Endocrine Tumors Flashcards
Answer C
This patient most likely has a glucagonoma, a rare tumor arising from the alpha cells of the pancreatic islets of Langerhans. Glucagonomas secrete large quantities of glucagon, so affected patients often have hyperglycemia or overt diabetes mellitus. A characteristic skin finding is necrolytic migratory erythema, an elevated painful and pruritic rash typically affecting the face, groin, and extremities. Over time, small erythematous papules coalesce to form large, indurated plaques with a central clearing that often appears brown or bronze-colored. Diagnosis is made by detecting elevated levels of glucagon in the serum.
(Choice A) Glucagon acts on the liver to promote amino acid oxidation and gluconeogenesis from amino acids. Circulating levels of amino acids are low in glucagonoma and thought to contribute to development of necrolytic migratory erythema.
(Choice B) Elevated gastrin levels in patients with gastrinoma are associated with hypersecretion of gastric acid and resultant gastrointestinal ulceration. The peptic ulcers that occur with gastrinomas are often in unusual areas, such as the jejunum. Patients with gastrinomas can also have diarrhea and abdominal pain.
(Choice D) Excess somatostatin secretion from a somatostatinoma typically presents with abdominal pain, gallbladder stones, constipation, hyperglycemia, and steatorrhea. These manifestations result from somatostatin-induced inhibition of insulin, glucagon, gastrin, secretin, and cholecystokinin secretion, and inhibition of gastrointestinal motility.
(Choice E) High levels of vasoactive intestinal polypeptide (VIP) are seen in patients with a VIPoma, which typically presents with intractable diarrhea, hypokalemia, and achlorhydria. Patients are usually hypotensive due to dehydration and the vasodilatory effects of VIP.
(Choice F) Diabetes mellitus is present in the majority of patients with glucagonoma, most likely due to excessive hepatic glucose production. Insulin levels tend to be normal but can be elevated secondary to hyperglycemia and glucagon-induced stimulation of the pancreatic beta cells.
(Choice G) Zinc deficiency causes erythematous skin lesions (mainly around body orifices) that are predominantly vesicular and pustular. Other features include hypogonadism, impaired taste and smell, night blindness, and impaired wound healing. Although the skin lesions in zinc deficiency can resemble necrolytic migratory erythema, this patient’s lack of additional findings and her recent diabetes mellitus diagnosis make glucagonoma more likely.
Educational objective:
Glucagonoma presents with hyperglycemia (often as newly diagnosed diabetes mellitus) and necrolytic migratory erythema (blistering erythematous plaques with central clearing) affecting the groin, face, and extremities. The diagnosis is made by detecting elevated glucagon levels.
Answer A
This patient has constipation associated with hypercalcemia and hypophosphatemia, which is a common presentation of primary hyperparathyroidism (PHPT). PHPT is usually caused by a benign parathyroid adenoma that autonomously secretes parathyroid hormone (PTH), leading to increased bone resorption, increased renal calcium reabsorption, and increased intestinal calcium absorption (due to increased production of 1,25-dihydroxyvitamin D). This patient’s history of renal stones also indicates hyperparathyroidism and is due to increased urinary calcium excretion despite maximal renal tubular calcium reabsorption.
Hypercalcemia inhibits nerve depolarization by interfering with sodium movement through voltage-gated sodium channels, leading to impaired smooth muscle contraction and reduced colonic motility. Symptoms include constipation, crampy abdominal pain, and nausea. Other potential gastrointestinal manifestations of hypercalcemia include acute pancreatitis (due to increased conversion of trypsinogen to trypsin) and peptic ulcer (due to increased release of gastrin).
(Choice B) Dyssynergic defecation is characterized by altered passage of stool through the anorectum due to uncoordinated contraction and relaxation of pelvic floor muscles. It is often caused by obstetric complications during vaginal delivery. However, hypercalcemia and hypophosphatemia would not be present, and most patients have either anal sphincter dysfunction or the absence of perianal descent (this patient’s rectal tone is normal).
(Choices C and E) Intestinal motor function is generally stimulated by the parasympathetic nervous system and inhibited by the sympathetic nervous system. Although constipation can occur due to autonomic dysfunction from demyelination (eg, multiple sclerosis) or nerve fiber interruption (eg, traumatic spinal cord injury), these disorders would not explain this patient’s electrolyte abnormalities.
(Choice D) Colon cancer can cause intestinal obstruction, which can interfere with the passage of stool, and can be associated with hypercalcemia (bone metastasis); however, this would result in PTH suppression, so it is unlikely to cause hypophosphatemia. This patient’s history of renal stones also is more consistent with primary hyperparathyroidism.
Educational objective:
Hypercalcemia inhibits nerve depolarization, leading to impaired smooth muscle contraction and reduced colonic motility. Symptoms include constipation, crampy abdominal pain, and nausea.
A researcher is investigating factors affecting adrenal hormone synthesis and release. An intact adrenal gland is obtained from a donor cadaver, and a histologic section of the gland is shown below. Cells from a specific part of the gland, indicated by the arrow, are extracted for further analysis.
These cells are most likely to be directly activated by which of the following substances?
A. Acetylcholine
B. ACTH
C. Angiotensin II
D. Epinephrine
E. Norepinephrine
Answer A
The adrenal gland is made up of an outer cortex (divided into 3 zones) and an inner medulla:
The zona glomerulosa is the outermost zone of the cortex and is composed of cells arranged in rounded or arched clusters (glomus is Latin for ball) that secrete mineralocorticoid hormones (primarily aldosterone).
The zona fasciculata is the middle zone and contains foamy-appearing cells in columns (fascis is Latin for bundle or stack) that secrete glucocorticoid hormones (primarily cortisol).
The zona reticularis is the inner zone of the cortex and contains cells in anastomosing cords (rete is Latin for net) that secrete androgens.
The adrenal medulla is sharply demarcated from the cortex and is composed of chromaffin cells with a deeply basophilic cytoplasm.
Chromaffin cells are modified neuroendocrine cells derived from the neural crest. They are stimulated by acetylcholine released by sympathetic preganglionic neurons and secrete catecholamines (80% epinephrine, 20% norepinephrine) directly into the bloodstream to amplify sympathetic nervous system activity.
(Choice B) ACTH stimulates secretion of glucocorticoid hormones from the zona fasciculata. Cortisol produced in response to ACTH increases activity of the adrenal medullary enzyme phenylethanolamine N-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. ACTH therefore indirectly upregulates medullary epinephrine production, but does not directly control it.
(Choice C) Aldosterone secretion from the zona glomerulosa is primarily regulated by angiotensin II and extracellular potassium levels.
(Choice D) Epinephrine released by the adrenal medulla acts on adrenergic receptors in the heart, lungs, liver, and skeletal muscle to increase sympathetic tone and mediate the acute stress response.
(Choice E) Most sympathetic postganglionic neurons release norepinephrine to activate adrenergic receptors on the target tissues. However, the preganglionic fibers innervating the adrenal medulla (and postganglionic sympathetic neurons innervating eccrine sweat glands) release acetylcholine.
Educational objective:
Chromaffin cells are modified neuroendocrine cells derived from the neural crest. Chromaffin cells in the adrenal medulla are stimulated by acetylcholine released by sympathetic preganglionic neurons and secrete catecholamines directly into the bloodstream to amplify sympathetic nervous system activity.
Answer D
This patient with severe hypertension, headaches, and an adrenal mass has typical features of pheochromocytoma, a catecholamine-secreting tumor of the chromaffin cells of the adrenal medulla. Pheochromocytoma can be sporadic or associated with several familial disorders, especially multiple endocrine neoplasia (MEN) type 2 (particularly likely in this patient given his family history of hyperparathyroidism). MEN type 2 is associated with germ-line mutations in the RET proto-oncogene and is characterized by:
Pheochromocytomas
Medullary thyroid cancer (malignancy of parafollicular C cells)
Either parathyroid hyperplasia (MEN 2A) or mucosal neuromas and marfanoid habitus (MEN 2B)
Neural crests are embryological structures composed of parallel strips of cells arising from the ectoderm at the margin of the neural tube. The chromaffin cells of the adrenal medulla are derived from neural crest tissue (the adrenal cortex is derived from the mesoderm). Structures arising from neural crest cells can be remembered with the mnemonic “SOME SALT” (Schwann cells, odontoblasts, melanocytes, enterochromaffin cells, spinal membranes [pia and arachnoid], adrenal medulla/ganglia, laryngeal cartilage, tracheal cartilage).
(Choices A, B, and C) Capillary endothelial cells and cardiac myocytes are mesodermal derivatives that arise from primitive endothelium. Interstitial fibroblasts also arise from the mesoderm.
(Choice E) Thyroid follicular cells are an endodermal derivative, arising from the pharyngeal epithelium at the base of the tongue. Although the parafollicular, calcitonin-secreting C cells were previously thought to originate from neural crest tissue, recent studies suggest that they have an endodermal origin.
Educational objective:
Neural crests are embryological structures composed of parallel strips of cells arising from the ectoderm at the margin of the neural tube. Structures derived from neural crest cells include Schwann cells, odontoblasts, melanocytes, enterochromaffin cells, spinal membranes, adrenal medulla/ganglia, laryngeal cartilage, and tracheal cartilage.
Answer F
The 4 main types of primary thyroid carcinoma include papillary, follicular, medullary (derived from the parafollicular, calcitonin-secreting C cells), and anaplastic. The papillary type is most common, accounting for >70% of cases. Risk factors include a positive family history of thyroid cancer and radiation exposure, especially in childhood.
Papillary carcinoma cells are characteristically large with overlapping nuclei containing finely dispersed chromatin, giving them an empty or ground-glass appearance (sometimes termed Orphan Annie eye nuclei after a cartoon character whose eyes were drawn without pupils or irises). Numerous nuclear grooves as well as intranuclear inclusions composed of cytoplasm (ie, pseudoinclusions) can be seen due to invagination of the nuclear membrane. Psammoma bodies (laminated calcium deposits) may also be found within the tumor.
(Choice A) Anaplastic thyroid carcinoma is an aggressive tumor with a very poor prognosis. It is most common in patients age >60. Cytologic features include markedly pleomorphic cells, including irregular giant and spindle cells.
(Choice B) Most benign thyroid nodules are colloid nodules formed from focal hyperplasia of normal thyroid follicular cells. On cytopathology, a colloid nodule consists of variable-sized thyroid follicles, colloid, and macrophages.
(Choices C and D) Follicular neoplasms lack the characteristic nuclear features and psammoma bodies found in papillary carcinoma. Distinguishing a benign follicular adenoma from a well-differentiated follicular carcinoma depends on the presence of vascular or capsular invasion, which cannot be determined on a fine-needle aspiration specimen.
(Choice E) Medullary thyroid carcinoma appears histologically as polygonal or spindle-shaped cells with a slightly granular cytoplasm that stains for calcitonin. Extracellular amyloid deposits consisting of calcitonin polypeptide may also be seen. Medullary thyroid cancer is a component of multiple endocrine neoplasia types 2A and 2B.
Educational objective:
Papillary thyroid carcinoma is the most common type of thyroid cancer. Characteristic microscopic features include large cells with nuclei containing finely dispersed chromatin, giving them an empty or ground-glass appearance (ie, Orphan Annie eye), as well as intranuclear inclusions and nuclear grooves.
Answer A
This patient’s symptoms are worrisome for a pituitary tumor. Large tumors can cause headaches due to mass effect, and compression of the optic chiasm by suprasellar extension of the tumor can cause bitemporal hemianopsia. These tumors can also cause loss of normal pituitary function by compression of surrounding cells. Pituitary adenomas typically arise from 1 of the 5 major cell types of the anterior pituitary; physiologic symptoms depend on the hormones produced by the tumor. The most common hormonally active (functional) adenomas are prolactin-secreting adenomas (prolactinomas).
Prolactin is a peptide hormone whose primary action is maintenance of lactation in the postpartum period; prolactinomas classically cause galactorrhea in premenopausal women. Prolactin also suppresses GnRH production from the hypothalamus, which in women leads to amenorrhea and in men causes hypogonadism (eg, impotence, decreased libido, infertility). Because the symptoms of hyperprolactinemia in men and postmenopausal women are often mild and nonspecific, patients may not seek care until the tumors are large and cause mass effect symptoms.
(Choices B, D, and F) Somatotroph (growth hormone-secreting) adenomas can present with gigantism (in children) or acromegaly in adults. Thyrotroph (TSH-secreting) adenomas cause central hyperthyroidism (eg, heat intolerance, tachycardia). Thinning of the skin, typically manifesting as abdominal stria, is a characteristic feature of Cushing syndrome; when hypercortisolism is due to a corticotroph (ACTH-producing) adenoma, it is referred to as Cushing disease. These tumors are significantly less common than prolactinomas.
(Choice C) Mass lesions involving the pituitary stalk or posterior pituitary could cause headaches and bitemporal hemianopsia in addition to central diabetes insipidus (due to decreased release of antidiuretic hormone [ADH] from the posterior pituitary). However, polyuria is typically only transient (lasting <6 weeks) because the hypothalamus is able to bypass the pituitary and directly release ADH into the circulation.
(Choice E) Hyperpigmentation in the context of pituitary disease is typically due to hypersecretion of ACTH, either due to a corticotroph adenoma or in response to primary adrenal insufficiency.
Educational objective:
Pituitary tumors can present with headaches, bitemporal hemianopsia, and hypopituitarism; the most common hormonally active (functional) adenomas are prolactin-secreting adenomas (prolactinomas). Prolactinomas can cause galactorrhea and amenorrhea in women. In men, they often present with hypogonadism.
Answer E
This patient’s hypertension, proximal muscle weakness, and hyperglycemia are suggestive of excess cortisol (ie, Cushing syndrome [CS]). Hypercortisolism can be confirmed by finding elevated cortisol levels in a late-night salivary sample or 24-hour urine collection. Additionally, low-dose dexamethasone suppression testing can also be useful for confirming the diagnosis; administration of a small dose of a potent glucocorticoid rapidly suppresses ACTH and cortisol secretion in normal individuals, but patients with CS are resistant to low-dose glucocorticoids so serum cortisol remains elevated.
Once the diagnosis is confirmed, the next step is establishing the cause of CS, which involves measurement of serum ACTH levels :
Low ACTH levels are seen with autonomous adrenal production of cortisol (eg, adrenal adenoma or carcinoma) or exogenous glucocorticoid exposure due to feedback suppression
High ACTH levels occur with pituitary adenomas (ie, Cushing disease) or ectopic ACTH production by nonpituitary tumors, which can be further distinguished with the high-dose dexamethasone suppression test :
Pituitary sources of ACTH are only relatively resistant to feedback inhibition, and high doses of dexamethasone will suppress ACTH and cortisol levels (Choice A)
Nonpituitary ectopic sources of ACTH (eg, small cell lung cancer) are completely resistant to feedback inhibition, and ACTH and cortisol will remain elevated following high doses of dexamethasone
This patient’s rapid symptom onset, heavy smoking history, and lung mass are consistent with paraneoplastic CS, likely due to small cell lung cancer. ACTH and cortisol production will likely be unchanged following high-dose dexamethasone.
(Choices B and C) In normal individuals, dexamethasone suppresses ACTH release from the pituitary. In patients with abnormal pituitary or ectopic ACTH production, dexamethasone affects ACTH levels as described above. However, dexamethasone does not stimulate ACTH release in any setting.
(Choice D) The fall in cortisol seen in dexamethasone suppression tests is due to feedback suppression causing decreased ACTH release. A fall in cortisol would not be seen without a corresponding fall in ACTH.
Educational objective:
Cushing syndrome caused by a pituitary adenoma or ectopic (paraneoplastic) ACTH secretion is associated with elevated ACTH levels. High-dose dexamethasone suppresses ACTH and cortisol secretion when Cushing syndrome is caused by a pituitary adenoma (Cushing disease) but not when it is caused by ectopic ACTH secretion (eg, small cell lung cancer).
Answer A
This patient has an enlarging thyroid nodule associated with an elevated calcitonin level, which is concerning for medullary thyroid cancer (MTC), a malignancy arising from the thyroid C (parafollicular) cells. These findings, in association with mucosal neuromas and marfanoid habitus (eg, arm span > height, long fingers, joint laxity), suggest multiple endocrine neoplasia type 2B (MEN2B). MEN2 syndromes are caused by germline mutations of the RET proto-oncogene. MTC is present in nearly all patients with MEN2 and is usually more aggressive and occurs at an earlier age than sporadic MTC.
Pheochromocytomas develop in roughly half of patients with MEN2 syndromes and cause paroxysmal hypertension and tachycardia due to the intermittent secretion of catecholamines. The abrupt, severe increase in blood pressure can precipitate episodic headaches and is often accompanied by other symptoms associated with catecholamine excess (eg, diaphoresis, tremor, chest pain).
(Choice B) Hyperparathyroidism with secondary hypercalcemia is the most common manifestation of MEN1. Hyperparathyroidism (due to parathyroid chief cell hyperplasia or adenoma formation) is also seen in 10%-20% of patients with MEN2A, but it is not a feature of MEN2B.
(Choices C and E) Many patients with MEN1 have endocrine pancreatic tumors that secrete gastrin, leading to refractory peptic ulceration and diarrhea (Zollinger-Ellison syndrome). In rare cases, endocrine tumors of the pancreas in MEN1 secrete other hormones, such as insulin, which can cause hypoglycemia.
(Choice D) Pituitary tumors are present in 50% of patients with MEN1. Large pituitary tumors with suprasellar extensions are likely to cause peripheral vision loss.
Educational objective:
Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer, pheochromocytomas, mucosal neuromas, and marfanoid habitus. Hyperparathyroidism is not a feature of this syndrome.
Answer B
Pheochromocytoma is a tumor of the chromaffin cells of the adrenal medulla characterized by excess production of catecholamines (norepinephrine, epinephrine, dopamine). Fluctuating catecholamine release results in increased vascular tone and hypertension, often associated with episodic headache, diaphoresis, and palpitations. The diagnosis is confirmed by detecting elevated levels of urinary and plasma catecholamines and metanephrines (catecholamine breakdown products).
Histopathology shows a highly vascular tumor with nests of spindle-shaped or polygonal cells. The neurohormonal character of the cells is confirmed with stains for synaptophysin, chromogranin, and neuron-specific enolase, and electron microscopy may show dense membrane-bound granules containing catecholamines.
(Choices A and C) Syndromes associated with steroid hormone-producing tumors of the adrenal cortex include hypercortisolism (Cushing syndrome), hyperaldosteronism (hypertension, hypokalemia, metabolic alkalosis), and hyperandrogenism (hirsutism, acne, androgenetic hair loss). Metabolically active ovarian tumors also can cause hyperandrogenism. Overproduction of steroid hormones is apparent on electron microscopy as well-developed smooth endoplasmic reticulum rather than membrane-bound secretory granules.
(Choice D) Parathyroid adenomas (or carcinomas) cause primary hyperparathyroidism resulting in hypercalcemia. Characteristic symptoms include constipation, abdominal pain, bone pain, and neuropsychiatric symptoms.
(Choice E) Toxic nodular thyroid disease could produce this patient’s symptoms (eg, diaphoresis, weight loss). However, metabolically active thyroid adenomas typically show a follicular structure, with uniform cells and large amounts of follicular colloid.
Educational objective:
Pheochromocytoma is a tumor arising from the chromaffin cells of the adrenal medulla characterized by excess production of catecholamines. Clinical features include episodic hypertension, diaphoresis, and palpitations. Microscopic examination of the tumor cells shows electron-dense, membrane-bound secretory granules, and immunohistochemistry is positive for synaptophysin, chromogranin, and neuron-specific enolase.
Answer C
This patient has a personal history of pheochromocytoma and a family history of thyroid cancer. His new thyroid malignancy therefore raises suspicion for multiple endocrine neoplasia type 2 (MEN2), which is characterized by:
Medullary thyroid cancer
Pheochromocytoma
Either parathyroid hyperplasia (type 2A) or marfanoid habitus and mucosal neuromas (type 2B)
Approximately 20% of medullary thyroid cancers are familial, occurring as part of MEN2 or familial medullary thyroid cancer syndrome due to germ-line mutations of the RET proto-oncogene. Medullary thyroid cancer is a neuroendocrine tumor that arises from parafollicular calcitonin-secreting C cells. Nests or sheets of polygonal or spindle-shaped cells with extracellular amyloid deposits are seen microscopically. These amyloid deposits are derived from calcitonin secreted by the neoplastic C cells and stain with Congo red. Despite overproduction of calcitonin, hypocalcemia is not a prominent feature.
(Choice A) Gross inspection of papillary thyroid cancer may reveal formation of visible papillae; microscopic inspection of papillae shows a fibrovascular core, often with laminar calcifications (psammoma bodies). The cells contain pale nuclei with finely dispersed chromatin, giving them an empty or ground-glass appearance (Orphan Annie eye nuclei). Intranuclear inclusions and grooves can be seen due to invagination of the nuclear membrane.
(Choice B) Hyperplastic follicles with tall, crowded cells forming intrafollicular projections can be seen in Graves disease, often with hyperactive resorption of colloid leading to scalloping of the colloid edges.
(Choice D) Anaplastic thyroid cancer is an aggressive tumor with a very poor prognosis. It is most common in older patients (age >60). Cytologic features include markedly pleomorphic cells, including irregular giant cells and biphasic spindle cells.
(Choice E) The presence of colloid-containing microfollicles suggests a benign follicular adenoma. Follicular carcinoma can also contain small follicles but will show vascular or capsular invasion.
Educational objective:
Medullary thyroid cancer is a neuroendocrine tumor that arises from parafollicular calcitonin-secreting C cells. It is characterized by nests or sheets of polygonal or spindle-shaped cells with extracellular amyloid deposits derived from calcitonin.
Answer D
This patient’s combination of hyponatremia and a lung mass is suggestive of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone (ADH) is normally produced in the hypothalamus and secreted from the posterior pituitary in response to changes in plasma osmolality and intravascular volume. However, small cell lung carcinomas, which are tumors of neuroendocrine origin, often release ADH independent of feedback inhibition (paraneoplastic effect). This inappropriate secretion of ADH leads to hyponatremia, decreased plasma osmolality, and elevated urine osmolality (which normally should be <100 mOsm/kg when hyponatremia is present). The profound hyponatremia that occurs in SIADH can cause headache, weakness, altered mental status, and seizures.
In SIADH, increased ADH causes excessive water absorption by the kidneys, leading to a transient, subclinical hypervolemia. This mild increase in extracellular fluid volume suppresses the renin-aldosterone axis and stimulates the production of natriuretic peptides, leading to excretion of sodium in the urine (natriuresis). As a result, patients with SIADH have a clinically normal extracellular fluid volume and low plasma osmolality (euvolemic hyponatremia). Features of volume overload (eg, peripheral edema, pulmonary crackles, elevated jugular venous pressure) are not seen (Choices A, B, and E).
(Choice C) Patients with SIADH have inappropriately concentrated urine (generally >100 mOsm/kg) for their degree of hyponatremia. Hyponatremia with a urine osmolality of <100 mOsm/kg (maximally dilute urine) indicates appropriate suppression of ADH secretion (as would be seen in primary polydipsia).
Educational objective:
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by low plasma sodium and osmolality, inappropriately concentrated urine, and clinically normal volume status (euvolemic hyponatremia). An important cause of SIADH is a paraneoplastic effect secondary to small cell carcinoma of the lung.
Answer B
This patient has medullary thyroid cancer (MTC), a neuroendocrine malignancy arising from the calcitonin-secreting parafollicular C cells. Most cases of MTC are sporadic, but approximately 20% are familial, due to germline mutations of the RET proto-oncogene. Multiple endocrine neoplasia type 2 (MEN2) is the most common inherited disorder associated with activating RET mutations, and is characterized by:
MTC
Pheochromocytoma
Parathyroid hyperplasia (type 2A) or marfanoid habitus (tall, slender build, increased limb to height ratio) and mucosal neuromas (type 2B)
Pheochromocytoma is a catecholamine-secreting neoplasm arising from the chromaffin cells of the adrenal medulla. Up to 50% of patients with MEN2 develop pheochromocytoma. In patients with undiagnosed pheochromocytoma, induction of anesthesia can precipitate a catecholamine (epinephrine and norepinephrine) surge, leading to hypertensive crisis, flash pulmonary edema, and atrial fibrillation. Therefore, patients who have MTC associated with germline RET mutations should be screened for pheochromocytoma (eg, 24-hour assay for urinary metanephrines and catecholamines) prior to surgery.
(Choices A, C, D and E) MEN1 is characterized by anterior pituitary adenomas, primary hyperparathyroidism (due to parathyroid adenomas or hyperplasia), and neuroendocrine tumors of the pancreas and gastrointestinal tract (eg, gastrinoma, insulinoma). A number of other tumors are also more frequent in MEN1, including adrenocortical adenomas and neuroendocrine thymomas (thymic carcinoid). However, MEN1 is due to mutations in the MEN1 gene (not RET) and is not associated with MTC.
Educational objective:
Multiple endocrine neoplasia type 2 is caused by germline activating mutations in the RET proto-oncogene and frequently results in both medullary thyroid cancer and pheochromocytoma. In patients with undiagnosed pheochromocytoma, induction of anesthesia (eg, preparation for thyroidectomy) can precipitate a catecholamine surge, leading to hypertensive crisis, flash pulmonary edema, and atrial fibrillation.
Answer A
This patient’s bitemporal hemianopsia and headaches suggest mass effect symptoms due to an expanding lesion near the optic chiasm. Cranial imaging (typically MRI scan) can confirm the diagnosis of a pituitary adenoma. Unlike other pituitary hormones, prolactin secretion is under negative regulation by dopamine from the hypothalamus, and any disruption of dopaminergic pathways in the pituitary stalk can cause a moderate increase in prolactin release. However, very high prolactin levels, as seen in this patient, suggest a prolactin-secreting adenoma (prolactinoma).
Increased circulating levels of prolactin suppress GnRH secretion, leading to a reduction in release of LH from the pituitary and decreased testicular testosterone production. In premenopausal women, prolactinomas typically present early with galactorrhea and amenorrhea. However, in men and postmenopausal women, early symptoms may be subtle and nonspecific (eg, decreased libido), and patients frequently present later with mass effect symptoms (eg, headache, visual field defects).
(Choices B and D) Physiologic GnRH secretion occurs in a pulsatile fashion and initiates gonadotropin (eg, LH, FSH) and subsequently testosterone secretion. However, prolonged, continuous GnRH secretion suppresses gonadotropins, resulting in lower levels of sex steroids. Long-acting GnRH agonists (eg, leuprolide) are used to suppress sex steroid–dependent diseases (eg, prostate cancer).
(Choice C) Primary hypogonadism with low testosterone levels results in loss of negative feedback on GnRH release, causing elevated levels of GnRH and LH.
(Choice E) Intake of exogenous testosterone (eg, anabolic steroid use) will suppress release of GnRH and subsequently LH.
Educational objective:
Large prolactin-secreting pituitary tumors can compress the optic chiasm, causing bitemporal hemianopsia. In addition, elevated prolactin levels suppress release of GnRH, leading to decreased LH secretion and subsequently impaired testosterone production in men.
Answer C
This patient’s small pituitary adenoma with an elevated prolactin level and secondary amenorrhea is consistent with a prolactin-secreting adenoma (prolactinoma). High levels of prolactin suppress GnRH secretion from the hypothalamus, leading to reduced secretion of LH (and to a lesser extent FSH) and subsequent hypogonadism. Nonsecretory (“nonfunctioning”) adenomas can also cause mild hyperprolactinemia due to pressure on the stalk, but these tumors primarily cause mass-effect symptoms (eg, hypopituitarism, headache, bitemporal hemianopsia) due to pressure on surrounding structures.
Estrogen maintains bone mass in premenopausal women. Low estrogen levels lead to increased production of inflammatory cytokines (especially IL-1 and tumor necrosis factor–alpha), increasing expression of the receptor activator of nuclear factor kappa B ligand (RANKL) and resulting in increased osteoclast activity. Loss of estrogen, whether from menopause, ovulatory dysfunction, or surgical removal of the ovaries, increases the risk of bone loss and osteoporosis.
(Choice A) Adenomas are associated with pituitary apoplexy (hemorrhage into the pituitary). However, this occurs more commonly with large adenomas and is not typically associated with strokes located in the cortex.
(Choice B) Multiple endocrine neoplasia (MEN) type 1 is characterized by pituitary adenomas, hyperparathyroidism, and endocrine tumors of the pancreas. Gastrin-secreting pancreatic tumors are common and may lead to recurrent peptic ulcers (Zollinger-Ellison syndrome). However, almost all patients with MEN type 1 have hyperparathyroidism with hypercalcemia.
(Choice D) Early menopause (age <40) is associated with an increased risk of cardiovascular events, but the effect of the prolactinoma-induced low estrogenic state on cardiovascular risk in older women is unclear.
(Choice E) Excess growth hormone secretion from a somatotroph pituitary adenoma can lead to diabetes mellitus due to increased insulin resistance in peripheral tissues. However, adults typically present with acromegaly.
Educational objective:
Hyperprolactinemia suppresses secretion of GnRH, which leads to reduced estrogen in women. Low estrogen levels are a risk factor for accelerated bone loss.
