Pathology Endocrine #3 - Lecture 10

Front 1

What is the effect of Thyroiditis?

Back 1

Hypothyroidism

Front 2

What are the 3 kinds of Thyroiditis?

Back 2

D) Thyroiditis
1) Subacute
2) Hashimoto’s
3) Riedel

Front 3

Subacute (granulomatous) thyroiditis

Back 3

Mostly women (~4:1), typically 40-50 years old
Often prior viral infection (echo, coxsackie, mumps, measles, influenza, adeno), triggering a cytotoxic T-cell reaction in thyroid with follicle damage
Transient hyperthyroidism (colloid leak)
Thyroid tender to palpation
Gland: diffusely or irregularly enlarged, with yellow-white foci
Micro: granulomatous inflammation
Outcome: mostly euthyroid, some hypothyroid
Don’t confuse with subacute lymphocytic thyroiditis (hyperthyroidism)

Front 4

What is the disease progression of Subacute (granulomatous) thyroiditis?

Back 4

Mostly in a woman, between the ages of 40-50 will get a viral infection (echo, coxsackie, mumps, measles, influenza, adeno).

Next, that virus attacks the thyroid gland and exposed antigens from the thyroid that were previously hidden.

The presentation of these new antigens triggers a cytotoxic t-cell response that infiltrates the thyroid and destroys the follicles.

In the beginning of this process, there may be hyperthyroidsism because asthe thyroid follicles are destoryed, some colloid leaks out into the circulation, and this colloid can cause hyperthyroidism.

Due to the infection, the thyroid gland is tender and palpable.

Front 5

What does subacute thyroiditis look like microscopically?

Back 5

Subacute thyroiditis – Huge giant cell around “naked” colloid. The colloid is within a giant cell. This is diagnostic for this disease.
OTHER FINDINGS:
In subacute granulomatous thyroiditis, there's a "PATCHY NATURE." There are some areas that are normal, and some areas and destroyed.

Then, later on in the disease, granuloma replaces the destroyed follicle, and you get hypothyroidism .

Front 6

What is the single most common cause of hypothyroidism in the USA?

Back 6

Hashimoto thyroiditis

Front 7

Hashimoto thyroiditis

Back 7

THINK: Hashimoto sounds like a Japanese warrior, think of the warrior from within. Within= Auto-immune disease.

Mainly women (10-20:1) > 40 years old
Autoimmune disease with production of antibodies against thyroglobulin, thyroid perxidase, microsomal antigen (diagnostically useful)
CD8+ cytotoxic T-cells, cytokine–induced, macrophage-mediated damage and Ab-dependent cell-mediated toxicity all contribute
Anti-TSH receptor blocks TSH effect

Front 8

How does the body attack the thyroid gland in Hashimoto's thyroiditis?

Back 8

There are three ways that the body attack the thyroid in Hashimoto thyroiditis:

1. The production of antibodies: These Abs are against
a. thyroglobulin
b. thyroid peroxidase
c. microsomal antigen within the thyroid.

2. The damage to the thyroid epithelium and follicles occurs from a 3-pronged attack.
a. CD8+ cytotoxic T-cells
b. cytokine–induced, macrophage-mediated damage
c. Ab-dependent cell-mediated toxicity

3. There are also anti-TSH receptors on the surface that block the affects of TSH - these adds to the hypo-thyroidism.

Front 9

How can you clinically determine if someone has Hashimoto thyroiditis?

Back 9

Measure their serum Ab levels.

These people should have Abs against:
a. thyroglobulin
b. thyroid peroxidase
c. microsomal antigen within the thyroid.

Front 10

What is the cause of Hashimoto thyroiditis?

Back 10

Genetic component with familial clustering; polymorphisms in genes associated with immune regulation
Associated with other autoimmune diseases (APS 2, [ Addison’s, Hashimoto’s and type 1 diabetes], SLE, myasthenia gravis, Sjogren’s syndrome)
Increased incidence in Turner and Down syndromes

Front 11

What does the Hashimoto thryroiditis gland look like?

Back 11

Hashimoto’s thyroiditis - Note pallor - because of all of the infiltration of immune cells

Gland: Diffusely , often asymmetrically enlarged and pale/rubbery; capsule intact

Front 12

What does the thyroid look like microscopically in Hashimotos thyroiditis?

Back 12

Micro: Infiltrates of lymphocytes, plasma cells (sometimes germinal centers), & macrophages, with Hurthle cell metaplasia of the follicular epithelium

Front 13

Hashimotos thyroiditis is associated with what unique type of cells?

Back 13

Hashimoto thyroiditis – germinal center & Hürthle cell change

Hürthle cell = a follicular cell with an enlarged, granular, eosinophilic cytoplasm because of an accumulation of mitochondria.

Front 14

What is this?

Back 14

Hashimoto thyroiditis – fibrous variant

Fibrous variant: Usually not goitrous

There are 2 main components of this fibrous variant:
1. There's an accumulation of immune cells such as lymphocytes and Hurthle cells in the follicular epithelium
2. deposition of a large amount of collagen (fibrous)

Front 15

What are the complications of Hashimotos thyroiditis?

Back 15

Complications:
1. Lymphoma: A low grade B-cell lymphoma that usually stays within the thyroid gland can transform into a higher grade lymphoma and my leave the thyroid.
2. ? papillary carcinoma: it is not clear if Hastimotos is associated with papillary carcinoma.

Front 16

Riedel thyroiditis

Back 16

Rare (unlike Hashimotos); M:F = 1:3; Most common in 30 - 60 years

Fibrous tissue replaces & often extends outside gland

THINK: Riedel - sounds like the name of a football player at UM. The football player was strong, muscular, and solid. ----> fibrous He was so good that he always used to push through the other team. ------> may extend outside of the thyroid gland

Causes dysphagia & stridor (Stridor is an abnormal, high-pitched, musical breathing sound caused by a blockage in the throat or voice box (larynx)) This fibrous tumor can impinge upon the esophagus, pharynx and larynx

Clinical concern for cancer because it's fibrous and firm

Gland: Asymmetric fibrosis, very firm

Micro: Keloid-like bands of fibrous tissue

Associated with RP fibrosis, sclerosing cholangitis & mediastinitis, and orbital pseudotumor

Outcome: about 1/3 hypothyroid

Front 17

What is this?

Back 17

Riedel thyroiditis – Note keloid-like bands of collagen

Front 18

What is this?

Back 18

Riedel thyroiditis – dissection into strap muscles

There's no distinct transition between the thryoid gland and the neck because the fibrous tissue (keloid) has infiltrated in the the skeletal muscle, in a carcinoma-like fashion.

Front 19

What other conditions is Riedel thyroiditis associated with?

Back 19

Riedel thyroiditis is Associated with:
1. RP fibrosis = retroperitoneal fibrosis,
2. sclerosing cholangitis - this may lead to common bile duct obstruction and then possible cirrohsis of the liver
3. mediastinitis - similar fibrosis tissue appears in the mediastinum and may obstruct the great vessels
4. orbital pseudotumor = fibrous tissue behind the eye.
Outcome: about 1/3 hypothyroid

Front 20

What are the causes of Hypothyroidism?

Back 20

A) Agenesis
B) Enzyme defects; goitrogens (natural and drugs)
C) THRB mutations
D) Iodine deficiency
E) Thyroiditis
F) Iatrogenic
1) Thyroidectomy
2) Radio-iodine
G) Hypothalamic-pituitary axis hypofunction
H) Rarely metastatic carcinoma (although metastases to thyroid are common autopsy findings)

Front 21

What are the causes of Hyperthyroidism?

Back 21

A) Graves disease
B) Toxic multinodular goiter (Plummer syndrome)
C) Toxic adenoma
D) Rare causes - subacute thyroiditis (granulomatous & lymphocytic), functioning thyroid carcinoma, gestational neoplasia and non-gestational choriocarcinoma, pituitary or hypothalamic dysfunction, struma ovarii

Front 22

Graves disease

Back 22

Graves disease (diffuse toxic goiter, diffuse thyroid hyperplasia) – 85% of hyperthyroidism

TETRAD OF FINDINGS:
1. Symmetric goiter 2.hyperthyroidism
3. ophthalmopathy
4. dermopathy

M:F = 1:6, most commonly 20 - 40 years

Familial clustering, HLA-DR3, & other autoimmune diseases (SLE, PA, type 1 diabetes, Addison’s)

Inherited polymorphisms in immune function genes that inhibit response to self antigens

Circulating autoantibodies stimulate the thyroid, including TSH receptor; T-cells react with retro-orbital cells & induce matrix production, causing proptosis

Gland: diffusely enlarged, hypervascular - therefore, bruies can be heard because of increased blood flow through the gland

Front 23

What does the thyroid look like in a patient with Graves disease.

Back 23

Micro: columnar, papillary epithelial hyperplasia, scalloped & depleted colloid, lymphoid infiltrates

THINK: In Graves disease, there's a significant thyroid hyperplasia. Therefore, the best way to deal with this is to increase surface area by allowing the follicular eithelium to fold into the lumen in these papillary projections.

The colloid within the follicle s being actively resorbed and depleted because of the increased surface area of the papillary folds and this causes the scalloping.

Front 24

Why is treatment of the thyroid prior to surgery important for Graves disease?

Back 24

Vascularity & “thyroid storm” make treatment prior to surgery important

Vascularity - because the thyroid has become very vascular with Graves disease, the thyroid must be suppressed before surgery or there would be excessive bleeding after surgery.

Thyroid storm - this means that too much thyroid hormone can be resorbed because of increased surface area. This would cause a possible hyper-pyrexic crisis during surgery in which the patient could become very tachycardia and could have fever of 105-106 degrees. This could end in death.

Front 25

Toxic multinodular goiter

Back 25

Iodine deficiency, goitrogens, partial enzymatic deficiencies cause decreased T3 &T4.

Since T3 &T4 provide negative feedback to both the pituitary and the hypothalamus, there's decreased negative feedback. This leads to increased TSH.

Increased TSH leads to nodular hyperplasia

Nodule autonomy develops, probably secondary to the development of TSH signaling pathway mutations. (Nodule autonomy means that the the goiter doesn't respond to TSH as a signaling pathway. Instead, it functions on its own. )

Front 26

Draw the Normal feedback loops for thyroid function

Back 26

Front 27

What is this?

Back 27

Toxic Multinodular goiter (nodular hyperplasia) - note variation in follicle size

These nodules are NOT encapsulated and they VARY in SIZE. This size variation is characteristic of Toxic Multinodular goiter

Front 28

Toxic adenoma

Back 28

A SINGLE nodule, which meets criteria for adenoma, secretes excess thyroid hormones

Cause: Mutations in genes for TSH receptor or signaling proteins that result in chronic c-AMP stimulation INDEPENDENT of TSH

Front 29

How is Toxic adenoma different from Toxic Multinodular Goiter?

Back 29

1. In Toxic adenoma, there's a single, circumscribed nodule in thyroid lobe. (Nodules in TMG are not encapsulated)

2. There are relatively uniform follicles in toxic adenoma.

Front 30

Rare causes of Hyperthyroidism

Back 30

Rare causes of Hyperthyroidism:
1. subacute thyroiditis (granulomatous & lymphocytic),
2. functioning thyroid carcinoma,
3. gestational neoplasia
4. non-gestational choriocarcinoma (increased hCG has TSH-like functions)
5. pituitary or hypothalamic dysfunction,
6. struma ovarii ( an ovarian teratoma that has thyroid tissue_

Front 31

Subacute lymphocytic thyroiditis

Back 31

Subacute lymphocytic thyroiditis

1-10% of hyperthyroid in the USA

Mostly women, especially middle age or post-partum

Autoimmune, related to Hashimoto thyroiditis, with anti-thyroid Abs

Usually transient hyperthyroid; may evolve to hypothyroidism

Histo: Lymphocytic infiltrates; NO Hurthle cell metaplasia (in contrast to Hashimotos)

Front 32

Euthyroid hyperplasia

Back 32

Euthyroid hyperplasia aka (Diffuse & Multinodular NON-toxic goiter) - sometimes the thyroid gland becomes hyperplastic in the absence of any functional abnormalites

Same etiology as toxic multinodular goiter, without the nodular anatomy.

Initial diffuse hyperplasia replaced by discrete nodules

Variable histology of large & small follicles

Infarcts, fibrosis, calcification (ischemic changes)

May compress airway – stridor, dysphagia

? frequency of cancer - not greatly different from a control population (<5%)

Front 33

What is this?

Back 33

Multinodular goiter

Front 34

Thyroid nodules

Back 34

Thyroid nodules

Autopsy thyroid glands - 12% have single nodules & about 1/3 have multiple nodules

Frequency of carcinoma in autopsy thyroids (excluding “microscopic only” cases) = 1-5%

Carcinoma of thyroid accounts for < 0.5% of cancer mortality

Therefore: most thyroid nodules are benign and most thyroid cancers are non-lethal

Front 35

Thyroid adenoma

Back 35

Strict criteria necessary to avoid confusion with nodular hyperplasia (multinodular goiter): single nodule (ideally), fibrous encapsulation, compression of surrounding gland, uniform histology which is different from surrounding gland

Hemorrhage may produce rapid and painful enlargement

<20% share mutations seen in follicular carcinomas

Front 36

What is this?

Back 36

Follicular adenoma (surrounding thyroid is to the left, the follicular adenoma is to the right.)

Strict criteria necessary to avoid confusion with nodular hyperplasia (multinodular goiter): single nodule (ideally), fibrous encapsulation, compression of surrounding gland, uniform histology which is different from surrounding gland

Front 37

Frequency of Thyroid Carcinomas

Back 37

Papillary carcinoma (including follicular
variants) – 85%

Follicular carcinoma - 5-15%

Medullary carcinoma - 5%

Anaplastic carcinoma - <5%

Front 38

Papillary carcinoma

Back 38

Papillary carcinoma

Most common type of thyroid carcinoma (includes “follicular variant” of papillary carcinoma)

M:F = 1:3 (estrogen receptors on follicular cells); patients most commonly 25 - 50 years old

Increased incidence in Gardner’s syndrome THINK: You Garden with you fingers - papilla

Mutations in MAP kinase pathway receptors (RET, NTRK1) or pathway intermediary (BRAF); BRAF correlates with more aggressive tumors

Gross: VARIABLE small scarred areas to large, fleshy tumors; circumscribed to infiltrative; 80% are multifocal
Micro: usually papillae, with fibrovascular cores, & epithelial cells with clear (“Orphan Annie eye”) nuclei, nuclear grooves & intranuclear inclusions of cytoplasm, psammoma bodies
Prognosis: Good (worse if extrathyroid extension, male, and >45 years)

Front 39

What is this? How do you know?

Back 39

Papillary carcinoma of thyroid

Micro: usually papillae, with fibrovascular cores, & epithelial cells with clear (“Orphan Annie eye”) nuclei, nuclear grooves & intranuclear inclusions of cytoplasm, psammoma bodies

Front 40

What defines a “papillary carcinoma”?

Back 40

The nuclei define “papillary carcinoma” 

Follicular tumors having the nuclear features of papillary carcinoma are considered “follicular variants of papillary carcinoma” because both show:
Increased lymphatic invasion/metastasis, increased psammoma bodies, decreased mitotic figures, decreased blood vessel invasion, decreased distant metastasis, decreased encapsulation – all features contrasting with follicular carcinomas

Front 41

What is this?

Back 41

Papillary carcinoma of thyroid – note radial arrangement of cells on fibrovascular cores


NOTE:
1. well defined papilla with fibrovascular cores
2. At the periphery of the cores are tumor cells with pale "Orphan Annie Eyes"

Front 42

What is this?

Back 42

Papillary carcinoma of thyroid – note targetoid psammoma bodies



NOTE:
1. well defined papilla with fibrovascular cores
2. At the periphery of the cores are tumor cells with pale "Orphan Annie Eyes"