Pathology of the Parathyroid and Adrenal Glands

Question 1

What are the two types of cells found in the parathyroid glands and which one is active?

Answer 1

Chief cells - cells with pale cytoplasm -> active

Oxyphil cells - cells with eosinophilic cytoplasm -> inactive

Question 2

What mutations give rise to sporadic parathyroid adenoma? Familial causes?

Answer 2

Sporadic: Usually a mutation and inactive of MEN1 (two hits sporadically)

Familial: Also associated with autosomal dominant loss of MEN1, and a second hit

Question 3

What mutations are associated with familial primary hyperparathyroidism (including parathyroid adenomas)?

Answer 3

1. MEN1 - autosomal dominant -> parathyroid adenoma
2. RET - MEN2A -> parathyroid hyperplasia by constitutive activation of tyrosine kinase
3. CaSR - loss of function mutation -> hypercalcemic hypocalciuria

Question 4

How is a parathyroid adenoma vs parathyroid carcinoma told apart histologically?

Answer 4

Much like for follicular adenoma of the thyroid, pretty much you need to see evidence of invasion or metastatic disease

• > parathyroid carcinoma remains well differentiated
• > much rarer condition than adenoma

Question 5

Does hyperparathyroidism cause osteoporosis or osteopenia? What’s the difference?

Answer 5

Osteopenia -> cortical thinning which is more prominent than in the medullary cavity. Especially subperiosteal thinning. Related to increased osteoclast activity with an attempted osteoblast rescue.

Osteoporosis happens more in spongy bone, typically a slow wasting away not due to massively increased osteoclast activity

Question 6

What is the end stage of hyperparathyroidism called and why?

Answer 6

Osteitis fibrosa cystica

Osteitis -> osteoclasts dissect through bone, causing fractures and bone pain. “-itis” because osteoclasts derived from monocytes.

Fibrosa -> marrow fibrosis and secondary reactive woven bone formation by osteoblasts (derived from osteoprogenitor cells, same precursor as fibroblasts)

Cystic -> formation of brown tumors

Question 7

What are brown tumors?

Answer 7

The cystic lesions found in osteitis fibrosa cystica

• > areas of hemorrhage, hemosiderin-laden macrophages, granulation tissue, and microfractures
• > osteoclasts have chewed a big gap into the bone

Question 8

What is the most common cause of secondary hyperparathyroidism and what is seen in the parathyroid glands in this condition?

Answer 8

Chronic kidney disease -> low Ca+2 levels from high serum phosphate and low vitamin D

Chief cell hyperplasia -> hyperplasia of multiple parathyroid glands

Question 9

What do the layers of the adrenal cortex look like histologically?

Answer 9

Glomerulosa - narrow layer of clear, vacuolated cells

Fasciculata - thick,middle layer of slighty more clear cells

Reticularis - narrower layer of eosinophilic cells

Question 10

Is exogenous or endogenous Cushing syndrome more common? What is the most common endogenous cause and what can be seen in the adrenal glands in this pathology?

Answer 10

Exogenous (iatrogenic) is most common

Endogenous cause - Cushing disease -> bilateral adrenal cortical hyperplasia (increased ACTH)

Question 11

What are the three possible causes of ACTH independent Cushing syndrome?

Answer 11

Primary gland problems:

1. Adrenal cortical adenoma
2. Adrenal cortical carcinoma
3. Primary adrenal cortical hyperplasia -> could be due to overexpression of non-ACTH hormones

Question 12

What change is seen pathologically in the pituitary as a result of increased circulating cortisol? Which cells experience it?

Answer 12

“Crooke hyaline change”

• > degenerative change in ACTH-producing cells in anterior pituitary
• > cytoplasmic keratin filament accumulation -> eosinophilic. Looks a bit like Hirano bodies

-> This change will occur in all cells not secreting any ACTH (atrophic), i.e. the entire pituitary in primary adrenal hyperplasia, or the non-pathologic areas of the pituitary in Cushing’s disease.

Question 13

How will the adrenal cortex look in adrenal cortical neoplasm?

Answer 13

Adenoma / carcinoma part will be enlarged, thickened, and yellow

All non-neoplastic parts will undergo atrophy due to negative feedback on ACTH and lack of stimulation

Question 14

What is the most comm cause of primary hyperaldosteronism?

Answer 14

Bilateral idiopathic hyperaldosteronism -> diffuse adrenal cortical hyperplasia most prominent at periphery (where zona glomerulosa is)

Question 15

What is Conn syndrome specifically?

Answer 15

An adrenal adenoma which secretes aldosterone

Would not include aldosterone-producing adrenal carcinoma

Question 16

What type of hyperaldosteronism can be treated with glucocorticoids?

Answer 16

Glucocorticoid-remediable aldosteronism (GRA)

• > a autosomal dominant familial condition in which aldosterone synthase responds to ACTH
• > Dexamethasone suppresses ACTH

Question 17

Is the non-neoplastic adrenal cortex thicker in Conn syndrome or adrenal cortical neoplasm?

Answer 17

Thicker in Conn syndrome -> all ACTH dependent areas of the cortex remain thick

Question 18

Is it more likely to have a benign or malignant cortical neoplasm which produces androgens?

Answer 18

Malignant -> carcinoma

Both conditions are very rare, but if a cortical neoplasm is making androgens, it’s more often malignant

Question 19

How does the adrenal cortex appear grossly in the most common form of congenital adrenal hyperplasia?

Answer 19

21-hydroxylase:

Appears bilaterally enlarged and brown -> composed of mostly lipid-poor cells
-> remember zona reticularis (secreting androgens) is more eosinophilic and filled less with lipid

Question 20

Will males with 21-hydroxylase deficiency reproduce easily?

Answer 20

No -> they generally have oligospermia since high androgen levels inhibit FSH / LH secretion via negative feedback

Question 21

What is adrenal crisis and what is its feared complication?

Answer 21

Primary acute adrenal cortical insufficiency

Crisis: Vascular collapse, due to lack of cortisol hypertensive effects

Question 22

What are three broad situations where adrenal crisis may occur?

Answer 22

1. Rapid withdrawal of exogenous corticosteroids
2. Adrenal insufficiecy in response to stress -> i.e. surgery, infections, trauma
3. Massive bilateral adrenal hemorrhage with secondary infarction

Question 23

Give three causes of bilateral adrenal hemorrhage with secondary infarction and who they tend to happen in?

Answer 23

1. Difficult delivery - newborns -> too much blood delivered to adrenals due to peripheral vasoconstriction
2. Infants / newborns -> Waterhouse-Friderichsen syndrome, hypotension because their glands are so big compared to their body the sepsis / shock has a larger effect
3. Those with hemorrhagic diathesis -> DIC / anticoagulant therapy -> hemorrhage since adrenals are so vascular

Question 24

What causes APS1 and what is it associated with?

Answer 24

Autoimmune polyendocrine syndrome - due to mutations in autoimmune regulator (AIRE) gene involved in T cell negative selection

-> associated with chronic mucocutaneous candidiasis

Question 25

What is the most common cause of Addison disease? What will be seen histologically? What syndromes is it a part of?

Answer 25

Autoimmune adrenalitis - > adrenal glands show a lymphocytic infiltrate and only very few active adrenal cortical cells - > often part of APS1 and AP2, but usually idiopathic

Question 26

Who is most susceptible to Addison's disease by infectious causes? Can cancer cause cause Addison's?

Answer 26

Usually patients with AIDS in developing countries -> especially associated with TB, destruction of gland via host inflammatory response Cancer -> lung carcinoma (all types but squamous) are known to invade adrenal gland and replace its architecture. Remember that the adrenal glands is one of the favorite places for lung cancer to spread to.

Question 27

Are adrenal cortical neoplasms usually functional or nonfunctional?

Answer 27

Nonfunctional -> reason why diagnosis of incidentaloma on MRI or CT is so common Functional neoplasms (i.e. Conn syndrome or Cushing syndrome-producing) are much rarer

Question 28

Is an adrenal cortical carcinoma most likely to be functional or nonfunctional?

Answer 28

Most likely to be functional, and most likely to be androgen-secreting (among other hormones possibly) -> kind of the opposite of thyroid cancer, where being functional means you are almost certainly benign

Question 29

What is the 10% rule for pheochromocytoma?

Answer 29

``` 10% are the exceptions: 10% - malignant (have metastasized) 10% - bilateral 10% - in extraadrenal sites 10% - not associated with hypertension 10% - arise in children 10%-25% familial ```

Question 30

What are common extra-renal sites where pheochromocytoma arises?

Answer 30

1. Organ of Zuckerkandl - paraganglion chromaffin cells involved in fetal control of blood pressure, around the IMA 2. Carotid body - paraganglion cells 3. Bladder wall - SANS paraganglion cells

Question 31

How does pheochromocytoma look grossly?

Answer 31

A tan mass which turns dark brown with oxidation of stored catecholamines, often with areas of hemorrhage and necrosis

Question 32

What do the cells of pheochromocytoma look like and can you tell when they're going to metastasize?

Answer 32

Salt and pepper chromatin neuroendocrine cells, look like little islets of Langerhans. Like all endocrine tumors, their degree of cytological atypia does not correlate well with their metastatic behavior

Question 33

What is the most common of tumor of the adrenal medulla in children? How old are they when they present? Is it often familial?

Answer 33

Neuroblastoma, kids are generally <5 years old. Sporadic is much more common than familial

Question 34

Where does neuroblastoma develop?

Answer 34

1. Adrenal medulla | 2. Along sympathetic trunk -> paravertebral, including posterior mediastinum and retroperitoneum.

Question 35

How does neuroblastoma appear / feel grossly and why is this important clinically?

Answer 35

Feels like an irregular, lobulated mass which can cross midline Wilms tumor is in similar age group, but is usually smooth and unilateral

Question 36

What is the precursor cell type for neuroblastoma and how does this relate to its histologic appearance?

Answer 36

Cell of origin is the neuroblast, the same cell of origin as Chromaffin cells and sympathetic ganglion neurons. Since it is a neuronal blast cell, it forms Homer-Wright Rosettes (like medullablastoma), along nerve processes (eosinophilic collections of neuropil)

Question 37

How does the range of prognosis depend on the degree of differentiation in neuroblastoma?

Answer 37

1. Neuroblastoma - malignant 2. Ganglioneuroblastoma -> some differentiation to ganglion cells -> intermediate prognosis 3. Ganglioneuroma -> fully differentiated, benign

Question 38

Where does neuroblastoma spread to?

Answer 38

Hematogenous dissemination to rather specific places -> bones and periorbital bone -> infiltration of periorbital bone leads to raccoon eyes Can also spread via lymph / hematogenously to go to usual spots, and is very locally invasive

Question 39

How is neuroblastoma diagnosed via lab tests? Does it usually cause hypertension?

Answer 39

Via urine increased vanillylmandelic acid (VMA) and homovanillic acid (HVA) -> for some reason, hypertension is rare despite increased catecholamines and their metabolites

Question 40

What are the clinical symptoms of neuroblastoma?

Answer 40

1. Abdominal mass, fever, weight loss 2. Neurologic compression of nerve roots if in sympathetic trunk 3. Proptosis with ecchymosis if spread to periorbital region

Question 41

Is it better to get neuroblastoma before or after 18 months of an age? What is stage 4-S?

Answer 41

Better to get it younger -> better prognosis Stage 4-S = special, when an infant has metastases to a few specific spots, the prognosis is better because neuroblastoma responds super well to chemotherapy

Question 42

What are two genetic markers which are associatied with poorer prognosis in neuroblastoma?

Answer 42

1. N-myc amplification (similar to Burkitt which has c-myc amplification) 2. Hypo-diploidy (tumor is so malignant it can survive with fewer chromosomes)