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Authors: Anastassios G. Pittas, M.D., Arthur S. Tischler, M.D.
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1. Case 1 Answers - Insulinoma

  1. Answer D. Teaching Aim: To understand the work-up of hypoglycemia based on the pathophysiology of the causes of hypoglycemia. The work-up starts with confirming the diagnosis of hypoglycemia. This patient has the Whipple's triad: symptoms, a documented low glucose level and improvement in symptoms with glucose administration. Next, measurement of insulin level while the patient is hypoglycemic is very helpful. The most common cause of hypoglycemia is "insulin reaction" in a patient with diabetes. In patients without diabetes, the clinician should perform the fasting test which aims at precipitating the same symptoms as the patient reports. In this case, the patient is already symptomatic and hypoglycemic, so you can do the required biochemical testing.
  2. Answer A. To interpret the results of the biochemical testing for hypoglycemia. High insulin, and high C-peptide suggests endogenous hypersecretion of insulin. The sulfonylurea level is key to rule out drug administration as the cause of these lab abnormalities.
  3. PATH – At least 75% of pancreatic endocrine tumors are clinically “functional” and produce signs and symptoms attributable to production of a particular hormone. The remaining 25% are clinically “non-functional”, although immunohistochemical or biochemical analysis of the tumor tissue will detect some hormone production most of those cases. An insulinoma is a clinically functional tumor that causes a characteristic syndrome due to hypersecretion of insulin. Additional hormones are often detectable by immunohistochemistry and their presence does not change the diagnosis. Other pancreatic endocrine tumors associated with characteristic syndromes include glucagonoma and somatostatinoma, in addition to tumors producing “ectopic” hormones that are not produced by normal pancreatic islets (e.g. gastrinoma, VIPoma). Tumors producing predominantly PP would most often be “non-functional” because there is no known PP syndrome.
  4. PATH – Endocrine tumors account for only ~1-2% of all pancreatic neoplasms. They can usually be distinguished from common adenocarcinomas in H & E sections by absence of gland formation and relatively bland cytology (monomorphous cells with non-vacuolated cytoplasm, uniform round or oval nuclei, small nucleoli and finely granular chromatin). For more difficult differential diagnoses, immunohistochemical staining is often required. Immunoreactivity for chromogranin and other generic neuroendocrine markers and immunoreactivity for specific hormones are used to establish the diagnosis.
  5. PATH – A. TRUE. See # 3 above.
  6. PATH - Insulinoma is the most common pancreatic endocrine tumor (~30%) and is also the least likely to be malignant (<10% metastasize, versus ~ 50-90% for other pancreatic endocrine tumor types). The prognosis is excellent if a tumor is solitary and completely excised. The prognosis for metastatic insulinoma is poor because of untreatable hypoglycemia. Modest therapeutic benefit has been reported in response to somatostatin analogs that exploit the physiological ability of somatostatin to inhibit insulin release.
  7. PATH – A finding of multiple tumors or of tumors superimposed on a background of hyperplasia is suggestive of familial disease. The presence of multiple “non-functioning” microadenomas (<0.5cm) is a distinctive pancreatic finding in MEN1. Nesidioblastosis (endocrine cells budding off ducts) and endocrine dysplasia (irregular islets < 0.5mm in greatest dimension with trabecular architecture and abnormal cell ratios) are also often present.

2. Case 2 Answers - Pituitary Adenoma, Chromophobe - Type

  1. Answer A. To understand the regulation of prolactin. The diagnosis of a prolactinoma can be established biochemically if the prolactin level is greater than 250 ng/ml. While a prolactinoma is still most likely the most common cause for lower prolactin levels, other etiologies need be considered. Since prolactin is primarily under inhibitory regulation by dopamine, anything that obstructs the transport of dopamine from the hypothalamus to the pituitary gland will result in an elevated prolactin level. In addition, drugs that reduce the concentration of dopamine or interfere with its binding to D2 receptors in the anterior pituitary will also cause an elevation in prolactin. This man may have a large pituitary mass that could be compressing the pituitary stalk, thereby responsible for the increase in prolactin (prolactin elevation is usually much less in this case).
  2. Answer A. Symptoms of adrenal insufficiency and panhypopituitarism may be non-specific and subtle, so that the diagnosis may be missed if the clinician is not astute. Fatigue, low blood pressure and an A.M. cortisol that is below 10 mg/dl are all suggestive of glucocorticoid deficiency. Assessment of adrenal reserve is of utmost importance to determine whether this man requires glucocorticoid replacement therapy. Therefore, a cortrosyn (synthetic ACTH 1-24) stimulation test should be performed as a preliminary test to assess adrenal reserve. A maximal response at 30 or 60 minutes following cortrosyn of less than 18 mg/dl establishes the diagnosis of glucocorticoid deficiency. The inappropriately low TSH for the low levels of thyroid hormone and LH for the level of testosterone are sufficient to establish the diagnosis of central hypothyroidism and hypogonadotropic hypogonadism, respectively, such that additional tests of the thyroid and gonadal axis are unnecessary.
  3. Answer A. Since biochemical testing suggests panhypopituitarism and prolactinoma, imaging of sella turcica to look for a mass lesion should be done next.
  4. Answer B. To appreciate the anatomy in the hypothalamus/pituitary area which includes vital nearby structures. Enlarging masses arising in the sella turcica or suprasellar region can compress the optic chiasm. As a result, abnormalities in peripheral vision may occur, classically seen as bitemporal hemianopsia when formerly evaluated by visual fields. Prolonged compression of the optic chiasm can lead to irreversible nerve damage and permanent loss of vision unless relieved by surgical or medical decompression. Most prolactinomas do not require surgery.
  5. Answer B. Pituitary apoplexy (due to bleeding or infarction) occurs in approximately 10% of patients with pituitary adenomas. Due to rapid expansion of the pituitary lesion by blood, severe headache is common and can be accompanied by the loss of anterior pituitary function (Addisonian crisis) and compression of adjacent structures including the optic chiasm (peripheral visual field abnormalities), hypothalamus (nausea, vomiting, somnolence, coma), cavernous sinus (palsies of cranial nerves III, IV, and VI; loss of sensation or facial pain in the distribution of the ophthalmic and maxillary divisions of cranial nerve V; Horner's syndrome), and temp oral lobes (seizures). Pituitary apoplexy is always an emergency and requires hospitalization for treatment and observation for at least 24 hours.
  6. PATH - The gland is composed of acidophils, basophils, and chromophobe cells. With immunohistochemical methods, it is possible to distinguish cells producing growth hormone, prolactin, ACTH, FSH, LH and TSH.
  7. PATH - This is a neoplasm composed of cells resembling those of the adenohypophysis. Cells are arranged in nests and sheets. The tissue is fragmented since it was removed by trans sphenoidal hypophysectomy.
  8. PATH – The differential diagnosis of masses in the region of the pituitary includes craniopharyngioma, dermoid and Rathke cleft cysts, meningioma and various other primary and metastatic tumors.
  9. PATH – The diagnosis would be established by immunohistochemical staining for pituitary hormones. Some pituitary adenomas are clinically non-functional and many of those express pituitary gonadotrophin alpha subunit and/or generic neuroendocrine markers such as chromogranin. When tumor is infarcted or necrotic, as in pituitary apoplexy, care must be taken to interpret staining only of viable-appearing cells, because antibodies may non-specifically stick to dead tissue.
  10. Adrenal insufficiency must always be evaluated and corrected first. Thyroid hormone replacement in a patient with adrenal insufficiency can precipitate an Addisonian crisis. After cortisol and thyroid deficiencies have been adequately replaced, sex hormones are often given especially in young individuals.
  11. GH replacement is not essential for survival but it can have a number of beneficial effects as we have recently learned. Hypopituitarism with adequate replacement of cortisol, thyroid and sex hormones is associated with a 2-fold increased cardiovascular mortality which may be due to GH deficiency. GH administration to adults may also reduce total body fat mass and have beneficial effects on serum lipids, cardiac output, exercise capacity, bone density, and psychological well-being. The indications for GH replacement, however, are still being investigated.

3. Case 3 Answers – Acromegaly due to GH-secreting Adenoma

  1. Answer A. Acromegaly needs to be suspected on clinical grounds. Since GH is secreted in pulses (1 pulse every 2-4 h), a single GH determination is of no value in the diagnosis of acromegaly, so that suppression tests are required to make the diagnosis. The oral glucose tolerance test is the best test to establish the diagnosis of acromegaly. In normal individuals, a glucose load (75-100g) should suppress serum GH levels to < 1 ng/ml if the two-site immunoradiometric or chemiluminescent assay are used, or to < 2 ng/ml if the regular GH RIA is used. In acromegaly, however, GH levels are not suppressed and in some patients, GH may paradoxically increase after glucose administration. Insulin-like growth factor-1 (IGF-1) is also a reliable indicator for the presence of acromegaly. GH stimulates IGF-1 production by the liver and because of its longer half-life; IGF-1 levels remain fairly constant in the bloodstream. An elevated IGF-1 level, therefore, is an excellent marker of GH excess but must be age and gender matched. IGF-1, however, can be elevated in certain physiological conditions such as puberty and falsely lowered by malnutrition, advanced liver disease, and estrogen administration. Because this patient most likely has acromegaly, which is caused by a pituitary macroadenoma in the majority of patients, deficiencies in other anterior pituitary hormones should be excluded. Thyroid hormone levels and a cortrosyn stimulation test should be performed to assess thyroid and adrenal function, respectively. If the cortrosyn stimulation test is normal, ACTH reserve could be further assessed with an insulin tolerance test or overnight metyrapone test. A testosterone level should be measured to exclude hypogonadism. Since GH-secreting adenomas can also secrete prolactin, a serum prolactin should also be determined.
  2. Elevated GH and IGF-1 levels induce generalized tissue enlargement, including the thyroid gland. With long-standing stimulation, nodular goiters may result. Some of these nodules may become autonomous resulting in thyrotoxicosis. Approximately 10% of patients with acromegaly have thyrotoxicosis and this may be the presenting complaint.
  3. GH is a counterregulatory hormone and it causes insulin resistance and stimulates the mobilization of glucose from the liver. Accordingly, up to 40% of patients with acromegaly have impaired glucose intolerance and many of these patients will develop frank diabetes mellitus if left untreated.
  4. Sweating is a common manifestation of acromegaly due to enlargement and over activity of the sweat glands.
  5. Answer E. The primary treatment of acromegaly is to normalize GH and IGF-1 levels with a combination of surgery, medical and radiation therapy. Transsphenoidal surgery is the procedure of choice for patients with microadenomas (< 1cm) that do not invade the cavernous sinus, since 70-80% of these patients will achieve cure. If GH and IGF-1 levels remain elevated after surgery, medical therapy should be instituted with the somatostatin analog, Octreotide. Octreotide is available as a short acting subcutaneous injection that is administered three times a day or as a long acting preparation (Octreotide LAR) that is administered as an intramuscular injection once a month. Octreotide has been shown to normalize IGF-1 levels in approximately 60-70% of patients with acromegaly. Tumor shrinkage occasionally occurs but is modest. Patients with macroadenomas have an approximately 40% chance of cure. Therefore, Octreotide can be considered as first line therapy, particularly if the macroadenoma has invaded local structures. Other treatment options include a dopamine agonist, such as bromocriptine or cabergoline but these drugs are successful in lowering GH and IGF-1 in only 10-20% of patients and usually not into the normal range. These drugs can be used in combination with Octreotide. Radiation therapy is of modest benefit in reducing GH and IGF-1 levels to normal and it may take years to see an effect. Therefore, radiation therapy should only be considered after other modalities discussed above have failed or the patient refuses other therapies.

    If untreated, acromegaly is associated with an increased mortality due to cardiovascular disease, respiratory compromise, and cancer. Contributing to the increased mortality are glucose intolerance, diabetes mellitus, hyperlipidemia, hypertension, central and obstructive sleep apnea, cardiomyopathy and colonic polyps. Patients should be carefully questioned about snoring or daytime somnolence that might suggest obstructive sleep apnea and should have a colonoscopy. Consideration should also be given to obtaining an echocardiogram. Elevated IGF-1 also causes cartilaginous overgrowth, ultimately resulting in joint damage and degeneration (arthropathy). Bone malformations such as a prominent mandible with malocclusion of the teeth and enlargement of the skull as well as soft tissue swelling and cartilaginous overgrowth resulting in thickened lips and a large nose can give rise to such severe cosmetic deformities that patients may develop a number of psychological problems including depression, poor self-image, decreased motivation and drive, and difficulties with interpersonal relationships.
  6. PATH - This is a neoplasm composed of cells resembling those of the adenohypophysis. Cells are arranged in nests and sheets. The tissue is fragmented since it was removed by trans sphenoidal hypophysectomy.
  7. PATH – The differential diagnosis of masses in the region of the pituitary includes craniopharyngioma, dermoid and Rathke cleft cysts, meningioma and various other primary and metastatic tumors.
  8. PATH – The diagnosis would be established by immunohistochemical staining for pituitary hormones. Some pituitary adenomas are clinically non-functional and many of those express pituitary gonadotrophin alpha subunit and/or generic neuroendocrine markers such as chromogranin. When tumor is infarcted or necrotic, as in pituitary apoplexy, care must be taken to interpret staining only of viable-appearing cells, because antibodies may non-specifically stick to dead tissue.
  9. TRUE. Chromogranin is a generic marker of neuroendocrine cells including those in the pituitary gland.

4. Case 4 Answers – Cushing’s due to Adrenal Cortical Carcinoma

  1. Answer D. To learn the specific symptoms of Cushing's syndrome. Non-specific symptoms which can be seen in many different conditions include: weight gain, weakness, irregular menses and depressed mood. The rest of her symptoms, plethora (rounding of face), spontaneous bruising, and wide purple striae over her abdomen are highly specific for Cushing's syndrome and the patient should be further evaluated for it. Based on her history, you suspect excess cortisol. During the physical examination, you want to concentrate on signs specific for this condition. To learn the physical signs of Cushing's syndrome. Although hypertension can be seen with excess cortisol syndromes, it is not a specific sign. The rest of her examination, however, is highly suggestive of Cushing's syndrome. Obesity is the most common manifestation of cortisol excess, with a very characteristic deposition in the face, neck (supraclavicular and dorsocervical areas), trunk and abdomen with sparing of the extremities. Fat deposition in the face causes "moon facies" and plethora. Excess glucocorticoids because of reduced skin and fibroblast protein synthesis leads to thin atrophic skin, easy bruising following minimal trauma and poor wound healing. Wide (over 1 cm) red to purple striae in areas of skin expansion due to fat accumulation (abdomen) occur because of loss of underlying connective tissue. These pathologic striae need to be distinguished from the more common physiologic striae that occur with rapid weight gain during pregnancy (white/slivery, less than 1cm wide). Weakness, especially in the proximal muscles of the extremities, occurs because of muscle wasting. The symptoms and signs of Cushing's syndrome vary based on the duration and severity of cortisol excess. One of the simplest and most economical tests to help in deciding whether a patient may have Cushing's syndrome is to look at serial pictures of the patient to appreciate the physical changes that take place over time.
  2. Answer B. When Cushing's syndrome is suspected, exogenous glucocorticoid therapy - the most common cause of Cushing's syndrome - needs to be ruled out prior to embarking on a diagnostic work-up. Hopefully, that will be apparent by the history. "Routine" blood work may provide additional evidence supporting the diagnosis of Cushing's syndrome. WBC tends to be elevated and it is often accompanied by a left shift. Patients may exhibit glucose levels diagnostic of diabetes mellitus.

    When Cushing's syndrome is suspected based on the history, physical examination and routine blood work, the first question that needs to be asked is: does this patient have Cushing's syndrome. In other words, one needs to demonstrate glucocorticoid excess. There are two ways to do this: (1) the 1 mg overnight dexamethasone suppression test and (2) measurement of free cortisol in a 24-hour urine specimen. The rationale behind the 1 mg overnight dexamethasone suppression test is that the hypothalamic-pituitary-adrenal axis is under precise negative feedback control. A dose of dexamethasone given at 11 pm should suppress the surge of CRH and ACTH (that occurs in the early morning) resulting in low morning cortisol (less than 5 mcg/dl). This test is easy to perform in outpatients and is the preferred screening test for Cushing's syndrome. Because the overnight dexamethasone test can have many false positives (a normal test rules out Cushing's but a positive test does not rule in Cushing's), usually a 24-hour measurement of urinary free cortisol is performed to confirm cortisol excess. Cortisol levels fluctuate widely during the day and values in healthy individuals overlap with those in patients with Cushing's. Therefore, in general, a random cortisol level measurement cannot establish the diagnosis of Cushing's syndrome. However, in Cushing's syndrome, there is loss of the normal diurnal variation of cortisol (normally high in the morning and low in the evening) resulting in an elevated evening cortisol. Probably the best test for the diagnosis of autonomous cortisol production is measurement of a midnight cortisol level which is always elevated in patients with Cushing's syndrome. This test is rarely used for logistic reasons.
  3. After making the diagnosis of Cushing's syndrome biochemically, determining the location of the problem is the next step. In our case, following the dexamethasone dose at 11 pm, the 8 am cortisol level was not suppressed, indicating autonomous production of cortisol and confirmed the presence of excess cortisol. Our patient did have a 9 pm cortisol measurement which was elevated at 25 mcg/dl (normal < 7.5 mcg/dl) which is highly suspicious for Cushing's. (Review differential diagnosis of Cushing's). The key concepts to keep in mind when determining the location of the excess cortisol production are: (1) pituitary tumors that secrete ACTH (Cushing's disease) are autonomous but maintain some feedback inhibition and (2) adrenal and ectopic tumors (in general) do not maintain feedback inhibition. The overnight dexamethasone suppression test is repeated with giving a high dose (8 mg) of dexamethasone. Suppression of morning cortisol to less than 50% of the baseline value suggests Cushing's disease. In this patient, there was no suppression, so adrenal causes are suspected.
  4. PATH - In adult patients, approximately 75% of resected adrenal glands will show evidence of cortical hyperplasia. Twenty five percent will show evidence of neoplasia (12.5% with cortical adenomas and 12.5% with cortical carcinoma). A much higher proportion of adrenals from children will show evidence of adrenal neoplasia (carcinoma or adenoma).
  5. PATH - In patients with cortical adenoma, the adjacent cortex shows evidence of atrophy. In patients with nodular hyperplasia, the cortex between the nodules will show evidence of diffuse hyperplasia.
  6. PATH - Cortical carcinomas typically weigh more than 100 grams. Important histological features of malignancy include vascular and capsular invasion, necrosis, and numerous and atypical mitoses. Softer features include “compact” lipid-depleted cells, high nuclear grade, diffuse architecture the presence of broad fibrous bands and abnormal nucleoli. As with other endocrine tumors, some adrenal cortical tumors can not be unequivocally characterized as benign or malignant unless they metastasize.
  7. PATH - Cortical carcinomas generally show weak or absent reactivity for keratin proteins. Most metastatic carcinomas are keratin positive.