIC NODULAR GOITER--mechanisms:

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*Decreased T3 andT4, leading to increased TSH

*Varying responsiveness of groups of follicular cells to TSH

*Perhaps autoimmune (thyroid stimulating immunoglobulins)

*Alternating cycles of hyperplasia and involution***

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NON-TOXIC GOITER
L: shows hyperplasticity
R: shows involution

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FINE NEEDLE ASPIRATION
-very important in goiters

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*from FNA; used to diagnose thyroid nodules.
*Lots of histiocytes, thus it's probably an adenomatous nodule.

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THYROID FNA CLASSIFICATION/BETHESDA:

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*don't have to memorize; just know the FNA results are important

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THYROID NODULES after irradiation:

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Exposure to ionizing irradiation increases prevalence of benign and malignant nodules

Prevalence of nodules in irradiated individuals is 20-30%

Rate of malignancy in irradiated individuals is 30-50%

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FOLLICULAR ADENOMA:

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Benign encapsulated neoplasm with evidence of follicular cell differentiation

F>M; 5-6th decade

Painless solitary neck mass

Most often, adenomas are cold

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*high power view of follicular adenoma
*this one looks just like normal thyroid tissue.

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*Hurthel cell adenoma
*No relationship to Hashimoto disease; that name is just based on appearance of the cells.

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ESTIMATED NEW CANCER CASES AND DEATHS (U.S.) 2013:

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Prevalence of types of thyroid carcinomas:

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*Know this slide*
-don't worry about poorly differentiated

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PAPILLARY THYROID CARCINOMA:

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*Most common thyroid carcinoma*
A malignant epithelial tumor showing evidence of follicular cell differentiation and characterized by the formation of papillae and/or a set of distinctive nuclear features.

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PAPILLARY CARCINOMA
This tumor occupies much of the upper portion of the lobe.

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PSAMMOMA BODIES

Psammoma (sand-like) bodies (arrows) are common in papillary carcinomas and represent areas of calcification surrounding degenerated/necrotic tumor cells.

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Refers to clear appearance of nuclear inclusions (orphan like) in papillary carcinoma.

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-black areas represent multiple tumor sites

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Papillary carcinoma prognosis: graph--

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pretty good prognosis; bigger ones aren't as good
extrathyroidal extension = poor prognosis (worse than lymph node mets)

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PROGNOSIS OF PAPILLARY CARCINOMA:

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*Overall prognosis is excellent with 10 yr survival >95%

*Poor prognostic factors
-Age >40 years
-Male gender
-Direct extrathyroidal extension
-Distant metastases
-Certain histologic subtypes (e.g. tall cell variant)

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MOLECULAR FEATURES of papillary carcinoma:

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*Activation of MAP kinase pathway:

-Rearrangement of RET or NTRK1 (neurotrophic tyrosine kinase receptor 1)

-Point mutations of BRAF

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FOLLICULAR CARCINOMA:

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A malignant epithelial tumor showing evidence of follicular cell differentiation and not belonging to any of the other distinctive types of thyroid malignancy; DON'T HAVE NUCLEAR INCLUSIONS.

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CAPSULAR INVASION=FOLLICULAR CARCINOMA

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VASCULAR INVASION=FOLLICULAR CARCINOMA

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SMALL FOLLICLES VISIBLE

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*TYPICALLY GO TO BONES

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-DEPENDS ON LEVEL OF INVASIVENESS

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Molecular features of Follicular Carcinoma:

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*Mutations in the phosphatidylinositol-3-kinase (PI-3K-/AKT) pathway:

-Gain of function mutations of RAS and PIK3CA; amplification of PIK3CA; loss of function mutations of PTEN; PAX8-PPARG translocations

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UNDIFFERENTIATED (ANAPLASTIC) CARCINOMA:

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A highly malignant tumor that appears partially or totally undifferentiated with standard light microscopic techniques but in which some degree of epithelial differentiation is found on immunohistochemical or ultrastructural studies.

Large (greater than 5 cm)
Soft; white-tan
Hemorrhage and necrosis
Extrathyroidal extension

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UNDIFFERENTIATED (ANAPLASTIC) CARCINOMA
This patient had a long standing goiter which had undergone rapid enlargement. The thyroid was surgically excised but the tumor re-grew rapidly through the skin and became ulcerated.

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UNDIFFERENTIATED (ANAPLASTIC) CARCINOMA
The thyroid lobe (left) is replaced by an extensively necrotic tumor. The contralateral lobe (right) contains a small tumor deposit.

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UNDIFFERENTIATED THYROID CARCINOMA
This tumor lacks evidence of papillary or follicular differentiation.
It is composed of sheets of undifferentiated cells with prominent mitoses.

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What's the prognosis of UNDIFFERENTIATED (ANAPLASTIC) CARCINOMAs?

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BAD!!!!!!!!!

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MOLECULAR FEATURES of UNDIFFERENTIATED (ANAPLASTIC) CARCINOMAs?

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Mutations of RAS, PIK3CA; inactivation of p53; activating mutations of beta-catenin.
-SIMILAR TO FOLLICULAR CANCERS

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POORLY DIFFERENTIATED CARCINOMA:

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A malignant thyroid neoplasm that occupies an intermediate place (both morphologically and clinically) between the well differentiated papillary and follicular carcinomas and undifferentiated carcinoma.

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POORLY DIFFERENTIATED CARCINOMA
This tumor has replaced most of the lobe.

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POORLY DIFFERENTIATED CARCINOMA (INSULAR)
This tumor has an insular (islet-like) growth pattern.

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POORLY DIFFERENTIATED CARCINOMA
A malignant thyroid neoplasm that occupies an intermediate place (both morphologically and clinically) between the well differentiated papillary and follicular carcinomas and undifferentiated carcinoma