Guerin: Thyroid Pathology Flashcards
What kind of receptor is the TSH receptor?
-GCPR
What does the thyroid C cell make?
calcitonin
-it secretes it too
What does calcitonins do?
- promotes absorption of calcium by the skeletal system
- inhibits the resorption of bone by osteoclasts
what do thyroid follicular cells produce?
-thyroglobulin
What do the follicular cells convert thyroglobulin into?
-T4 and T3
Which thyroid hormone is more potent?
T3
What does T3 and T4 bind to in circulation?
-thyroxine-binding globulin and transthyretin
What happens to T4 in the periphery?
gets deodinated to T3
-remember that is the more active kind
What are Goitrogens?
chemical agents that inhibit thyroid gland functions
- suppress T3 and 4 synthesis (High TSH)
- hyperplastic enlargement of the thyroid (goiter)
- Propylthiouracil (PTU)
- Idonine
what does PTU do?
- stops thyoid hormone production by inhibiting oxidation of iodine
- also inhibits peripheral deiodination of T4
What does iodine (large doses) do?
-blocks the proteolysis of thyroglobulin thus preventing release of thyroid hormone
What comes first, TRH or TSH?
TRH from the hypothalamus makes the pituitary release TSH… THAT goes to the actual thyroid
What is thyrotoxicosis?
- hypermetabolic state caused by elevated circulating levels of free T3 and T4
- most commonly from hyperthyroidism
What are some of the most common disorders with thyrotoxicosis associated with Hyperthyroidism?
- Diffuse hyperplasia (Graves disease)
- Hyperfunctioning multinodular goiter
- Hyperfunctioning adenoma
What are some clinical manifestations of a hypermetabolic state?
- increase in basal metabolic rate
- heart
- symp nervous system
- eyes
- skeletal system
What happens with the basal metabolic rate?
skin is soft, warm, and flushed because of increased blood flow and peripheral vasodilation
- increases heat loss so heat intolerance is common
- sweating
- weight loss with increased appetite
What happens with the heart?
- tach, palpitations, cardiomegaly common
- arrhythmias, a fib
- congestive heart failure
- thyrotoxic or hyperthyroid cardiomyopathy
What happens because of an overactive symp nervous system?
- Tremor
- Hyperactivity
- Emotional lability
- Anxiety
- Inability to concentrate
- insomnia
- Prox muscle weakness
- hyperstimulation of Gut: diarrhea and malabsorption
What happens with the eyes?
Wide, staring gaze and lid lag
-from symp overstimulation of the superior tarsal muscle
-True thyroid ophthalmopathy associated with proptosis occurs only in Graves disease
What happens with the skeletal system?
- Thyroid hormone stimulates bone resorption
- Atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates
What is Thyroid storm?
- abrupt onset of severe hyperthyroidism
- underlying graves disease
- acute elevation in catecholamine levels
- febrile and tachycardic
- medical emergency: cardiac arrhythmias
Apethetic Hyperthyroidism
- thyrotoxicosis in older adults
- advanced age and co-morbidities may blunt features that typically bring younger patients to attention
- Diagnosis is often made during lab work-up for unexplained weight loss or worsening CV disease
Lab findings for Apethetic hyperthyroidism
- Serum TSH concentration: most useful single screening test… low
- confirmed with free T4… increased
What excludes secondary hyperthyroidism?
-a normal rise in TSH after administration of TRH
What can help us determine the etiology of hyperthyroidism?
Radioactive Iodine
- duffusely increased uptake in the whole gland (Graves disease)
- Increased uptake in a solitary nodule (toxic adenoma)
- Decreased uptake (thyroiditis)
Tx of hyperthyroidism?
- B blocker
- thionamide to block new hormone synthesis
- Iodine soln to block the release of thyroid hormone
- agents that inhibit peripheral conversion of T4 to T3
- Radioiodine: incorporate into thyroid tissues…. ablation of thyroid function
IF someone comes in and it looks like they have hyperthyroidism, what is the best test to order?
- TSH
- if it’s low, then it’s hyperthyroidism
- confirm with free T4 test
Hypothyroidism
- W»»M
- can be accompanied by “goiter”
Causes of hypothyroidism?
- HAshimoto thyroiditis (autoimmune)
- Iodine deficiency
What is Cretinism?
- hypothyroidism in infancy or early childhood
- found where dietar iodine deficiency is endemic
- Rarely from dyshormonogenetic goiter
- maternal T3 and T4 cross the placenta and are citical for fetal brain development
Clinical features of Cretinism?
- severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia
- if maternal deficiency before fetal thyroid development
Myxedema: Hypothyroidism in older child or adult
- insidious
- decreased symp activity: constipation and sweating
- increased cholesterol and LDL levels
- large tongue
- deepening of voice
- intolerance to cold (remember that hyperthyroid is intolerant to heat)
- nonpitting edema (there it is ;) )
Testing for hypothyroidism
- serum TSH level: most sensitive screening test
- T4 levels: decreased
How are the TSH levels in primary hypothyroidism?
-increased
TSH levels in secondary hypothyroidism?
-not increased
Thyroiditis
inflammation of the thyroid gland
Hashimoto Thyroiditis
- most common cause of hypothyroidism in areas where iodine levels are sufficient
- autoimmune destruction of the thyroid gland
- Autoantibodies
- Strong genetic component: CTLA4 and PTPN22
Pathology of Hashimoto
- large thyroid
- prominent mononuclear inflammatory infiltrate
- thyroid follicles are atrophic/lost
- Areas with Hurthle cell metaplasia
- fibrosis
clinical course of hashimoto?
- most often comes to clinical attention as painless enlargement of the thyroid
- typically with hypothyroidism
- in some pts, hypothyroidism is preceded by transient thyrotoxicosis: disruption of thyroid follicles leads to release of thyroid hormones
- increased risk of developing other AI diseases
- marginal zone B-cell lymphomas increased risk
Lab values in that transient thyrotoxicosis
- free T3 and 4 is elevated
- TSH in low
- radioactive idoine uptake is decreased
Subacute lymphocytic Thyroiditis
- painless
- mild hypERthyroidism and/or goitrous enlargement
- most common in middle-aged pts
- W>M
- Postpartum thyroiditis: 5 % women postpartum
- variant of AI thyroiditis
- 1/3 evolve into hypothyroidism
Histology of Subacute lymphocytic thyroiditis
- lymphocytic infiltration with large germinal centers
- patchy disruption and collapse of thyroid follicles
- No fibrosis or Hurthle cell metaplasia
How do we differentiate between subacute lymphocytic thyroiditis and Hashimoto thyroiditis?
-There’s no hurthle cell metaplasia in Subacute lymphocytic thyroiditis
Granulomatous thyroiditis
-aka De Quervain thyroiditis
- 40 to 50 years
- W>M
- URI just before onset of thyroiditis
- seasonal incidence… occurrences peaking in the summer
- self limited
Morphology of granulomatous thyroiditis?
- unilaterally or bilaterally enlarged and firm
- capsule is intact, but may be stuck to surround structures
- histology can be patchy
- different histologic stages are sometimes found in the same gland, suggesting waves of destruction over a period of time
clinical course of Granulomaous thyroiditis?
- most common cause of thyroid pain
- variable enlargement of thyroid
- inflammation and thus hyperthyroidism are transient
- high serum T4 and T3 levels and low serum TSH levels
- radioactive iodine uptake is diminished, unlike Graves disease
Riedel Thyroiditis
- rare
- Extensive fibrosis of the thyroid and surrounding structures: clinically mimicis thyroid carcinoma
- a form of systemic AI IgG4-related sclerosing disease
Graves Disease
- most common cause of endogenous hyperthyroidism
- triad of clinical findings:
1. ) hyperthyroidism associated with diffuse enlargement of the gland
2. ) infiltrative ophthalmopathy with resultant exophthalmos
3. ) Localized, infiltrative dermopathy, sometimes called pretibial myxedema (only in a minority of patients)
Pathogenesis of Graves disease
- AI
- 90% of pts have thyroid-stimulating immunoglobulin (TSI)… most important and specific one
- genetic susceptibility linked to polymorphisms in immune-function genes like CTLA4 and PTPN22 and the HLA-DR3 allele
Graves Ophthalmopathy
- AI plays a role
- appears that orbital preadipocyte fibroblasts express the TSH receptor
- protrusion of the eyeball!
Morphology of graves disease
- thyroid gland is symmetrically enlarged
- diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells
- follicular cells are tall and more crowded
- colloid is pale with scalloped margins
- inflammatory infiltrates of lymphocytes and plasma cells
Sx that are uniquely with Graves disease
- diffuse hyperplasia of the thyroid, opthalmopathy, and dermopathy
- increased blood flow thorugh the hyperactive gland can produce an audible “bruit”
What can persist after the treatment?
exophthalmos
Lab and radiology findings of graves disease?
- low TSH levels
- high free T4 and T3
- radioiodine scans show a diffusely increased uptake
Tx of graves disease
- B blockers
- decrease thyroid hormone synthesis with: thionamide, radioiodine ablation, thyroidectomy
- surgery typically only those with large goiters that are compressing surrounding structures
Diffuse and multinodular Goiters
- enlargement of thyroid
- caused by impaired synth of thyroid hormone: most often result of iodine deficiency
- Impairment of thyroid hormone synth….rise in serum TSH… hypertrophy and hyperplasia of thyroid follicular cells… gross enlargement of the thyroid gland
- euthyroid state in most
- degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency
What do we call it when the compensation isn’t enough?
goitrous hypothyroidism
Diffuse nontoxic (simple) Goiter
- enlargement of the entire gland without nodularity
- endemic or sporadic
Endemic goiter
- low levels of iodine
- mountainous areas of the world
- Lack of iodine… idecreased synth of thyroid hormone… increased TSH…. follicular cell hypertrophy and hyperplasia… goitrous enlargement
Sporadic Goiter
- F»>M
- peaks at puberty or in young adult life
- caused by ingestion of substances that interfere with thyroid hormone synth
- hereditary enzymatic defects that interfere with thyroid hormone synthesis
- mostly unknown
clinical course of goiter
- majority are euthyroid
- Although TSH is usually elevated (T3 and T4 levels are normal)
- symptoms are from mass effects
Multinodular goiter
- simple goiter…. multinodular goiter
- recurrent episodes of hyperplasia and involuteion
- virtually all long-standing simple goiters convert into multinodular goiters
- produces the most pronounced thyroid enlargements
- can be mistaken for neoplasms
- occur in both sporadic and endemic forms
clinical course of multinodular goiter
- most symptoms are from mass effects
- most pts are euthyroid
What is plummer syndrome
Workup for multinodular goiter
- radioiodine scan
- uneven iodine uptake and sometimes a “hot” nodule
- from an admixture of hyperplastic and involuting nodules
- A fine needle aspiration can be helpful in evaluating a dominant nodule
- hyperplasia vs. neoplasm
How many solitary thyroid nodules are malignant?
<1%
-people with a lot of money are cancer….
What makes a thyroid nodule more likely to be neoplastic?
- solitary nodules
- nodules in younger patients
- nodules in males
- hx of radiation to the head and neck
What make a thyroid nodule more likely to be benign?
- multiiple nodules
- nodules in older patients
- nodules in females
- functional nodules that take up radioactive iodine (hot nodules)
Follicular adenomas
- discrete, solitary masses
- present as unilateral painless masses discovered during routine physical examination
- larger masses may produce symptoms
- nonfunctional ingeneral
morphology of follicular adenomas
- solitary, spherical, encapsulated lesion
- made up of uniform-appearing follicles that typically contain colloid
- cells uniform and bland
- occasionally the cells have eosinophilic, granular cytoplasm (Hurthle cell change)… also in hashimotos
What is the key to distinguishing between a follicular adenoma and follicular carcinoma?
-integrity of the capsule!!!
Diagnosis of follicular cell adenoma
- Radionuclide scan: cold nodules that don’t take up as much iodine
- Ultrasonography and fine-needle aspiration
- ultimately need to evaluate capsule for a definitive diagnosis
- capsule is evaluated grossly and histologically to exclude carcinoma
Thyroid Carcinomas
- ionizing radiation exposure
- dietary iodine deficiency is linked with a higher frequency of follicular carcinomas
What is the most common type of thyroid carcinoma?
papillary carcinoma (85%)
- then follicular
- anaplastic
- medullary
What is the adverse prognostic indicator for thyroid carcinoma?
-BRAF
Papillary carcinoma
- most common form of thyroid cancer (85%)
- peaks at 25-50 yrs, but can occur at any age
Morphology of papillary carcinoma
- solitary or multifocal
- areas of fibrosis and calcification
- cystic
- Nuclei are large and overlapping, nuclear groove, invaginations of the cytoplasm gives the appearance of intranuclear inclusions (pseudo-inclusions)
What is the key for diagnosis of papillary carcinomas?
- Nuclei
- large and overlapping
- nuclear groove
- orphan annie eye nuclei
- Invaginations of the cytoplasm gives the appearance of intranuclear inclusions… pseudoinclusions
Follicular variant of PTC (papillary thyroid carcinoma)
- follicular rchitecture
- can be encapsulated (better prognosis) or poorly circumscribed and infiltrative
Tall-cell variant of PTC
- tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures
- older=worse prognosis
- BRAF mutations in most cases (worse prognosis)
- Often also have RET/PTC translocations
clinical presentation of Papillary thyroid carcinoma
- asymptomatic thyroid nodules
- mass in cervical lymp node sometimes
- distant mets…. lung
- more advanced disease can have hoarseness, dysphagia, cough, or dyspnea
Diagnosis of PTC
- radionuclide scanning: cold nodules… not taking up iodine
- Fine needle aspiration cytology: can be diagnostic if nuclear features are present
Tx of PTC
- thyroidectomy
- radioactive iodine or external radiation
- chemo, hormone, and trageted therapy
- excellent prognosis
- 10 yr survival rate
Follicular Carcinoma
- 5-15% of thyroid cancers
- more frequent in areas with dietary iodine deficiency
- W>M
- More often in older patients than papillary carcinomas… peaks 40-60 years
Morphology of follicular carcinoma
- single nodules that may be well circumscribed or widely infiltrative
- sharply demarcated lesions are very difficult to distinguish from follicular adenomas… may require examining the entire capsule microscopically to find invasioin
- small follicles with colloid with uniform cells
- Hurthle cell variant: cells with abundant granular, eosinophilic cytoplasm
- *****nuclei lack the features typical of papillary carcinoma
How to tell between follicular adenoma vs follicular carcinoma?
-capsular and/or vascular invasion (beyond the capsule)
Clinical course of follicular carcinoma
- presents as slowly growing painless nodules
- typically cold nodules on scnitigrams
- dont invade lympatics, so lymph nodes are rarely involved
- Vascular hematogenous dissemination
- prognosis depends on the extent of invasion and stage at presentation
Tx of follicular carcinoma
- total thyroidectomy followed by the radioactive iodine
- also treated with thyroid hormone to suppress endogenous TSH levels
- residual follicular carcinoma may respond to TSH stimulation
- Serum thyroglobulin levels are used for monitoring tumor recurrence
Anaplastic Carcinoma
- undifferentiated tumors of the thyroid follicular epithelium
- highly aggressive; mortality rate essentially 100%
- 65 y/o
- arise de novo, or by “dedifferentiation” of a well-differentiated papillary or follicular carcinoma
clinical course of anaplastic Carcinoma
- rapidly enlarging bulky neck mass
- sx of dyspnea, dysphagia, hoarseness, and cough
- no effective therapies
- death usually from aggressive growth and compromise of vital structures in the neck
Medullary Carcinoma
- neuroendrocrine neoplasms derived from the parafollicular cells (C cells)
- Secrete calcitonin
- tumors also sometimes secrete other hormones
- 70% are sporadic, 30 familial (MEN 2A or 2B)
Genetics of medullary carcinoma
- Familial form associated with germline RET mutations
- RET mutations are also seen in ~1/2 sporadic
Morphology of medullary carcinoma
- sporadic: solitary nodule
- familial: often found bilaterally with multiple foci
- tumor cells + for calcitonin by immunohistochemistry
- Amyloid deposits are present in the stroma
- familial medullary cancers: multicentric C-cell hyperplasia in the surrounding thyroid parenchyma
Presentation of sporadic Medullary carcinoma
- mass in neck
- some cases present with paraneoplastic syndrome caused by secretion of a hormone
- ***hypocalcemia is not a prominent feature, even though calcitonin levels are elevated
- cacinoembryonic antigen (CEA) is also secreted by many tumors… so that’s a useful tumor marker for disease burden and follow-up
Presentation of familial medullary carcinoma
- symptoms localized to the thyroid
- endocrine neoplasms in other organs
- medullary carcinomas in MEDN-2B pts are generally more aggressive (so they’re offered prophylactic thyroidectomy)
Thyroglossal duct Cyst
- congenital anomaly
- vestige of tubular thyroid leading to a persistent sinus tract
- parts of the tube remain to form cysts
- may not become evident until adulthood
- cysts can collect mucinous, clear secretions
- midline of the neck (anterior to the trachea)
- epithelium with an intense lympocytic infiltrate
- can become infected and form abscess cavities
- rarely give rise to cancers
What kind of epithelium is lining a thyroglossal duct cyst located high in the neck?
-lined by stratified squamous epithelium
What about the lower neck?
-lined by epithelium resembling the thyroidal acinar epithelium
