Endocrine Pathology Flashcards
Endocrine hyperfunction is usually due to what three things?
- increased trophic hormone
- artificial hormone
- neoplasms (primarily adenomas)
Endocrine hypofunction is usually due to what five things?
- inflammation
- surfical excision
- circulation defect (infarct or hemorrhage)
- mass effect
- congenital enzyme defect
What are the endocrine cells in the adrenal medulla called?
chromaffin cells
What do chromaffin cells in the adrenal medulla produce?
catecholamines, especially epinephrine
What are paraganglia?
- neuroendocrine cells similar to chromaffin cells, which are dispersed in nodules
- associated with the sympathetic and parasympathetic nervous system
- divided into three groups based on location: branchiomeric, intravagal, aorticosympathic
- give rise to pheochromocytomas in the adrenal medulla or paragangliomas in the organ of Zuckerkandl or in associated with the carotid bodies
What is the “rule of 10s” associated with pheochromocytomas?
- 10% arise in association with a familial syndrome
- 10% are extra-adrenal
- 10% of the non-familial ones are bilateral
- 10% are biologically malignant
- 10% occur in childhood
How do pheochromocytomas present?
- triad of headache, sweating, and palpitations
- if accompanied by hypertension, these signs are 90% specific and sensitive
Pheochromocytoma
- a tumor of chromatin cells leading to excess catecholamines
- associated with MEN2, VHL, and neurofibromatosis type 1
- presents as episodic release of catecholamines (hypertension, headaches, palpitations, tachycardia, and sweating)
- diagnosed by increased catecholamines, metanephrines and VPA (catecholamine metabolites) in urine and elevated metanprhines and chromogranin A in plasma
- gross exam reveals a brown tumor
- treatment is preparation with an irreversible alpha blocker called phenoxybezamine and then a beta blocker (prevents hypertensive crisis during surgery) before removal
- follow the rule of 10s: 10% bilateral, 10% familial, 10% malignant, 10% located outside the medulla
- most frequent ectopic location is in the bladder wall, in which case symptoms are tied to urination
How are pheochromocytomas diagnosed?
- elevated plasma metanephrines and chromogranin A
- elevated urinary catecholamines, metanephrines, and VMA
What familial syndromes are risk factors for pheochromocytoma?
- VHL
- neurofibromatosis, type I
- MEN, type 2
- familial paragangliomas
Where are paragangliomas most likely to arise?
- most commonly in the adrenal medulla as a pheochromocytoma
- paravertebral paraganglia (organ of Zuckekandl) and paragnaglia related to the great vessels of the head and neck are the most common extra-adrenal locations
Head and neck paraganglioma
- a neuroendocrine tumor of the paraganglia related to the great vessels of the head and neck, including the carotid bodies
- innervated by the parasympathetic nervous system and rarely release catecholamines
Neuroblastoma
- a neuroendocrine tumor that can occur anywhere along the sympathetic chain
- most common presentation is as an adrenal medulla tumor in children under 4
- the most common extra-cranial solid tumor in children
- derived from post-ganglionic sympathetic nervous system and of neural crest cell origin
- associated with N-myc oncogene over expression (more copies predict worse outcome) but hyperdiploid tumors with over expression of TKA do well
- presents with abdominal distension and a firm, irregular mass that can cross the midline
- this distinguishes it from a Wilms tumor which is smooth and unilateral
- less likely to develop hypertension that with a pheochromocytoma but may present with opsoclonus-myoclonus syndrome (“dancing eyes and dancing feet”)
- unique in that they can mature to ganglioneuroblastoma or ganglioneuromas or even spontaneously regress
- catecholamine metabolites HVA and VMA are elevated in urine
Describe the histology of a neuroblastoma.
- prominent mitotic activity, karyorrhexis, and pleomorphism
- faintly eosinophilic fibrillary material called neuropil in the background
- form rosettes with tumor cells arranged around a central space filled with this eosinophilic material
- cells contain catecholamine secretory granules
Neuroblastomas are associated with what genetic change?
amplification of N-myc
Carcinoid Tumor
- a neuroendocrine tumor most commonly arising in the GI tract or in association with the bronchial tree
- most are asymptomatic unless they cause angulation or obstruction of the small intestine; may cause respiratory obstruction and hemoptysis if found in the lungs
- some patients develop carcinoid syndrome, thought to arise from excess serotonin
- this can be a helpful diagnostic markers if elevated in the serum or if the inactive metabolite 5-HIAA is
- excess serotonin produced by these tumors is usually metabolized by the liver, so carcinoid syndrome doesn’t arise until the liver parenchyma has been destroyed by a metastasis or the tumor has metastasized outside the GI tract
- prognosis is good unless there there are disseminated metastases
- treatment is primarily surgical but anti-serotonergics and anti-histamines can be used to control symptoms
- follows the rule of 1/3s such that ⅓ metastasize, present with 2nd malignancy, and are multiple
Carcinoid Syndrome
- a syndrome that arises in associate with a carcinoid tumor
- typically not until that tumor has spread beyond the GI tract or destroyed the liver
- mediated by excess serotonin
- most patients present with vasomotor disturbances in the form of cutaneous flushes and apparent cyanosis as well as intestinal hypermotility causing diarrhea, cramps, and n/v
- other symptoms include asthmatic bronchoconstrictive attacks, hepatomegaly, or systemic fibrosis with cardiac involvement
- an increase in 5-hydroxyindoleacetic acid (5-HIAA) is detectable in urine
VIPoma
- an endocrine tumor that secretes vasoactive intestinal polypeptide
- presents with watery diarrhea
- any tumor of neural crest cell origin can also be associated with secretion of VIP
Any tumor of neural crest cell origin can be associated with secretion of what endocrine hormone?
vasoactive intestinal polypeptide
The thyroid is in close proximity to which nerves?
the recurrent laryngeal nerve
How does the parathyroid gland of a young individual compare to that of an older individual?
as we age, much of the cellular parenchyma is replaced with fat
How does hypoparathyroidism typically present?
- hypocalcemia
- hyperphosphatemia
- neuromuscular irritability (tetany) including laryngospasms, twitching, and convulsions
- positive Chvostek and Trousseau sign
What is the most common cause of a congenitally absent parathyroid?
DiGeorge’s syndrome
What is Chvostek sign?
a twitch that is elicited by tapping on the facial nerve indicating hypocalcemia
What is Trousseau sign?
a twitch elicited by pumping up a blood pressure cuff, indicating hypocalcemia
How does hyperparathyroidism present?
- hypercalcemia (stones, moans, groans, thrones, and psych overtones)
- cardiac arrhythmias
- coma
- resorption of bone (osteitis fibrosa cystica)
- kidney stones
- metastatic calcification
What is the most common cause of primary hyperparathyroidism?
solitary parathyroid adenoma
Hyperparathyroidism induces what state of serum calcium?
hypercalcemia
How does the histology of a parathyroid adenoma compare to that of a normal gland?
adipose tissue is largely absent or pushed aside in the presence of an adenoma
What is osteitis fibrosa cystica?
- a change in bone seen in those with hyperparathyroidism
- histology reveals numerous osteoclasts with elevated activity, widely spaced trabecular separated by fibrous tissue, and foci of hemorrhage and cyst formation
Renal failure will cause what parathyroid dysfunction?
secondary hyperparathyroidism: renal insufficiency leads to a decrease in phosphate excretion, which lowers free calcium, and triggers excess PTH release
How can primary hyperparathyroidism be differentiated from secondary?
- primary typically will involve one lesion, while secondary results in hyperplasia of all four glands
- furthermore, primary is associated with hypercalcemia and hypophosphatemia while secondary is associated with hypocalcemia and hyperphosphatemia
What is the most common cause of secondary hyperparathyroidism?
renal insufficiency leading to a decrease in phosphate excretion, which lowers free calcium, and triggers excess PTH release
What is tertiary hyperparathyroidism?
- a state of excess PTH seen long after a secondary hyperparathyroidism has been corrected
- potentially after hypocalcemia is rapidly corrected by kidney transplant for instance
- typically requires parathyroidectomy to control
How does the prognosis of pancreatic endocrine tumors compare to exocrine tumors of the pancreas?
endocrine have relatively good prognoses
Pancreatic endocrine neoplasms account for what percentage of all pancreatic neoplasms?
only 2%
Pancreatic endocrine tumors resemble what other tumor?
carcinoid tumors
How are endocrine tumors determined to be malignant?
- only once evidence of metastasis is found; there are no markers for identification before
- in other words, it is a biologic diagnosis
What are the three most common clinical syndromes associated with functional pancreatic endocrine neoplasms?
- hyperinsulinism
- hypergastrinemia and Zollinger-Ellison syndrome
- MEN
What is the most common functional endocrine tumor of the pancreas?
insulinomas
Insulinoma
- the most common pancreatic endocrine tumor
- typically benign
- symptoms arise from the elevated insulin levels and hypoglycemia, including sweating, fainting, weakness, and confusion, which are promptly relieved by food
- most patients, however, are asymptomatic and the only signs are an elevated glucose-to-insulin ratio and mild hypoglycemia
- infrequently arise in ectopic pancreatic tissue, most commonly in a Meckle’s diverticulum
- histology reveals architecture that resembles giant islets without anaplasia; deposition of eosinophilic amyloid is common
Gastrinoma
- an endocrine tumor of the pancreas
- gastrin secretion leads to hypertrophy of parietal cells, an excess of gastric acid, and ulcers throughout the GI tract
- presenting syndrome is usually duodenal ulcer or chronic diarrhea
- commonly arise from the duodenum and peri-pancreatic soft tissue in addition to within the pancreas (this is referred to as the gastrinoma triangle)
- endoscopy will show hypertrophy of gastric mucosa, serum gastrin level is virtually diagnostic, and imaging may locate the tumor
- more than half are locally invasive or have metastasized at the time of diagnosis
- histology is typically bland and shows no evidence of anaplasia
- often arise in the setting of MEN1
- initial treatment is surgical, but PPIs and somatostatin analogs can help
Zollinger-Ellison syndrome
- a syndrome of hyper secretion of gastric acid, severe peptic ulceration, and pancreatic islet cell lesions
- commonly associated with and reminiscent of the pathophysiology of gastrinomas
Glucagonomas
- an endocrine neoplasm of the pancreas
- presents with mild diabetes, a characteristic skin rash known as necrolytic migratory erythema, and anemia
- occurs most frequently in peri- and post-menopausal women
- plasma glucagon levels are extremely high
Somatostatinomas
- delta cell tumors of the pancreas
- present with mild diabetes, cholelithiasis, steatorrhea, and hypochlorhydria
- difficult to localize preoperatively
- high plasma somatostatin is used for diagnosis
Ppomas
- pancreatic polypeptide-secreting endocrine tumors
- a pancreatic carcinoid tumor producing serotonin and an atypical carcinoid tumor
- these are endocrinological asymptomatic despite high hormone levels in plasma
What are indicators that may suggest a diagnosis of MEN?
- tumors occurring at a younger than usual age
- tumors arising in multiple endocrine organs at the same or different times
- multifocal tumors within a single organ
Multiple Endocrine Neoplasia Syndromes
a familial neoplastic disorder characterized by early, multifocal endocrine tumors, typically preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin
MEN, Type 1
- also known as Wermer syndrome, it is a familial neoplastic disorder characterized by early, multifocal endocrine tumors
- due to a germline mutation in the MEN1 tumor suppressor gene
- most commonly the three Ps: parathyroid, pancreas, pituitary
- but not restricted to these
- parathyroid adenomas are the most common
- pancreatic micro-adenomas like gastrinomas and insulinomas are responsible for most mortality
- pancreatic polypeptide is the most commonly secreted product, so these may not be accompanied by a hyper secretion syndrome
- prolactinomas are the most common pituitary manifestation
MEN, Type 2A
- also known as Sipple Syndrome, it is a familial neoplastic disorder characterized by early, multifocal endocrine tumors
- due to an autosomal dominant RET oncogene mutation
- associated with medullary thyroid carcinoma (life-threatening), pheochromocytoma, and parathyroid hyperplasia
- screening the family and performing prophylactic thyroidectomy is advised as soon as the diagnosis is made
MEN, Type 2B
- a familial neoplastic disorder characterized by early, multifocal endocrine tumors
- due to an autosomal dominant RET oncogene mutation
- associated with medullary thyroid carcinoma (life-threatening), pheochromocytoma, ganglioneuromas of the oral mucosa, and marfanoid habits
- screening the family and performing prophylactic thyroidectomy is advised as soon as the diagnosis is made
What is the most common origin of pineal gland tumors?
germ cells
What is the principal secretory product of the pineal gland?
melatonin
Primary Brain Germ Cell Tumors
- tumors of germ cell origin, most commonly arising in the pineal and the suprasellar regions
- CSF levels of alpha-fetoprotein and B-hCG are important markers
- histology reveals, large, round-to-polyhedral cells with a clear or watery-appearing cytoplasm and large, central nucleus with prominent nucleoli
