Lecture 4: Thyroid Pathology Flashcards
How do patients with thyroid storm typically present; if left untreated what is a common cause of death?
- Febrile and present w/ tachycardia out of proportion to the fever
- Death due to cardiac arrhythmias
What is the MOA of the antithyroid agent, propylthiouracil?
- Inhibits the oxidation of iodide and thus blocks production of thyroid hormone
- Also inhibits the peripheral deiodination of circulating T4 into T3
How does large doses of iodide given to an individual act as a goitrogen?
Blocks release of thyroid hormones by inhibiting the proteolysis of thyroglobulin
Inborn errors of thyroid metabolism causing congenital hypothyroidism is known as what?
Dyshormonogenetic goiter
What is the most common cause of hypothyroidism in iodine-sufficient areas of the world?
Autoimmune hypothyroidism i.e., Hashimoto thyroiditis
Which circulating autoantibodies are seen in association with Hashimoto Thyroiditis?
- anti-thyroid peroxidase (TPO)
- anti-thyroglobulin
What are the clinical features of Cretinism?
- Mental retardation
- Short stature
- Coarse facial features
- Protruding tongue
- Umbilical hernia
What are 2 possible causes of Cretinism?
- Areas w/o iodine supplementation
- Result of genetic alterations in normal thyroid metabolic pathways i.e., dyshormonogenetic goiter
The term Myxedema is applied to what situation?
Hypothyroidism developing in older children or adults
Histologically there is an accumulation of what in Myxedema; leads to what clinical findings?
- Matrix substances, such as glycosaminoglycans and hyaluronic acid in skin, subcutaneous tissue, and some visceral sites
- Leads to nonpitting edema, a broadening and coarsening of facial features, enlarged tongue, and deepening of the voice
Measurement of what in the serum is the best screeing test for both hyper- and hypothyroidism?
Serum TSH
What will levels of TSH be like in pt with primary hypothyroidism and primary hyperthyroidism?
- Primary hypothyroidism = ↑↑↑ TSH
- Primary hyperthyroidism = ↓↓↓ TSH
What is a major cause of nonendemic goiter in the pediatric population?
Hashimoto Thyroiditis
Polymorphisms in which immune-regulation associated genes are implicated in Hashimoto Thyroiditis?
CTLA4 and PTPN22
In Hashimoto Thyroiditis there is diffuse enlargement of the thyroid which is (painful or painless)?
Painless
In Hashimoto Thyroiditis there is extensive infiltration of the parenchyma by what cells and also the development of well-developed what?
- Mononuclear inflammatory infiltrate
- Well-developed germinal centers
What characteristic cell type is seen as part of the metaplastic response to injury in Hashimoto Thyroiditis?
Hurthle cells = atrophic follicle cells w/ eosinophilic change + granular cytoplasm
The presence of what in fine-needle aspiration biopsy samples is characteristic of Hashimoto Thyroiditis?
Hurthle cells + heterogenous population of lymphocytes
How does the fibrosis seen in Hashimoto’s differ from Reidel Thyroiditis?
In Hashimoto’s the fibrosis does NOT extend beyond the capsule of the gland
In the case of Hashitoxicosis what is seen with levels of free T3 and T4, TSH, and radioactive iodine uptake?
- T3 and T4 levels are elevated
- TSH is diminshed
- Radioactive iodine uptake is decreased
Patients with Hashimoto Thyroiditis are at an increased risk of developing what malignancy within the thyroid gland?
Extranodal marginal zone B-cell lymphoma
Although similar in presentation to Hashimoto’s what morphological features are not as prominent in Subacute Lymphocytic Thyroiditis?
Fibrosis and Hurthle cell metaplasia are NOT prominent
Granulomatous Thyroiditis (De Quervain) is thought to be triggered by what?
Viral infection (i.e., hx of URI just before onset of sx’s)
What histological findings are associated with Subacute thyroiditis (de Quervain)?
- Granulomatous inflammation w/ multinucleate giant cells
- Initially has more neutrophilic infiltrate w/ microabscess formation; then replaced by a more generalized inflammatory infiltrate with macrophages and multinucleated giant cells
Granulomatous thyroiditis (De Quervain) will present with what sized thyroid and other distinguishing feature?
Variably enlarged thyroid that is PAINFUL!
What is the typical course of Granulomatous Thyroiditis (De Quervain)?
- Transient inflammation of thyroid, usually diminishing within 2-6 weeks = Self-limited!
- After recovery, normal thyroid function restored within 6-8 weeks
Riedel thyroiditis is characterized by replacement of thyroid tissue with what and has what type of infiltrate?
Extensive fibrosis of the thyroid and neck structures w/ tissue infiltration by lymphocytes and plasma cells
Riedel thyroiditis is considered a manifestation of _______ related systemic disease, which includes autoimmune pancreatitis, retroperitoneal fibrosis, and noninfectious aortitis
IgG4-related disease
Riedel thyroiditis presents as a ________ (consistency) and _________ (painful/painless) goiter
Riedel thyroiditis presents as hard as wood/cement and painless goiter
Subacute lymphocytic thyroiditis often occurs in association with what?
After a pregnancy (postpartum thyroiditis)
Although not always present, what is the classic triad of Graves disease?
- Hyperthyroidism w/ gland enlargement = Diffuse hyperplasia
- Infiltrative ophthalmopathy –> exophthalmos
- Pretibial myxedema
Peak incidence of Graves disease is btw what ages; which sex is 10x more affected?
20-40 y/o and 10x more common in women
What is the most common antibody subtype seen in Graves disease?
Thyroid stimulating immunoglobulin (TSI)
What HLA subtypes are associated with Graves disease?
HLA-DR3 and B8
What are the levels of TSH like in Graves Disease?
LOW
The exopthalmos associated with Graves Disease is caused by what underlying process?
- Infiltration of retroorbital space by T cells
- Fibroblasts have TSH receptor and proliferate
- EOM swelling from edema + inflammation
- Accumulation of EC matrix components i.e., GAG and chondroitin sulfate
- ↑ number and expansion of adipocytes
The exopthalmos associated w/ Graves disease appears to stem from activation of which cells in the orbit and via which receptor?
Orbital preadipocyte fibroblasts expressing TSH receptors
Diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells is characteristic of what?
Graves Disease
What is a histological characteristic of the follicular epithelial cells in untreated Graves Disease?
Taller and more crowded –> formation of small papillae which project into the follicular lumen and encroach on the colloid
How do the papillae seen in graves disease differ histologically from those of papillary carcinoma?
Lack fibrovascular cores
What feature of the colloid is a characteristic histological finding in Graves disease?
Scalloped margins of colloid
How does pre-operative therapy with iodine vs. propylthiouracil alter the morphology of the thyroid in Graves Disease?
- Iodine causes involution of the epithelium and accumulation of colloid
- Propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia
Radioiodine scans of pt with Graves Disease will show what?
Diffusely ↑↑↑ uptake of iodine
Diffuse nontoxic (simple) goiter causes enlargement of the entire gland without producing what?
Nodularity
Toxic multinodular goiter is most often due to _________ mutations
Toxic multinodular goiter is most often due to TSH receptor mutations
What are some of the goitrogens that when ingested in large quantities may lead to the endemic form of diffuse nontoxic goiter?
- Cassava root (thiocyanate)
- Brassicaceae (i.e., cabbage, cauliflower, brussel sprouts, turnips..)
What are the 2 phases identified in the evolution of diffuse nontoxic goiter?
- Hyperplastic phase
- Phase of colloid involution
The clinical manifestations of diffuse nontoxic (simple) goiters are most often due to what?
Mass effect as most pt’s are clinically euthyroid (normal T3 and T4)
Virtually all long-standing simple goiters convert into what?
Multinodular goiters
Which type of goiter produces the most extreme enlargements and are more frequently mistaken for neoplasms than any other thyroid disease?
Multinodular goiters
What morphological feature is missing from multinodular goiters which is distinct from follicular neoplasms?
A prominent capsule is NOT present
Older lesions of multinodular goiter show what histological change?
Areas of hemorrhage, fibrosis, calcification, and cystic change
What are some of the signs/sx’s which can be produced by mass effect of both simple and multinodular goiters?
- Dysphagia
- Hoarsness
- Stridor
- SVC syndrome
When an autonomous nodule develops within a long-standing multinodular goiter and produced hyperthyroidism this is known as what?
Toxic multinodular goiter (aka Plummer syndrome)
How is a toxic multinodular goiter (plummer syndrome) distinct from Graves?
Does not produce infiltrative opthalmopathy and dermopathy
What are the levels of T3 and T4 + TSH like in older pt (>55 y/o) with multinodular goiter?
- ↑ T3 and T4
- ↓ TSH
Which type of nodule is more likely to be neoplastic (cold or hot)?
Cold nodules
Thyroid nodules in which age group and sex are more likely to be neoplastic?
Younger pt’s and males
What morphological features are the hallmark of all follicular adenomas and are important for making the distinction from multinodular goiters?
Solitary, spherical, encapsulated lesion demarcated from surrounding thyroid parenchyma by well-defined, intact capsule
Careful evaluation of what morphological feature of follicular adenomas is important for making the distinction from follicular carcinomas?
Integrity of the capsule; should be intact (not invaded)
Definitive diagnosis of thyroid adenomas can be made only after what?
Careful histologic examination of the resected specimen
Thyroid papillary carcinomas are associated with gain-of-function mutations in which genes?
- RET or NTRK1RTK’s
- serine/threonine kinase BRAF
What are the 2 most common fusion partners of RET observed in sporadic papillary cancers?
PTC1 and PTC2
Presence of which mutation in papillary carcinomas correlates with adverse prognostic factors like metastatic disease and extrathyroidal extension?
BRAF
Follicular thyroid carcinomas are associated with gain-of-function mutations in which genes or loss-of-function in?
- G.O.F = RAS or PIK3CA
- L.O.F = PTEN
Which unique fusion gene product is seen in a minority of follicular carcinomas?
PAX8-PPARG
Both familial and sporadic medullary thyroid carcinomas are associated with germline mutations in what gene; what chromosome?
RET on chromosme 10
What is the major enviornmental risk factor predisposing to thyroid cancer?
Exposure to ionizing radiation, especially during the first 2 decades of life
Deficiency of dietary iodine is linked with higher frequencies of what type of thyroid cancer?
Follicular carcinomas
Between what ages is the highest prevalence of papillary thyroid carcinoma?
25-50 y/o
Which malignancy of the thyroid accounts for the majority of thyroid carcinomas associated with ionizing radiation?
Papillary carcinoma
When present, how do the papillae of papillary carcinoma differ from those seen in areas of hyperplasia?
Are more complex and have dense fibrovascular cores
What are the hallmark morphological features of the nuclei of thyroid papillary carcinomas?
- Optically clear or empty appearance
- Ground-glass or Orphan Annie eye nuclei
The diagnosis of thyroid papillary carcinomas can be made based on what morphological features?
NUCLEAR features, even in absence of papillary architecture
Which morphological feature seen on FNA is unique to thyroid papillary carcinoma and is almost never seen in follicular and medullary carcinomas?
Concentrically calcified structures, Psammoma bodies
Metastasis of thyroid papillary carcinoma to which LN’s is seen in up to 50% of cases?
Cervical LN’s
Which variant of papillary carcinoma has nuclear features of papillary carcinoma and an almost totally follicular architecture?
Follicular variant
The follicular variant of papillary carcinoma has a higher frequency of mutations in which gene?
RAS
Follicular variant papillary carcinomas can be either encapsulated or poorly circumscribed; which has a better prognosis?
Encapsulated
The follicular variant of papillary carcinoma has a higher propensity for spread how?
Angioinvasion
Which thyroid papillary carcinoma variant is more commonly seen in older patients and tends to follow a more aggressive course?
Tall-cell variant
Tall-cell variant of papillary carcinomas most often harbor which mutations?
- BRAF
- RET/PTC translocations
Which thyroid papillary carcinoma variant occurs in younger pt’s, including children?
Diffuse sclerosing variant
The diffuse slcerosing variant of papillary carcinoma is often associated with a prominent lymphocytic infiltrate, simulating what other disease of the thyroid?
Hashimoto thyroiditis
Metastases to where are seen in almost all cases of the diffuse sclerosing variant of papillary carcinoma?
Lymph node metatases
What is often the first manifestation calling attention to a thyroid papillary carcinoma?
Mass in cervical LN
Which sx’s associated with thyroid papillary carcinoma suggest more advanced disease?
Hoarsness, dysphagia, cough, or dyspnea
Some patients with thyroid papillary carcinoma will have hematogenous spread; which organ is most commonly affected?
Lung
What is the prognosis (10-year survival) of papillary thyroid carcinomas?
Excellent; 10-year survival >95%
What factors is the prognosis of papillary thyroid cancers dependent on?
- Age (less favorable in those >40 y/o)
- Presence of extrathyroidal extension
- Presence of distal metastases (stage)
What are 2 therapeutic options for papillary thyroid carcinoma?
- Surgery
- Radioactive iodine (I131)
Peak incidence of follicular thyroid carcinomas is btw what ages?
40-60 y/o
How is the distinction between follicular adenomas and minimally invasive follicular carcinomas made?
Extensive histo sampling of tumor-capsule thyroid interace to exclude capsular and/or vascular invasion
Metastasis from follicular carcinoma is most often via which route and to which sites?
- Hematogenous –> angioinvasion
- Bone, lung, and liver = common
Most follicular carcinomas are treated how?
Total thyroidectomy followed by radioactive iodine
Serum levels of what are used for monitoring follicular carcinoma recurrence?
Serum thyroglobulin; as should be barely detectable
Anaplastic (undifferentiated) thyroid carcinoma tend to occur most often in whom?
Elderly pt’s
What is the prognosis of anaplastic (undifferentiated) thyroid carcinoma; most common cause of death?
- Highly aggressive w/ almost 100% mortality within one year
- Death from compromise of vital structures in the neck (mass effect)
Microscopically anaplastic (undifferentiated) thyroid carcinomas can have what 3 variable types of morphology and cells?
1) Large, pleomorphic giant cells
2) Spindle cells w/ a sarcomatous appearance
3) Mixed spindle and giant cells
The neoplastic cells of anaplastic (undifferentiated) thyroid carcinoma express which epithelial marker and are negative for which marker of thyroid differentiation?
- (+) cytokeratin
- (-) thyroglobulin
How do anaplastic (undifferentiated) thyroid carcinomas most often present clinically; what signs/sx’s?
- Rapidly enlarging bulky mass in neck
- Sx’s such as: cough, dyspnea, hoarsness,anddysphagia
Anaplastic (undifferentiated) thyroid carcinoma is associated with inactivating mutations of what?
TP53
Which variant of follicular thyroid carcinoma is dominated by cells with abundant granular, eosinophilic cytoplasm?
Hurthle cell or oncocytic variant
Since medullary thyroid carcinomas are neuroendocrine neoplasms, the tumor cells may elaborate what polypeptide hormones?
- Calcitonin (always)
- Serotonin
- ACTH
- VIP
Medullary thyroid carcinomas may arise in what 3 ways?
- Sporadic MTC
- Familial (FMTC)
- Associated with MEN types 2A and 2B
When do medullary thyroid carcinomas associated with MEN 2A or 2B arise vs. those that are sporadic or familial?
- MEN 2A/2B arise in younger pt’s; may be during first decade
- Sporadic and familial arise in adulthood w/ peak incidence of 40-50 y/o
Which type of medullary thyroid carcinoma presents as a unifocal solitary nodule?
Sporadic MTC
Which medullary thyroid carcinoma presents with bilaterality and multicentricity?
Familial MTC
Which morphological feature present in familial medullary thyroid cancers is believed to be a precursor lesion?
Multicentric C-cell hyperplasia
Misfolded calcitonin polypeptides are often seen deposited in the stroma of medullary thyroid carcinomas as what; can be stained how?
- Amyloid deposits (A Cal)
- Congo Red Stain —> “Apple-green” birefringence
Blue cells with dispersed chromatin admixed with deposits of amyloid is characteristic of what thyroid neoplasm?
Medullary thyroid carcinom
The presence of multiple prominent clusters of C cells scattered thoughout the parenchyma of a medullary thyroid carcinoma should raise suspicion for what?
An inherited predisposition EVEN if a family hx is not present
Is hypocalcemia a prominent feature of sporadic medullary thyroid carcinomas?
NO
Which biomarker is useful in the presurgical assessment of tumor load and in calcitonin-negative medullary thyroid carcinomas?
Carcinoembryonic antigen
Medullary carcinomas arising in which setting are generally more aggressive and metastasize more frequently?
MEN-2B
Asymptomatic MEN-2 patients with germline RET mutations are offered what?
Prophylactic thyroidectomy as early as possible
Medullary thyroid carcinomas arising in which setting have the best prognosis of all forms?
Familial MTC
