Endocrine System Flashcards
What histologic features distinguish a pituitary adenoma from normal pituitary gland?
- Cellular monomorphism
2. Absence of a significant reticulin network
Most common cause of hyperpituitarism
Anterior lobe pituitary adenoma
Characteristic mutation in pituitary adenomas
Mutation of the GNAS1 gene which results in constitutive activation of Gs protein
Most common type of hyperfunctioning pituitary adenoma
Prolactinoma
Causes of hyperprolactinemia
Prolactinoma Pregnancy High dose estrogen Renal failure Hypothyroidism Hypothalamic lesions Dopamine inhibiting drugs (reserpine Suprasellar mass (stalk effect)
This pituirary adenoma stain positively with PAS due to accumulation of this protein
Corticotroph cell adenoma
Glycosylated ACTH
Many tumors previously classified as “null cell adenomas” were in fact ___.
Gonadotroph adenomas (These are essentially nonfunctioning tumors.)
How many % of pituitary adenomas are nonfunctioning?
25%
Hypofunctioning of the pituitary occurs with loss of ___% or more of the anterior pituitary parenchyma.
75
Sheehan syndrome does NOT usually affect the posterior pituitary. Why?
The posterior pituitary receives its blood directly from arterial branches and are less susceptible to ischemic injury.
Hypothalamic nuclei that send axons into the posterior pituitary
Paraventricular
Supraoptic
Are the actions of thyroid hormone catabolic or anabolic?
Both.
Catabolic due to upregulation of carbohydrate and lipid catabolism.
Anabolic due to stimulation of protein synthesis.
Causes of thyrotoxicosis but not hyperthyroidism
Subacute granulomatous thyroidits (painful)
Subacute lymphocytic thyroiditis (painless)
Struma ovarii
Factitious thyrotoxicosis
Most common cause of hypothyroidism in areas where iodine levels are sufficient
Hashimoto’s thyroiditis
In Hashimoto’s thyroditis, is the thyroid gland enlarged or atrophic?
Both!
Usually it is diffusely and symmetrically enlarged; but it may be small in the fibrosing variant of this condition.
Middle aged woman comes in with painless enlargement of the thyroid with hypothyroid symptoms. This is most probably?
Hashimoto’s thyroiditis
Patients with Hashimoto’s thyroiditis are at higher risk of developing this malignancy.
B cell non-Hodgkin lymphoma
Histology of thyroid gland reveals disruption of thyroid follicles with extravasation of colloid leading to a polymophonuclear infiltrate. Granulomatous reaction may be seen. What is the cause of this condiiton?
DeQuervain thyroiditis
Probably viral
Postpartal woman comes in with painless mass and signs of thyrotoxicosis. What is this condition? Histologic features?
Subacute lymphocytic thyroiditis
Lymphocytic infiltration and hyperplastic germinal centers (This is an autoimmune condition like Hashimoto’s; absence of Hurthle cell changes and follicular atrophy differentiates this condition from Hashimoto’s.)
Most common cause of endogenous hyperthyroidism
Grave’s disease
HLA haplotypes associated with Grave’s disease
HLA-B8
HLA-DR3
Thyroid antibodies found in Grave’s disese
- Antibodies to the TSH receptor
- Antibodies to thyroglobulin
- Antibodies to thyroid peroxisomes
Antibodies to TSH-R include:
- Thyroid stimulating immunoglobulin (specific for Grave’s)
- Thyroid growth-stimulating Ig
- TSH-binding inhibitor Ig
Why is there ophthalmopathy in Grave’s disease?
- Marked infiltration of the retro-orbital space by mononuclear cells
- Inflammatory edema of EOMs
- Accumulation of ECM components (GAGs)
- Fatty infiltration
Follicular cells are tall, columnar and crowded resulting in the formation of papillae projecting into the lumen; papillae lack fibrovascular cores (vs papillary CA).
Grave’s Disease
Endemic is used when goiters are present in more than >___% of the population.
10
Goitrogenic foods
Brassicaceae (cabbage, cauliflower, Brussel sprouts, turnips)
Excess calcium
How does a colloid goiter form?
TSH induces hypertrophy and hyperplasia of thyroid follicular cells; causing crowded columnar cells which form projections. If the dietary iodine subsequently increases of it the demand for thyroid hormones decrease, the stimulated epithelium involutes to form an enlarged, colloid-rich gland.
Adenomas are characterized by which mutations.
Gain of function mutations in TSH receptor signaling pathways (a-subunit of Gs; or on the TSH-receptor)
Hallmark of all follicular adenoma
Presence of an intact well-formed capsule encircling the tumor
How does one differentiate follicular adenoma from MCAG?
- Well-defined intact capsule
- Single nodule
- Compression of adjacent thyroid parenchyma
- Papillary change NOT a typical feature (presence of papillary change should raise suspicion for CA)
How many percent of cold nodules are malignant?
10%
T/F. An excision biopsy is sufficient for a diagnosis of thyroid CA.
False!
The definitive diagnosis of thyroid adenoma can only be made after careful histologic examination of the resected specimen (check for capsular integrity.)
What is the cell of origin of the following types of thyroid Ca? A. Papillary B. Follicular C. Medullary D. Anaplastic
All derived from follicular epithelium, except for medullary which is derived from parafollicular or C cells.
What genetic alterations are common in: A. Papillary thyroid CA B. Follicular C. Medullary D. Anaplastic
A. Formation of ret/PTC fusion genes which constitutively activate RET
B. RAS and PAX8-PPARY1 fusion
C. RET (but NOT via ret/PTC fusion)
D. p53
Thyroid CA Quiz!
Most common type after exposure to ionizing radiation
Papillary CA
Thyroid CA Quiz!
T/F. The diagnosis of papillary CA requires demonstration of a papillary architecture.
False! Diagnosis is based on nuclear features.
Nuclei with very finely dispersed chromatin
“ground glass / Orphan Annie nuclei”
Thyroid CA Quiz!
Histology reveals tumor composed predominantly or exclusively of follicles. The nuclei of cells contain very finely dispersed chromatin; invaginations of the cytoplasm in cells lead to formation of “pseudoinclusions.”
Papillary!
Although growth pattern is follicular, what matters in the diagnosis is the nuclear features! What was describes was characteristic of papillary CA.
Thyroid CA Quiz!
Concentrically calcified structures present within papillae with dense fibrovascular cores
Papillary
Psammoma bodies were described.
Thyroid CA Quiz!
Hematogenous spread is more common than lymphatic spread
Follicular CA
Thyroid CA Quiz!
Histology reveals fairly uniform cells forming small follicles, reminiscent of normal thyroid.
Follicular CA
Thyroid CA Quiz!
Medullary CA secrete this peptide
Calcitonin
also, somatostatin, serotonin, vasoactive intestinal peptide (may cause diarrhea)
Thyroid CA Quiz!
How many % of medullary CA is associated with familial syndromes
20%
Thyroid CA Quiz!
Necrotic and hemorrhagic mass. Polygonal to spindle-shaped cells forming nests, trabeculae and follicles. Acellular amyloid deposits present in adjacent stroma.
Medullary CA
Thyroid CA Quiz!
What is one histologic feature of familial medullary thyroid CA that differentiates it from sporadic?
Multicentric C cell hyperplasia
Thyroid CA Quiz!
Because of the propensity of medullary thyroid CA to secrete calcinotin, hypocalcemia is a common feature. T/F.
False!
Thyroid CA Quiz!
Elderly patient with long-standing goiter notes rapid growth of the mass.
Anaplastic CA
Thyroid CA Quiz!
T/F. In most cases, medullary CA causes death within one year due to distant metastasis.
False!
Metastases to distant sites are common, but in most cases death occurs in less than 1 year as a result of aggressive local growth and compromise of vital structures in the neck.
How many % of thyroid nodules are neoplastic?
ONE
Most common cause of primary hyperparathyroidism
Adenoma (75 - 80%)
Primary hyperplasia (10 - 15%) Parathyroid carcinoma (<5%)
Primary hyperparathyroidism is seen in:
MEN1
MEN2A
Inactivating mutations in the Ca-sensing receptor on parathyroid cells leading to constitutive PTH secretion
Familial hypocalciuric hypercalcemia
Two common genetic alterations in parathyroid adenoma
- PRAD1 (parathyroid adenoma gene 1) - overexpresses cyclin D1 in PTH gland
- MEN1 (tumor suppressor gene)
T/F. Presence of bizarre and pleomorphic nuclei in parathyroid samples clinch a diagnosis of parathyroid CA.
False. These are common even in adenomas. Mitotic figures are rare in the latter.
Only 2 valid criteria for malignancy of parathyroid glands
- Metastatic dissemination
2. Invasion of surrounding structures
Which of the parathyroid pathologies affect a single gland only? which affects >1 gland?
Parathyroid adenoma and Ca affect only a single gland.
Parathyroid hyperplasia affects > 1 gland.
MOST COMMON CAUSE OF:
- Clinically silent hypercalcemia
- Clinically apparent hypercalcemia in adults
- Primary hyperparathyroidism
2. Malignancy
Most common cause of secondary hyperparathyroidism
Renal failure
Neurologic features of hypocalcemia
Increased ICP
Seizures
Drugs which can cause DM
Glucocorticoids
Thyroid hormone
B-agonists
Infections associated with DM
CMV
Coxsackie B
Genetic syndromes associated with DM
Down syndrome
Klinefelter syndrome
Turner syndrome
Amino acids which stimulate insulin release but not its synthesis
Arginine
Leucine
Clinical features of thyroid nodules that increase likelihood that the lesion is neoplastic
- Solitary
- Young patients
- Males
- History of radiation treatment
- Hot nodules more commonly benign than malignant
Principal susceptibility locus for type 1 DM resides in the region that encodes ___
Class II MHC molecules Chromosome 6p21 (HLA-D)
Risk of developing DM in the population at large
5 - 7%
Best predictor for subsequent progression to diabetes
Insulin resistance
Name three adipocytokines.
Which contributes to insulin sensitivity? which contributes to insulin resistance?
Leptin
Adiponectin
Resistin
RESISTIN = RESISTANCE;
The other two are good guys and increase insulin sensitivity.
How do TZDs (hypoglycemic agents) work?
They act on the nuclear receptor and transcription factor PPAR-Y highly expressed in adipocytes.
- Modulate expression of adipocytokines with the net effect of decreasing insulin resistance
- Decreases concentration of FFAs
How does DM accelerate atherosclerosis?
AGE formation on collagen causes cross-links between polypeptides which may trap plasma proteins. In large vessels, LDL is trapped retarding its efflux from the vessel wall and enhances deposition in the intima.
How does DM cause nephropathy?
Basement membrane is glycated; binding plasma proteins such as albumin; causing basement membrane thickening.
De novo synthesis of this ___ from glycolytic intermediates is stimulated by intracellular hyperglycemia in DM.
Diacylglycerol. This then leads to activation of DAG signal transduction pathway leading to production of:
- Pro-angiogenic proteins (VEGF in neovascularization of DM retinopathy)
- Pro-fibrogenic molecules (TGF-B)
These tissues are insulin-independent in their intracellular uptake of glucose.
Nerves
Lens
Kidneys
Blood vessels
Most common form of monogenic DM is characterized by a mutation in:
HNF-1a (MODY3)
Most common cause of death in DM
MI caused by atherosclerosis of coronary artries
Special pattern of acute pyelonephritis more prevalent in diabetics
Necrotizing papillitis
Most common of the pancreatic endocrine neoplasms
Insulinoma
Boundaries of the gastrinoma triangle
- Junction of cystic and common bile ducts
- Junction of the 2nd and 3rd parts of the duodenum
- Junction of the neck and body of the pancreas
Syndrome consisting of mild diabetes mellitus, necrolytic migratory erythema, and anemia
Glucagonoma
Diabetes mellitus, cholelithiasis, steatorrhea, and hypochloridia
Somatostatinoma
Watery diarrhea, hypokalemia, achlorydia, or WDHA syndrome
VIPoma
Biochemical sine qua non of adrenal Cushing syndrome is:
Elevated cortisol
Low ACTH
Tumor most commonly causing ectopic ACTH secretion
Small cell lung CA
Other (carcinoid tumor, medullary CA, islet cell tumors of the pancreas)
Eosinophilic, laminated cytoplasmic inclusions in cells of the adrenal gland, suggests intake of this drug.
Spironolactone
Treatment of choice for primary adrenal hyperplasia
Medical management with spironolactone. Adrenalectomy no very beenficial
The adrenal cortex secretes the two adrenal hormones.
- Dehydroepiandrosterone
2. Androstenedione
Most common congenital adrenal hyperplasia
21-hydroxylase deficiency (encoded by CYP21B gene)
Patients with congenital adrenal hyperplasia are given:
Glucocorticoids
- Provide adequate glucocorticoid levels
- Suppress ACTH levels
Waterhouse-Friderichsen syndrome is seen in septicemia with ___.
Neisseria meningitidis
Pseudomonas sp
Streptococcus pneumoniae
Haemophilus influenzae
Most common cause of primary adrenal insufficiency in developed counties
Autoimmune adrenalitis
Disseminated infections with these two fungi result in chronic adrenocortical insufficiency.
- Histoplasma capsulatum
2. Coccidioides immitis
Causes of adrenal insufficiency in AIDS patients
- CMV
- MAC
- Kaposi sarcoma
Most metastatic cancers to the adrenals arise from the:
Lung
Breast
How does one differentiate Addison disease from secondary adrenocortical insufficiency?
With secondary disease (parathyroid does not secrete ACTH), there is no hyperpigmentation because melanotropic hormone levels are low.
Two rare causes of adrenal cortical carcinoma
Li-Fraumeni
Beckwith-Wiedemann
Rule of 10s in pheochromocytoma
10% associated with familial syndromes
10% bilateral
10% malignant
10% extra-adrenal
Pheochromocytomas may occur outside of the medulla in these two sites; in these sites, they are called paragangliomas
Organ of Zuckerkandl
Carotid body
Definitive diagnosis of malignancy in pheochromocytomas is based exclusively on:
Presence of mets. Both capsular, vascular invasion, mitotic figures may be present in benign pheochromocytoma.
MEN1 is characterized by lesions in the:
3 P’s
Parathyroid (hyperplasia)
Pancreas (endocrine tumors, e.g. gastrinoma)
Pituitary (most frequently, prolactinoma)
Which MEN is AR? AD?
What are the underlying genetic abnormalities
MEN1: AR. MEN2: AD.
MEN1: MEN1 gene, tumor suppressor (11q13)
MEN2: RET, protooncogene (10q11.2)
Involvement of these two organs is seen in both subtypes of MEN2.
Thyroid: Medullary CA
Adrenal medulla: 50% with pheochromocytomas
Which is unique to MEN2A? MEN2B?
MEN2A: Parathyroid gland hyperplasia
MEN2B: Extraendocrine manifestations
(ganglioneuromas of mucosal sites, marfanoid habitus)
