{25394} adrenal cortical atrophy (key says "hypoplasia", I doubt this)
{24607} adrenal amyloidosis, gross
{15960} cytomegalic inclusion disease, adrenal
{37216} adrenal leukodystrophy ("Lorenzo's oil") case, gross brain
{37218} adrenal leukodystrophy case, gross brain
{37221} adrenal leukodystrophy case, histology brain
{37224} adrenal leukodystrophy case, gross adrenal
{37225} adrenal leukodystrophy case, histology adrenal

Adrenal amyloidosis WebPath Photo

Adrenals Atrophic, normal, hyperplastic WebPath Photo

NOTE: Hollywood is Hollywood. Evidence that "Lorenzo's oil" benefits adrenoleukodystrophy patients remains "anecdotal" (Brain & Dev. 14: 409, 1992); it failed controlled studies miserably (NEJM 329: 745 & 801, 1993; NEJM 330: 1904, 1994; Ann. Neuro. 34: 121 & 169, 1993), and poisons platelets (NEJM 328: 1126, 1993; Am. J. Hem. 44: 290, 1993; J. Inh. Metab. Dis. 17: 628, 1995) and (at least sometimes) natural-killer lymphocytes (J. Inh. Metab. Dis. 18: 101, 1995). We've now got two series of dead adrenoleukodystrophy patients who were treated in life with Lorenzo's oil. It turns out that the stuff doesn't even cross the blood-brain barrier, which is probably why it doesn't work (Neuroch. Res. 19: 1073, 1995; Ann. Neuro. 36: 741, 1995). Yet another massive failure: J. Neurol. Neurosurg. Psych. 67: 290, 1999. Interest continues, and a study from Hopkins (Arch. Neuro. 62: 1073, 2005) that claimed success in preventing lesions in asymptomatic boys had no controls and also included other dietary alterations.

ACTH deficiency ("secondary hypoadrenocorticism")

These patients have almost always lost their adenohypophysis and have "panhypopituitarism". (Treat the whole person.... Caring for a little pituitary dwarf? Don't get focused on the height so that you forget the likely adrenal insufficiency.... J. Clin. End. Metab. 81: 1693, 1996) Less often, they have selective, presumably autoimmune, loss of the ACTH-producing cells: Arch. Int. Med. 152: 1705, 1992.

Clinical picture:

"Addisonian" patients show weakness, nausea, and weight loss, and are usually hypotensive (*  110/70 or less) and have other complaints. Like most endocrine patients, the problems are likely to appear "emotional".

In primary hypoadrenocorticism, the skin and buccal mucosa will usually be hyperpigmented, due to increased ACTH (MSH?) -- also look at freckles, nipples, palmar creases, old scars.

Lab studies typically show hyponatremia, hyperkalemia, metabolic acidosis, hypoglycemia, low serum cortisol, low urinary 17-OH-steroids, and (most important) failure to respond to various "stimulation tests" by increasing cortisol output.

It is common for these patients to die suddenly and unexpectedly before anyone thinks of adrenocortical insufficiency. This still happens (Br. Med. J. 312: 1085, 1996).

* Osteoporosis is severe in post-menopausal women with Addisonism, because of loss of adrenal androgens.

Replacement therapy is life-saving. (And get your patient a syringe of cortisol and an ID bracelet.)

* Some women feel better and have better sexuality if they get some DHEA. Makes sense. Why? (NEJM 341: 1013, 1999).

{09371} Addison's disease; pigmentation and vitiligo (mother and daughter)
{09372} Addison's disease, face
{09373} Addison's disease, buccal pigmentation
{49438} Addison's disease, pigmentation
{49439} Addison's disease, pigmentation
{49440} Addison's disease, atrophy of the adrenal gland

Selective hypoaldosteronism is rarely due to primary disease of the adrenal cortex. (Clinicians talk about "hyporeninemic hypoaldosteronism".)

Much more often, the problem is really that the JGA is not producing renin (REE-nin, remember?). Usually the problem is diabetic arteriolar disease (no surprise); less often, it is one of the diseases of the renal tubules and/or interstitium.

* These patients have type IV renal tubular acidosis, exhibit normal response to ACTH stimulation testing, and need a prescription for oral 9α-fludrocortisone.

Acute hypoadrenocorticism ("adrenal apoplexy", "Addisonian crisis"): Sudden collapse, often fatal (the mechanisms are not fully understood, but it involves opening of the peripheral vasculature and shock with high cardiac output; consider giving any such patient glucocorticoid: Arch. Surg. 128: 673, 1993.)

Please do not miss this one.

It may result from undiagnosed adrenal insufficiency (iatrogenic, or patients stressed by infection, surgery, or treatment of concurrent myxedema; see for example J. Traum. 32: 94, 1992), or from known Addison's disease when extra glucocorticoids are not provided during stress.

Waterhouse-Friderichsen syndrome ("adrenal apoplexy") features hemorrhage, fibrin thrombi, and sometimes necrosis in the adrenals in a setting of sepsis. It's not clear whether death is due to adrenal shutdown, but it's not helping.

This occurs when there is overwhelming sepsis with hemorrhage into, and destruction of, the adrenals. Patients develop purpura, shock, and die in a few hours.

The etiologic agent is classically N. meningitidis, though staphylococci (possible new WF-producing strain NEJM 353: 1245, 2005), pneumococci, and H. influenzae are other important causes (J. Clin. Path. 57: 208, 2004).

W-F is not rare, and is often overlooked. One group suggests that if your patient in shock does not have elevated serum cortisol, he or she presumably has W-F. Draw blood, then give 200 or 300 mg of hydrocortisone (West. J. Med. 150: 582, 1989). Another protocol, for anybody who's septic: Am. J. Med. 98: 266, 1995.

* Expect the unexpected. A lady dies because toluene inhalation somehow produces adrenal necrosis: J. Tox. 36: 365, 1998.

{24606} Waterhouse-Friderichsen adrenal, gross
{09224} adrenal hemorrhage, consistent with Waterhouse Friderichsen
{07570} adrenal hemorrhage, gross, consistent with Waterhouse-Friderichsen syndrome

Waterhouse-Friderichsen WebPath Photo	Waterhouse-Friderichsen WebPath Photo
Waterhouse-Friderichsen Patient photo WebPath Photo

CUSHING'S SYNDROME: too much glucocorticoid. Review NEJM 332: 671, 1995.

Etiologies, from most to least common

1. Iatrogenic (the most common cause nowadays, preventable in part by giving "alternate-day" glucocorticoid therapy). Of course, the adrenals will be atrophic if glucocorticoids were administered, hyperplastic if ACTH was administered.

2. ACTH-producing pituitary lesion, usually a basophilic microadenoma ("Cushing's disease", "pituitary Cushingism")

The adrenals will be nodular, often with one or more large nodules (CT scanners take note -- a single "adenoma" does not necessarily rule out the need for pituitary surgery).

"Nelson's syndrome" -- rapid enlargement of the pituitary adenoma leading to hyperpigmentation, blindness and death -- followed adrenalectomy in many of these patients. (Why? It still happens -- sometimes the only way to relieve Cushingism is to remove the adrenals.)

3. Adrenal cortical adenoma or carcinoma ("adrenal Cushingism"); the tumor may be primary, or an autonomous adrenal tumor may develop after years of "pituitary Cushingism")

4. ACTH- (or CRH-) producing cancers of other organs: oat-cell carcinoma (very well-known), bronchial and thymic carcinoids (rather common; S. Med. J. 87: 855, 1994; Mayo Clin. Proc. 69: 594, 1994), medullary thyroid carcinoma, islet cell cancer; other APUDomas. Full-blown Cushingism is rare in oat cell patients, only because they don't live long enough....

{49441} looks like an oat cell case; adrenal cortex is hyperplastic, and bears a metastasis

* Urocortin is a hormone widely distributed in the nervous system, with CRH-like activities; it is presently in search of a disease. Both CRF and urocortin are potent anorectic agents. The newly-discovered "urocortin 3" is also called stresscopin. The truly hardcore can see J. Clin. Endo. Metab. 90: 4671, 2005.

* 5. Really "primary" adrenal hyperplasia (not due to excess ACTH):

• "primary pigmented nodular adrenocortical hyperplasia", a "newly discovered disease" that is part of the autosomal dominant Carney complex (along with weird tumors and a paradoxical response to the dexamethasone suppression test: Ann. Int. Med. 131: 585, 1999).
• Circulating antibodies against the ACTH receptor (analogous to Graves disease) can occasionally stimulate the gland into hyperactivity. Call a surgeon.
• Macronodular hyperplasia with marked adrenal enlargement. Arch. Path. Lab. Med. 123: 167, 1999.
• * Genetic syndrome with too many cortisol receptors, low plasma cortisol: J. Clin. Endo. Metab. 85: 14, 2000.
Future pathologists: Don't get excited over a lumpy adrenal. Many people have a few adrenal nodules, including a few pigmented ones.

* 6. Cushingism with a burst of cortisol after eating: inappropriate expression of GIP receptors on the adrenal cortex / adrenal adenoma (NEJM 327: 974, 1992; J. Clin. End. Metab. 81: 3168, 1996; J. Clin. Endo. Metab. 86: 583, 2001). There are other aberrant receptor problems as well: J. Clin. Endo. Metab. 88: 416, 2003.

* 7. Recurrent cushingism of pregnancy: Nobody understands it; the adrenal cortex must over-respond to some non-ACTH hormone made during gestation J. Clin. End. Metab. 81: 15, 1996; Clin. Endo. 54: 277, 2001.

Both Cushing's disease and glucocorticoid-secreting adenomas are most common in women ages 15 to 45, but can hit anybody, anytime. (*  Cushingism in kids and teens: NEJM 331: 629, 1994).

Symptoms and signs that should alert you to possible Cushingism:

• truncal obesity with "buffalo hump" and "moon face"

• increased appetite

• insomnia and mental changes (*  Cushing's psychosis seems to be treatable using RU486, i.e., mifepristone, better known as "the abortion pill", a fact that held up its use in the U.S. for years; at high doses it is an effective cortisol antagonist: Ann. Int. Med. 114(2): 143, 1991; review NEJM 329: 404, 1993; it is now mainstream J. Clin. Endo. Metab. 86: 3568, 2001).

• vascular and connective tissue changes: thinning of the dermis (helps you spot it: Arch. Int. Med. 154: 777, 1994), bruisability, striae ("purple stripes"), very poor healing, purpura -- * look at old band-aid sites)

• high blood pressure

• glucose intolerance (diabetes, with complications)

• osteoporosis (loss of the bone substance)

• loss of normal circadian rhythm of cortisol secretion (this is important, because it helps you and the lab make the diagnosis)

• other: acne, cellulitis, edema, gastric ulcers, hirsutism, acne, oligomenorrhea (scanty menstrual flow), hypokalemia, muscle wasting, ringworm

{09367} Cushingism, face
{09370} Cushingism, face
{16109} Cushing's syndrome
{16110} Cushing's syndrome
{16112} Cushing's syndrome "before"
{16111} Cushing's syndrome "after"
{49426} Cushingism, 40 y/o patient
{49427} Cushingism
{49428} Cushingism, hyperplastic adrenal cortex

* Future pathologists: Heavy negative feedback on pituitary basophilic ACTH-producing cells produces "Crooke's hyaline change".

PRIMARY HYPERALDOSTERONISM ("low-renin hyperaldosteronism"): too much mineralocorticoid (review: Postgrad. Med. 95(4): 199, March 1994; NEJM 339: 1820, 1999; Lancet 353: 1341, 1999; Surg. Clin. N.A. 84: 887, 2004)

This results from "idiopathic" adrenal hyperplasia, or an adrenal adenoma.

This is important as a cause of surgically-correctable high blood pressure. Maybe 0.5% of hypertensives have primary hyperaldosteronism.

Classically, patients exhibit hypokalemia, alkalosis, and low renin, and a failure of plasma aldosterone levels to increase significantly when the patient goes from supine to standing position.

Surprisingly, these patients do not have edema. (The effects of aldosterone in hanging onto body salt is overridden by atrial natriuretic peptide.)

Low potassium is likely to cause muscle weakness, and even paralysis.

Trap: These patients can die from hypokalemia if you give them thiazide diuretics to treat their high blood pressure.

Today, we screen by looking for the plasma aldosterone / plasma renin activity ratio. Around 5-10% of hypertensives have elevated levels, and many of these people will indeed have an aldosteronoma that can be removed (Am. J. Med. Sci. 324: 227, 2002); the rest will usually have hyperplastic cortices.

The most familiarr cause is an "autonomous" adrenal cortical adenoma (Conn's syndrome), often very small. It produces aldosterone (*  rare Conn-omas produce DOC instead). You'll clinch the diagnosis by sampling aldosterone levels in the adrenal veins (J. Clin. End. Metab. 86: 1066, 2001). Surgery is curative (Ann. Surg. 219: 347, 1994; Postgrad. Med. 95(4): 199, Mar. 1994); it is now routinely done via laparoscope (review J. Urol. 169: 32, 2003).

The rest of the patients have "idiopathic hyperaldosteronism", with normal or hyperplastic adrenals. These patients get spironolactone. Not surprisingly, the borderland between these and the adenomas is blurry (Surgery 106: 1161, 1990); probably it's best to operate only if the hypertension is unsuppressible medically like a Conn-oma.

A few patients have glucocorticoid-correctable hyperaldosteronism and hypertension. This is transmitted autosomal-dominant. It is now clear that the problem is a chimeric beta-hydroxylase/aldosterone synthetase gene (Nature 355: 262, 1992; Lancet 339: 1024, 1992; screening kids Arch. Dis. Child. 71: 40, 1994; J. Urol. 154: 510, 1995). Update J. Clin. Endo. Metab. 87: 3187, 2002. When the cell is told by ACTH to make cortisol, it pumps out huge amounts of aldosterone, too. (Thinkers: Giving a tiny amount of exogenous glucocorticoid solves the problem. How? If you can't answer this, consider taking year I over again.)

* Hypertension from a mutated aldosterone receptor stuck in the "on" position: Science 289: 119, 2000.

* Another cause is "apparent mineralocorticoid excess syndrome", a lack of 11-β-hydroxysteroid dehydrogenase type 2, which turns cortisol to cortisone in the renal tubules; cortisol ends up overstimulating the mineralocorticoid receptors. The forme fruste may be a common contributor to "idiopathic" low-renin hypertension even with normal potassium. See J. Clin. Endo. Metab. 86: 1247, 2001; Lancet 353: 1341, 1999. Yet another is a 21-deoxyaldosteronoma (J. Clin. End. Metab. 80: 737, 1995). Rarely an ovarian cancer produces aldosterone (series Arch. Int. Med. 156: 1190, 1996).

Secondary aldosteronism is much more common. It is part of the picture in CHF, cirrhosis, nephrotic syndrome, Goldblatt hypertension, and other common problems.

Don't forget Bartter's hypokalemia (vessels are insensitive to angiotensin and/or the sodium pump in the ascending loop of Henle doesn't work -- Hosp. Pract. 29(5): 103, 1994.

Don't confuse this with salt-retaining congenital adrenal hyperplasia (see below).

CONGENITAL ADRENAL HYPERPLASIA: autosomal-recessive virilization syndromes that, in their most severe forms, affect young children.

Deficiencies (mild or severe) of the various enzymes required to synthesize cortisol result in decreased production of cortisol and other hormones.

This results in increased ACTH, with resulting adrenal cortical hyperplasia.

Steroid precursors are shunted into the production of abnormally large amounts of the androgen androstenedione (ambiguous genitalia in girls, "infant Hercules" and Leydig cell nodules in boys, etc.)

Remember these two types (there are at least six others):

21-hydroxylase deficiency (most common): no cortisol, aldosterone, or DOC, hence salt wasting. This gene is inside the HLA locus. Review J. Clin. Endo. Metab. 88: 2624, 2003.

11-betahydroxylase deficiency: huge amounts of DOC, causing salt retention and high blood pressure (molecular biology of the gene Proc. Nat. Acad. Sci. 90: 4552, 1993).

Full-blown congenital adrenal hyperplasia is a devastating illness, especially for women. Mild variants of these syndromes (i.e., relatively ineffective enzymes -- especially 21-hydroxylase deficiency) are probably widespread -- causing, for example, amenorrhea in girls or hirsutism in older women.

It's important to find these people because a little dexamethasone given daily will greatly improve the internal milieu.

To test your female patient with amenorrhea or hirsutism, administer ACTH and measure plasma 17-hydroxyprogesterone one hour later. It will be elevated if your patient has even mild 21-hydroxylase deficiency.

{49437} adrenogenital syndrome 2 year old girl
{24450} adrenogenital syndrome, virilized baby girl
{49432} 11-hydroxylase deficiency, 11 month old boy

ADRENAL CORTICAL ADENOMAS

These are round, yellow (like the adrenal cortex) nodules. (*  Purists call them "nodular hyperplasia" if the surrounding cortex is at all lumpy-bumpy).

Adrenal cortical adenomas are surprises at around 2% of autopsies and abdominal CT scans. They can cause Cushing's syndrome, Conn's syndrome, or virilization -- but the vast majority seem to produce nothing.

They are commonly discovered on CT scans too, and clinicians are learning to ignore small adrenal masses ("incidentalomas", so long as there is no evidence of steroid or catecholamine over-production).

* It's probably smart to screen for Cushingism. Maybe 20% of these really are active, and contribute to hypertension, diabetes, obesity, and osteoorosis, even if the patient is not floridly Cushingoid. Common sense triumphant. See Surg. Clin. N.A. 84: 875, 2004. "Occult/subclinical Cushingism due to incidentaloma" is now a recongnized entity: J. Clin. Endo. Metab. 88: 5808, 2003. NIH Consensus Conference: Ann. Int. Med. 138: 424, 2003.

* Leave discussions of the arcana of these common lesions to us. This includes "spironolactone bodies" (pink scroll-like things, also found in the ZG of folks taking spironolactone), "black adenomas", and much more.

"Adrenal cysts" seen on scans have unpredictable pathology: Cancer 101: 1537, 2004.

{09220} adrenal cortical adenoma, gross
{20312} adrenal cortical adenoma, gross
{49436} adrenal cortical adenoma, gross; this one produced Conn's syndrome
{10298} adrenal cortical adenoma
{20315} adrenal cortical adenoma, histology
{09221} adrenal cortical adenoma, histology
{09222} adrenal cortical adenoma, histology
{08964} adrenal cortical adenoma, histology (hard to tell from normal cortex)
{09052} adrenal cortical adenoma, electron micrograph; note tubular cristae in mitochondria (spaghetti instead of lasagna)
{09375} effect of masculinizing adrenal cortical adenoma, "before"
{09374} effect of masculinizing adrenal cortical adenoma, "after"
{49434} gynecomastia in five-year old boy, feminizing adrenal cortical adenoma

Adrenal cortical adenoma This was a cushingoma WebPath Photo

Adrenal cortical adenoma This was a connoma WebPath Photo

Adrenal cortical adenoma WebPath Photo

* Adrenal myelolipoma: a metaplasia-choristoma made of bone marrow. They can be big but are generally harmless. You can see bone marrow in adrenal cortical hyperplasia too.

{25412} adrenal myelolipoma, gross
{49443} adrenal myelolipoma, gross
{25413} adrenal myelolipoma, histology

Adrenal myelolipoma
Pittsburgh Pathology Cases

ADRENAL CORTICAL CARCINOMA (Am. J. Clin. Path. 105: 76, 1996; J. Urol. 169: 5, 2003)

These are rare cancers that are often lethal. The majority are hormonally active.

Future pathologists: These are usually obviously malignant, grossly and microscopically, with ten or more mitotic figures per high power field.

* Another tipoff is broad fibrous bands, but you usually won't need this to know you're looking at cancer.

* Mixed endocrine syndromes usually mean cancer. Adrenal tumors that feminize, or that produce androgens without glucocorticoids, are most often malignant. Mitotane, an analogue of the old-fashioned insecticide DDT, is the classic mainstay of therapy.

* Future pathologists: Use electron microscope to find tubulovesicular mitochondria, which are characteristic of adrenal cortex. Criteria for malignancy have been developed; since this cancer is not particularly treatable, their usefulness is limited.

Adrenal cortical carcinoma Pittsburgh Pathology Cases

Adrenal cortical carcinoma Pittsburgh Pathology Cases

Adrenal cortical carcinoma WebPath Photo

Adrenal cortical carcinoma WebPath Photo

Adrenal cortical carcinoma WebPath Photo

{24087} adrenal cortical carcinoma, gross
{40196} adrenal cortical carcinoma
{24090} adrenal cortical carcinoma, histology

NOTE: Cancer in the adrenals is usually metastatic carcinoma. Half of all lung cancers metastasize to the adrenals. Adrenal insufficiency often results, but is usually missed clinically.

Metastatic cancer in the adrenals

WebPath Photo

THE ADRENAL MEDULLA: "An organ not essential to life".

Around 10% of the normal adrenal by weight. The source of "adrenalin" (epinephrine, also norepinephrine). At autopsy it is gray, unless it has autolyzed.

The only diseases are two tumors that may arise here or at the other chromaffin tissue masses -- pheochromocytoma (well-differentiated, adults) and neuroblastoma (poorly-differentiated, children).

* The story of the old adrenal-to-brain transplant for parkinsonism: Mayo Clin. Proc. 65: 305, 1990.

PHEOCHROMOCYTOMA ("paraganglioma", "pheo", "ten percent tumor"; big NIH consensus review Ann. Int. Med. 134: 315, 2001).

This tumor is named for its colorful reaction in fixatives containing chromic acid salts.

Pheochromocytomas secrete norepinephrine (most common) and/or epinephrine (usually less, * and often other things, including dopamine, serotonin, ACTH, somatostatin, neuropeptide Y, and/or VIP; Cancer Res. 49: 7010, 1990).

The infamous paroxysms of extreme hypertension, accompanied by sweating, headache, and other autonomic disturbances, probably result from physical compression and/or ischemia of the "pheo".

Even a tiny (1 gm) benign pheochromocytoma can make a person very sick and will eventually cause death.

Most (50-90%, estimates vary) occur in the adrenal medulla (you may learn "10% are extra-adrenal"). Other sites are the organs of Zuckerkandl (i.e., the little nubbins of chromaffin tissue at the origin of the inferior mesenteric artery and/or aortic bifurcation), paravertebral sympathetic chain, urinary bladder (patients get terrible headaches whenever they urinate), or "paraganglia" such as the carotid body. Ten percent occur in children.

Ten percent of pheo cases involve both adrenals, and many of these are also among the 10% that are familial. Syndromes include:

• MEN IIa or IIb
• von Recklinghausen's neurofibromatosis (NF-I)
• von Hippel-Lindau (JAMA 275: 839, 1996, pheo-only allele J. Clin. Endocrin. Metab. 81: 147, 1996)
• succinic dehydrogenase mutation (really; J. Clin. End. Metab. 86: 2890, 2001; Lancet 357: 1181, 2001).
* A large minority of people with non-familial, non-syndromic pheochromocytoma have a copy of one of these anti-oncogenes (except NF-I) deleted in their non-tumor tissues: NEJM 346: 1459, 2002. No surprise.

You will often be reminded of the MEA ("MEN", "multiple endocrine adenoma/neoplasia syndromes") -- common autosomal dominant conditions that predispose patients to certain endocrine tumors. Pre-natal diagnosis is available for these tumor-gene syndromes. Learn them now:

MEN I: PPP (Wermer's syndrome), * protein menin, on 11q13

Parathyroid adenoma(s) (1 or, often, more glands) / "chief cell hyperplasia" (i.e., all four glands): NEJM 321: 213 1989)

Pituitary adenoma (anterior)

Pancreatic islet cell adenoma (gastrinoma)

* Bronchial and thymic carcinoids too... the latter mostly in middle-aged men who smoke a lot. Medicine 76: 21, 1997.

MEN IIa: PAC (Sipple's syndrome); the RET gene (Nature 367: 315, 375, 377 & 378, 1994; NEJM 335: 943, 1996; J. Clin. End. Metab. 81: 2711, 1996; screening for the gene J. Clin. Endo. Met. 78: 1261, 1994 and Mayo Clin. Proc. 72 430, 1997; new alleles keep appearing J. Clin. Endo. Metab. 89: 4142, 2004; surveillance J. Clin. End. Metab. 82: 897, 1997).

Parathyroid adenoma(s) (1 or, often, more glands) / "chief cell hyperplasia"

Adrenal medullary tumor (pheochromocytoma) or hyperplasia

Calcitonin-producing hyperplasia-carcinoma of thyroid

MEN IIb:

Similar to MEN IIa; the patients have Marfanoid body habitus and mucosal (ganglio)neuromas (bumps on the edges of their tongues and elsewhere), and probably will not have parathyroid problems. Same locus, different allele (Nature 1994, see above.)

Patients with MEN II may first have adrenal medullary hyperplasia, which can be nodular. * Nodules over 1 cm are considered pheos.

Grossly, pheos are very bloody (because they are very vascular), and often show fibrosis, calcification, cystic change, or even * fatty change (?!)

Microscopically, pheos resemble adrenal medulla.

* Special stains are available that show norepinephrine and/or epinephrine in granules (*  future pathologists: aqueous fixation washes them out.) Contrary to what anybody else may have told you, the granule morphology means nothing: Br. J. Surg. 85: 1681, 1998.

For pheos, there are no histologic criteria for malignancy, not even vascular invasion. The honest pathologist cannot predict the tumor's behavior. Although 10% of these tumors can metastasize, to prove malignancy you must find pheo in a location where it could not have arisen. Five-year survival rate with malignant pheo is around 50%.

* "Pheo balls" are hyaline spheres that can be very big. You can see them in most normal medullas if you look hard enough. Nobody knows for sure what they are, but they seem to stain for vimentin and glial filament acid protein (Am. J. Clin. Path. 102: 163, 1994, which deals with how to spot bits of neuroblastoma which may be present on pheo's.) Fun to know: They are acid-fast and autofluorescent!

More fun: A pheo or neuroblastoma, as a frozen section, exposed to formalin, fluoresces yellow-green from the catecholamines getting altered.

Regardless of location and appearance, the patients will report anxiety, headache, palpitations, "panic attacks", sweating, dizziness, etc. (Again, you may suspect the basic problem is emotional. "Pheo is a great imitator.")

"Textbook" pheochromocytoma patients have paroxysms of severe hypertension. Actually, the majority show sustained high blood pressure.

Pheochromocytoma is present in fewer than 1% of people with high blood pressure, but it's a diagnosis you don't want to miss.

Pheos are still often missed clinically (Am. J. Surg. 179: 212, 2000) and are all-too-familiar surprises at autopsy (Lancet 335: 1189, 1990). The patients typically had been told they had "benign essential hypertension" and "emotional problems".

In addition to causing bad high blood pressure and all that goes with it, high levels of circulating catecholamines can directly (though reversibly) damage the myocardium can cause coronary spasm, and can play havoc with smooth muscle (renal arteries, bowel, brain, etc. -- angiographers may report "vasculitis".)

Screening tests for pheos detect increased amounts of catecholamines or their metabolites in blood or urine.

The classic screen for pheos (24 hour urinary vanillylmandelic acid -- VMA) is being superseded by more sensitive and specific tests.

Today's "most sensitive screen" is the plasma free metanephrine assay (Ann. Int. Med. 134: 315, 2001; Arch. Int. Med. 160: 2521, 2000; JAMA 287: 1427, 2002).

There's a radioisotope scanner/treatment for pheo and neuroblastoma -- I-131 labeled metaiodobenzylguanidine (MIBG); it's not very sensitive for diagnosis (J. Clin. Endo. Metab. 86: 685, 2001).

Using 131-I-MIBG for metastatic malignant pheochromocytoma, with very good results: Cancer 98: 239, 2003; J. Clin. Endo. Metab. 90: 5888, 2005.

* Finding the hidden pheo using novel techniques, including 6-[¹⁸F]-fluorodopamine: J. Clin. Endo. Metab. 86: 3641, 2001.

* The Mayo crew examines how much it would cost to screen every hypertensive patient for pheo using each of three methods, and simply states that spending $50,000 or $100,000 per patient found isn't worth it; I disagree (J. Clin. Endo. Metab. 89: 2859, 2004), and certainly you need to work up the young ones, the ones with headaches, and the ones with "nerves".

Treatment is surgical, with very careful management of fluid status and blood pressure before and after surgery (J. Urol. 161: 764, 1999). The anesthesiologist, of course, has an extra challenge (Anesth. Analg. 91: 1118, 2000). And surgeons must be careful manipulating the tumor! Adrenal sparing surgery, i.e., let's leave a bit of cortex behind: Br. J. Surg. 86: 94, 1999. Today, it's likely that the tumor will be removed successfully via the laparoscope (Urol. Clin. N.A. 28: 97, 2001).

* Injecting epinephrine to fake a pheo: JAMA 266: 1553, 1991 (weird!).

{20316} pheochromocytoma in adrenal, gross
{25417} pheochromocytoma, gross
{49444} pheochromocytoma, gross
{09226} pheochromocytoma, gross
{09227} pheochromocytoma, showing positive brown staining with chromic acid ("chromaffin")
{08874} pheochromocytoma, histology
{08873} pheochromocytoma, histology
{25418} pheochromocytoma, histology
{09228} pheochromocytoma, histology
{09229} pheochromocytoma, histology, positive chromaffin reaction
{09080} pheochromocytoma, electron micrograph showing granules
{09081} pheochromocytoma, electron micrograph showing granules
{08056} pheochromocytoma cardiotoxicity
{08053} pheochromocytoma cardiotoxicity; note contraction bands

Pheochromocytoma WebPath Photo

Pheochromocytoma Chromaffin reaction WebPath Photo

Pheochromocytoma WebPath Photo

Pheochromocytoma WebPath Photo

Pheochromocytoma Electron micrograph WebPath Photo

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Paragangliomas Pittsburgh Pathology Cases

Pheochromocytoma Virtual Hospital

NEUROBLASTOMA (CA 45: 179, 1995, Ped. Clin. NA 44: 919, 1997.)

The second commonest solid pediatric cancer (after Wilms tumor). It is derived from primitive nerve elements (*  and the cells will always grow neurites, at least in tissue culture). Discovered by Virchow.

A majority of neuroblastomas arise in or near the adrenals.

Grossly, neuroblastomas are soft, white tumors.

Portions often undergo dystrophic calcification (which helps the radiologist make the diagnosis.)

The tumor eventually metastasizes widely. "Blueberry muffin baby" is a repulsive, classic description for a neuroblastoma patient with multiple skin metastases.



Histologically, neuroblastoma is a tumor of "small blue cells" (i.e., cancers with small, fairly-uniform cells with scanty cytoplasm). Often (but not always) the cells are arranged in "rosettes" (recalling neural tubes) around a tangle of neurites (*  "Homer Wright rosettes", pretty-much diagnostic). EM shows neurosecretory granules and * sometimes neurites too. (*  Purists: True rosettes surround a hole. Think of ependymomas or retinoblastomas.)

* Future pathologists: Immunohistochemistry helps differentiate this from other "tumors of small blue cells" (the LEMON family), and will also help you recognize their nondescript cells in bone marrow. The better-differentiated neuroblastomas are likely to stain positive for neuron specific enolase, S-100, and/or synaptophysin, but the more primitive ones will be negative for everything. In tissue culture, neuroblastoma cells sprout neurites almost at once.

Grading of the tumor is based on mitotic figure counts, with karyorrhexis being taken into account nowadays also: Cancer 77: 1582, 1996 updates the older Shimada system. The most recent update is the "International Neuroblastoma Pathology Committee" system (Cancer 86: 364, 1999; Cancer 92: 2451 & 2699, 2002; Cancer 94: 1574, 2002).

Most neuroblastomas produce catecholamines, resulting in elevated urinary metabolites. (*  They also produce certain characteristic protein markers, etc., etc.)

The classic test involves checking urine for homovanillic acid (HVA) and vanillylmandelic acid (VMA). Japan screens all babies at six months of age (Lancet 2: 152, 1988); skeptical Brits suggest that they find only regressing tumors (Lancet 337: 344, 1991). The Germans now screen at one year and find it lot of cases, but I couldn't tell whether they're saving lives (J. Clin. Onc. 17: 1200, 1999 -- anybody want to do a lab presentation on this?). Now the Japanese are doubting whether they've saved any lives, either (Canc. Caus. Contr. 9: 631, 1998; "we haven't" J. Ped. Surg. 37: 949, 2002). Neuroblastoma screening has not caught on in the US in the "managed care era"; both big studies indicate it's a bad idea NEJM 346: 1041 & 1047, 2002.

There are also a variety of curious paraneoplastic syndromes that result from neuroblastomas, including neurodegenerative disorders similar to those in oat-cell carcinoma.

Prognosis in neuroblastoma:

• better for younger patients


• paradoxically, it's also BETTER when the tumor is aneuploid (a robust finding: Cancer 91: 435, 2001)


• Calcification is a good sign


• n-myc amplification is a bad sign;


• the more S100+ cells the better
• mitotic counts <100/5000 cells good, >200/500 cells bad



And prognosis depends on differentiation:

• undifferentiated: no cells show maturation (i.e., turning into neurons)


• poorly differentiated: <5% of cells show maturation


• differentiating: 5+% of cells show maturation

In a baby, the tumor is likely to regress/differentiate/mature (to a stroma-rich GANGLIONEUROBLASTOMA or a thoroughly benign GANGLIONEUROMA; Br. J. Surg. 83: 263, 1996). In 2% of autopsies on infants dying of unrelated causes, there is a neuroblastoma-like "incidentaloma". Obviously most of these cure themselves. We wish we knew exactly why/how this happens.

* The process begins with the appearance of S100-positive Schwann cells, which are from outside the tumor. If the tumor is to self-cure, it must be near-triploid and have intact chromosome 1 (NEJM 334: 1505 & 1537, 1996).

{24716} neuroblastoma, histology, good rosettes
{25420} neuroblastoma, gross
{25422} neuroblastoma, histology
{39049} neuroblastoma, gross; probably an incidental finding in a newborn
{09009} neuroblastoma, histology
{09232} neuroblastoma, histology
{20046} neuroblastoma, histology
{20047} neuroblastoma, histology
{09011} neuroblastoma, histology, good rosettes
{08963} neuroblastoma histology (sorry, no good rosettes)
{25424} ganglioneuroblastoma, histology
{25426} ganglioneuroblastoma, histology
{24608} ganglioneuroma, gross

Thoracic Neuroblastoma Virtual Hospital	Neuroblastoma Nice pictures Rockford Case of the Month
Neuroblastoma WebPath Photo	Neuroblastoma WebPath Photo

Neuroblastoma WebPath Photo

Neuroblastoma WebPath Photo

Presacral neuroblastoma

Virtual Hospital

Neuroblastoma
Electron micrographs
VCU Pathology

In toddlers, spontaneous remission is less likely, but even metastatic disease is often cured by chemotherapy.

In older kids and adults, neuroblastomas grow slower but seldom self-cure or respond well to therapy (Cancer 79: 2028, 1997).

* Stay tuned for monoclonal antibodies as a mainstay in the treatment of difficult neuroblastoma patients: Heme-Onc. Clin. N.A. 15: 853, 2001.

Oncogenes, especially N-myc, are clearly important in the origin and progression of neuroblastoma.

N-myc amplification is common and is a bad sign as far as final outcome. It correlates with high mitotic rates and * large nucleoli (Cancer 103: 174, 2005).

* Neuroblastomas also commonly have a break in the short arm of chromosome 1, leading to loss of a (presumed) anti-oncogene in the region 1p32-36 (Science 254: 1153, 1991; bad prognosis NEJM 334: 225, 1996, means it won't mature NEJM 334: 1505, 1996).

Retinoblastomas (cones of the eye), medulloblastomas (cerebellum), pinealoblastomas (pineal), and adult neuroblastomas (lots of places) are related pediatric tumors that look like neuroblastomas microscopically.

* The tendency today is to call these "primitive neuroectodermal tumors", despite obvious differences in their basic biology.

Adult neuroblastomas share with Ewing's sarcoma the characteristic translocation t(11:22)(q24;q12) and a distinctive tumor antigen (Cancer 67: 1886, 1991).

* Neuroblastoma of the olfactory epithelium is a special entity.

"Primitive neuroectodermal tumor"
This one's in the kidney
Loyola Med

INTRODUCTION TO ADRENAL TESTING

The aphorism -- "A physician is only as good as his/her index of suspicion" -- is especially applicable to endocrine disease. As an alert clinician, you will often suspect adrenal gland problems and will want to order sensitive tests.

Some classic cases:

• the thin, tired patient who has no appetite: Addison's disease?

Order a rapid ACTH ("cosyntropin") stimulation test

• the patient who is gaining weight and who is depressed, has high blood pressure, has hyperglycemia, or has one of many other problems: Cushing's syndrome?

Order serum cortisol determinations at 8 AM and 8 PM (circadian rhythm is always lost in Cushingism), plus a low-dose dexamethasone suppression test, or just order one (or maybe two or three) 24 hr urinary free cortisol assays.

• the patient with high blood pressure (with or even without a low serum potassium): aldosteronoma?

Screen with a serum aldosterone/renin ratio. If high, measure urine aldosterone on a high-salt diet and/or see whether you can suppress the aldosterone using fludrocortisone and/or check to see if plasma aldosterone fails to increase on standing up and/or consider performing a saline infusion aldosterone-suppression test and/or consider a CT scan. Nobody really knows what's best.

• the lady who's starting to grow a mustache: late-onset congenital adrenal hyperplasia?

  Administer ACTH and measure blood 17-OH-progesterone.

• the nervous patient with high blood pressure and headaches: pheochromocytoma?

Check serum/urine catecholamines and/or metabolites, ask your lab.

Of course, only some of these patients are endocrine cases. As a rule, meaningful hormone assays are performed under conditions of attempted stimulation (if you suspect deficiency) or attempted suppression (if you suspect over-production). If your screening tests are positive, or if you have any doubts, get consultation. (One problem is that reliable, cheap plasma ACTH assays are still not routinely available.)

If you diagnose endocrine disease that is not present, the patient gets lifelong medication, unnecessary surgery, or unnecessary radiation. If you fail to diagnose a disease that is present, the patient is likely to die of a disease that might have had an excellent prognosis. (Suicide is common among patients with untreated Cushing's syndrome.) If you make the correct diagnosis, the treatment of endocrine disease is very satisfying to physician and patient alike -- because it works.

PARATHYROID GLANDS: ANATOMY AND PHYSIOLOGY

Parathyroid Exhibit Virtual Pathology Museum University of Connecticut

Parathyroids
"Pathology Outlines"
Nat Pernick MD

The parathyroids arise from the third and fourth branchial clefts. They are each 3-4 mm across and weigh maybe 35 mg each (there is no consensus about "ideal total weight").

* They were first discovered by Richard Owen in 1850 in a rhinoceros in the London zoo. Virchow (who else?) discovered them in humans.

Future surgeons: The key to telling a parathyroid gland / tumor at surgery is that (unlike fat, thyroid nubbins, or lymph nodes), a droplet of blood will ooze up when the gland is pricked by your scalpel blade. Why?

Normal parathyroid WebPath Photo

Parathyroid Histology Ed's Histology Notes

Textbooks show four. Most people have 3 or 4 parathyroids, less often 5 or even 6.

Unusual locations (especially for the lower pair) are common and explainable embryologically.

"Ectopic" parathyroid glands may be found in the carotid sheaths, behind the esophagus, in the anterior mediastinum, in the thyroid gland, etc. The new sestamibi scan has made finding these much easier.

Cysts are uncommon but do occur (J. Otol. 18: 311, 1990).

Cell types in the normal glands:

Chief cells: typical hormone-secreting endocrine cells

Oxyphils: large, pink-staining cells that appear after puberty and occur in clusters. (By EM, these are seen to be packed with mitochondria, like Hürthle cells. They do not contain secretory granules, and the mitochondria are probably not metabolically active. Oxyphils are more numerous in older people.)

"Water-clear cells" ("wasserhelle" cells): seen in some parathyroids. (They are full of glycogen, and their functional status is uncertain.)

Fat cells: after puberty. "Fatty ingrowth", if you like.

Parathyroid hormone is the major regulator of calcium homeostasis in humans.

Its production-secretion is regulated by serum calcium levels.

The N-terminal assay measures the active hormone, though the form measured by the C-terminal portion stays around longer. (Pitfall: the C-terminal portion is filtered through the kidneys, and is increased when the kidneys are underfunctioning even if parathyroid function is normal.)

I suggest measuring both. With high PTH, high calcium, and low phosphorus, you have your diagnosis. Other labs aren't so useful. (Did you know that urinary cyclic AMP is a good estimate of parathyroid hormone levels?)

Effects:

Kidney: Promotes conversion of 25-OH-D₃ to the very active 1,25-OH-D₃ that increases calcium absorption from the gut.

Promotes resorption of calcium from the glomerular filtrate, and promotes loss of phosphate.

This effect is mediated by activation of adenylate cyclase. Serum parathyroid levels are accurately reflected by measuring urinary c-AMP concentrations.

Bone: Promotes resorption of calcium by osteoclasts (via activation of adenylate cyclase.)

Increased levels of parathyroid hormone causes proliferation of osteoclasts. (Finding of an osteoclast in a section of bone from an adult usually means hyperparathyroidism.)

Gut: Promotes calcium absorption (indirect effect, via vitamin D activation).

HYPERPARATHYROIDISM ("stone and bone disease"; review Mayo Clin. Proc. 77: 87, 2002)

Primary hyperparathyroidism: Due to disease of the parathyroid glands.

80%... parathyroid "adenoma"
5%... parathyroid carcinoma
15%... parathyroid "hyperplasia" (i.e., all four glands)

<1%... iatrogenic seeding causing lots of little glands: Hum. Path. 21: 234, 1990, (*  by my teacher, Dr. David Roxe); Surgery 116: 111, 1994.

Some people may also use this term to include hypercalcemia caused by production of parathyroid-hormone-like activity (PTH-rP) by cancers, notably squamous lung cancer.) Today the term "pseudohyperparathyroidism" is preferred.

Primary hyperthyroidism is a common clinical problem. About 1 person in 1000 will need parathyroid surgery during his or her lifetime.

Calcium rises because of enhanced GI absorption and renal reabsorption. There is also a tiny contribution from increased osteoclastic activity (Am. J. Med. Sci. 320: 334, 2000).

Symptoms and signs:

Elevated serum calcium on routine screening (probably the commonest presentation today)

Mental changes (depression, psychosis; Am. J. Med. 101: 111, 1996)

Kidney stones (the commonest presentation in the past)

Nephrocalcinosis (metastatic calcification in the tubular basement membranes with eventual damage to the tubules)

Bone changes (first osteomalacia, then widespread involvement of the skeleton by increased osteoclastic activity especially in the centers of trabeculae; finally cystic lesions variously known as "osteitis fibrosa cystica", "von Recklinghausen's disease of bone", or "brown tumors." All this heals after the hyperparathyroidism is fixed.)

Brown tumor Pittsburgh Pathology Cases

Brown tumor WebPath Tutorial

Brown tumor WebPath Tutorial

Just not feeling right. Hypercalcemia makes you fatigued before anything else. People who eventually turn out to have primary hyperparathyroidism are much more likely to have been missing a lot of work "for being sick" for several years prior to diagnosis (BMJ 317: 848, 1998.) After surgery, "asymptomatic" people with parathyroid adenomas feel a lot better (Surgery 128: 1013, 2000).

Brown Tumor of Hyperparathyroidism
Pittsburg Illustrated Case

Resorption of the tufts of the phalanges on x-ray

* "Band keratopathy" of Bowman's membrane in the cornea

* Loss of lamina dura on dental x-rays

Gastric ulcers (5%; hypercalcemia from any cause enhances gastrin secretion)

Hypertension (50%, cured by parathyroid surgery only if the kidney is undamaged)

Pancreatitis (occasionally)

Pseudogout (occasionally)

* NMJ problems (denervation-atrophy picture on muscle biopsy)

* Skin ulcers (following metastatic calcification of vessels: Arch. Path. Lab. Med. 114: 482, 1990).

Labs:

high serum calcium

low serum phosphate

high 24-hour urine calcium excretion (i.e., you absorb a lot more through your gut)

high urinary cAMP

high serum parathyroid hormone (PTH; remember you can choose between N-terminal and C-terminal assays) for your screening

PARATHYROID ADENOMA

The commonest cause of primary hyperparathyroidism.

* In the mid-1980's, there was a fad notion that these all represented "nodular hyperplasia". Newer genetic studies have shown these tumors truly are monoclonal.

These tumors are most common in older women, but may occur in anyone. They average around a gram but are sometimes bigger. * I've seen several at autopsy that were probably non-functional.

The basic biology very often involves translocations that deregulate the oncogene PRAD-1 (bcl-1, cyclin D1, a cell-cycle regulator; Nature 350: 512, 1991, more since).

The surgeon finds three normal glands and an adenoma that is easily removed (10% are in an "ectopic location.)

In the late 1990's, parathyroid surgery was revolutionized by the introduction of the Tc⁹⁹ sestamibi scan to locate the lesion(s) preoperatively, and intraoperative radioguidance (Arch. Surg. 135: 481 & 550 & 844 & 1461, 2000; Ann. Surg. 23: 31 & 331 732, 2000; J. Am. Coll. Surg. 190: 540, 2000; Surg. Clin. N.A. 80: 1399, 2000; Surgery 129: 720, 2001; Arch. Surg. 137: 659, 2002). The sestamibi scan is very specific. The surgeon can draw a iPTH (intact PTH) level before and soon after (half life is five minutes) excising the suspected lesion; if it drops 50% or more, supposedly your operation was a success. (See Arch. Surg. 136: 536, 2001; Surgery 128: 1029, 2000.) Nowadays, it seems quite clear that iPTH it can indeed be used as a "chemical frozen section", and satellite labs are appearing in operating suites. Pathologists will be doing a lot fewer frozen sections / imprint cytologies on the cases (Arch. Path. Lab. Med. 127: 1424, 2003; shucks, I used to love doing these). It's usually an outpatient procedure done under a local anesthetic.

Occasional overfunctioning do fail to "light up", especially if they are very small or lack abundant mitochondria (Arch. Oto. 131: 493, 2005).

* Imprint cytology of the parathyroid and other neck structures at surgery: Arch. Path. Lab. Med. 127: 64, 2003; Am. J. Clin. Path. 118: 895, 2002.

The adenoma often has a rim of compressed normal gland at the edge. Most adenomas contain few if any adipocytes, and most of the cells do not have intracytoplasmic fat.

An adenoma can be composed of any of the three kinds cells (chiefs, oxyphils, waterclears).

As you would expect, parathyroid adenomas (even in people with no family history) often lack 11q13 (the MEN-I locus).

* Every once in a while, there is so much fat in a parathyroid adenoma that it looks like a lipoma, i.e., the infamous "lipoadenoma".

{10827} parathyroid adenoma, histology

Parathyroid adenoma Note rim of normal tissue WebPath Photo

Parathyroid adenoma Oxyphilic type WebPath Photo

PARATHYROID CARCINOMA (Cancer 100: 900, 2004)

A rare cause of primary hyperparathyroidism.

By definition, this cancer arises in a parathyroid gland and produces parathyroid hormone.

* Future pathologists may enjoy reading about the trabecular pattern that is supposed to be distinctive. Desmoplasia also is a marker of parathyroid cancer. You are less likely to see obvious invasion or numerous or weird mitotic figures. As in adrenal adeonomas, thyroid adenomas, and pheochtomocytomas, hyperchromatic nuclei ("endocrine atypia") don't mean cancer.

* Loss of parafibromin nuclear reactivity as a marker for malignancy: Clin. Canc. Res. 10: 6629, 2004.

These cancers are not very aggressive. About a third are cured with simple excision, another third recur and require re-operation for cure, and only a third eventaully metastasize and ultimately cause death, usually from refractory hypercalcemia.

* Loss of Rb seems to be the rule for parathyroid carcinoma, in contrast to parathyroid adenomas: NEJM 330: 757, 1994; J. Clin. End. Metab. 81: 3194, 1996. No surprise; it will probably prove useful in telling the lesions apart. A familial syndrome involves mutant HRPT2 (parafibromin: NEJM 349: 1722, 2003).

Parathyroid carcinoma WebPath Photo

Parathyroid carcinoma WebPath Photo

PARATHYROID HYPERPLASIA

The second most important cause of primary hyperparathyroidism. All four glands are big, for no obvious reason. Even though this is "a different disease from adenomas", the masses are often clonal, and (in the case of chief-cell hyperplasia) the same genes put you at risk.

* Watch for the name of "primary parathyroid hyperplasia" to change to "multiple parathyroid gland neoplasia." The lesion in kidney disease is a true hyperplasia.

This may occur in anyone, but is suspicious for one of the multiple endocrine neoplasia (multiple endocrine adenomatosis) syndromes. See below.

Hyperplastic glands usually lack the usual fat cells.

Chief cell hyperplasia is the common kind. It raises the possibility of MEN I or MEN II. Today's pathologists may tentatively distinguish a hyperplastic gland from an adenoma because hyperplastic chief cells still contain intracellular fat (uh, supposedly).

Water-clear hyperplasia is a different disease with the same symptoms. All four glands are quite big, probably because there is much non-functioning cytoplasm in the clear cells. This time, there is no intracellular lipid but plenty of glycogen.

The MEN syndromes do NOT place you at risk for it. Waterclear hyperplasia is becoming uncommon for some reason. And you must have a blood group "O" allele to get it (Hum. Genet. 94: 195, 1994)!!! Gee whiz. Waterclear adenomas are almost unknown (Arch. Path. Lab. Med. 125: 256, 2002).

{27260} parathyroid hyperplasia (arrow sign helps)
{09271} primary parathyroid hyperplasia, histology

Parathyroid hyperplasia WebPath Photo

Parathyroid hyperplasia You cannot tell this from adenoma by itself WebPath Photo

In parathyroid hyperplasia, the bulk of the parathyroid tissue must be removed, leaving a small amount behind. (Sometimes a small amount of parathyroid tissue gets transplanted to the forearm, for future whittling.)

This is now routine. You can use the sestamibi scan to see if the graft is over-functioning: South. Med. U. 93: 215, 2000.

NOTE: The honest pathologist CANNOT distinguish a hyperplastic gland from an adenoma! The surgeon must send samples of two glands. (Why?)

Secondary hyperparathyroidism: Parathyroid hyperplasia due to hypocalcemia (or hyperphosphatemia, or hPTH resistance, or vitamin D deficiency, or vitamin D resistance) from some other cause, usually renal failure (less often malabsorption or malnutrition).

In people who are vitamin D deficient, the extra parathyroid hormone keeps calcium levels normal (J. Clin. Endo. Metab. 85: 4125, 2000; Am. J. Med. Sci. 319: 380, 2000; remember there's plenty of this in the US).

Less common causes are intestinal malabsorption, calcitonin-producing tumors (i.e., medullary carcinoma of the thyroid) and rickets (low serum phosphate, in contrast to renal failure, in which serum phosphate levels are high.)

Serum calcium is low-normal.

Bone disease (as in primary hyperparathyroidism, but now called "renal osteo-dystrophy") is a big problem. Some patients may need partial parathyroidectomy to control it.

Today's patient with secondary hyperparathyroidism of renal origin will probably be controlled adequately with oral, or perhaps intravenous, calcitriol (Am. J. Med. Sci. 320: 100 & 107, 2000).

Tertiary hyperparathyroidism: Hypercalcemia develops in a setting of secondary hyperparathyroidism.

One or more glands has "become autonomous" and overproduces parathyroid hormone. Probably this means it has lost the MEN-I anti-oncogene on chromosome 11 (J. Clin. End. Met. 76: 139, 1993). Thankfully rare.

* NOTE: Genetic typing of parathyroid masses has helped us recognize that the above scheme, while a bit simplistic, is fundamentally accurate. If one gland is involved, it's an adenoma and will show one of two different genetic profiles. If two, three, or four glands are involve, it's "multiple gland parathyroid neoplasia", with different genetic signatures. See Am. J. Path. 165: 565, 2004.

Other hyperparathyroidism syndromes:

Familial hypocalciuric hypercalcemia, also called "familial benign hypercalcemia", a mild, autosomal dominant disorder.

The mutation is in CaSR, the calcium sensing receptor (Clin. End. 50: 537, 1999; Am. J. Hum. Genet. 64: 189, 1999), which tells the nucleus what the plasma calcium level is. Parathyroid hormone is overproduced as a result.

* Two doses gives neonatal severe primary hypercalcemia requiring total parathyroidectomy.

* Other mutations give a familial hypocalcemia (J. Clin. Endocrin. Metab. 84: 363, 1999), i.e., in these "activating" mutations, the receptor is stuck in the "on"-position. An autoantibody that causes the same problem: NEJM 351: 362, 2004.

Order a calcium-creatinine clearance ratio, which will be very low (less than .01) in these patients.

Jansen's metaphyseal chondrodysplasia, an autosomal dominant syndrome caused by an overactive PTH1R parathyroid hormone receptor. Hypercalcemia and short-limbed dwarfism.

HYPERCALCEMIA: Differential diagnosis for beginners. Review Postgrad. Med. 115: 69, 2004.

• Hyperparathyroidism (primary or tertiary or familial hypocalciuric hypercalcemia or Jansen's)
• Ectopic hPTH-like substance (i.e., from tumor, most often squamous cell carcinoma of lung, occasionally renal cell carcinoma or others). Now called PTH-related peptide (PTH-rP). Pseudohyperparathyroidism.
• Vitamin D toxicity (ask about vitamin A and "dolomite" pills, too)
• Lytic bone metastases
• Plasma cell myeloma
• Sarcoidosis (vitamin D activation by granulomas)
• Milk-alkali syndrome
• Thiazide diuretics (especially in new users)
• * Williams microdeletion syndrome (supersensitive to vitamin D)

HYPOPARATHYROIDISM

The most common cause is iatrogenic (following thyroid surgery).

Next is autoimmunity (remember the syndrome with addisonism, ectodermal dysplasia, and mucosal candida? -- J. Clin. Endo. Metab. 88: 4602, 2003). In both familial and sporadic cases, the autoantigen is often CaSR (J. Clin. Inv. 97: 910, 1996; update J. Clin. Endo. Metab. 89: 4484, 2004). You also remember DiGeorge's syndrome.

* Zebras: Kearns-Sayre / mitochondriopathy (J. Clin. Endo. Metab. 83: 125, 1998), Wilson's, Riedel's struma.

Symptoms and signs of hypocalcemia begin with mental changes, circumoral paraesthesia, Chvostek's sign, Trousseau's sign, and progress to carpopedal spasm, convulsions, tetany. Check for cataracts, too; nobody knows why they tend to occur when ionized calcium is low.

The diagnosis is confirmed by finding low serum calcium and high serum phosphate.

* Treatment includes vitamin D and calcium gluconate cookies (lifelong.) Injectable parathormone is now becoming available (J. Clin. Endo. Metab. 88: 4214, 2003).

Pseudohypoparathyroidism

Some curious disorders. In each, there is an inability to carry the parathyroid hormone receptor signal to the cell's machinery. (Proc. Nat. Acad. Sci. 95: 10038 & 11798 & 15475, 1998; Am. J. Med. Genet. 77: 261, 1998; J. Clin. End. Metab. 81: 1660, 1996).

As you'd expect, serum calcium runs low, phosphate runs high, and (except in type II) urinary cAMP fails to rise in response to parathyroid hormone administration.

In Pseudohypoparathyroidism type Ia, there is a mutation of a portion of the GNAS1 gene that codes for G_sα. There is a striking imprinting effect.

Imprinting: Am. J. Hum. Genet. 68: 1283, 2001. In kidney (PTH-receptor), thyroid (TSH receptor), ovary (FSH-LH recptors), pituitary (getting worked out), and elsewhere (growth hormone recetors: J. Clin. Endo. Metab. 88: 4070, 2003); only Mom's allele is expressed. In bone, both Mom and Dad's alleles are expressed.

Hence, if you inherited a bad allele from your mother, you get resistance to parathyroid hormone (marked), plus some resistance to other endocrine hormones. Plus, you get the bony deformities ("Albright's hereditary osteodystrophy"), with short stature, short fingers, and a round face.

If you inherited a bad allele from your father, you get ONLY the bony deformities ("pseudopseudohypoparathyroidism").

* Certain bad alleles inherited from Dad produce the thankfully-rare progressive osseous heteroplasia, in which skin and muscle transform into bone (NEJM 346: 99 & 128, 2002).

In Pseudohypoparathyroidism type Ib, the bones are formed normally. The kidney is resistant to the effects of parathyroid hormone and there is milder resistance to TSH as in type Ia. The mutated gene (* STX16 / syntaxin 16) is adjacent to the GNAS1 locus; it's recently been identified as a portion of the complex that's responsible for its being imprinted (J. Clin. Inv. 1255: 112, 2003). It can only be expressed if it is inherited from Mom.

In pseudohypoparathyroidism type Ic, the alpha subunit is normal but there is the osteodystrophy. Too rare to know anything more yet; I'm betting on a different allele at the GNAS1 locus.

In Pseudohypoparathyroidism type II, there is resistance to the effects of parathyroid hormone in bone and kidney, and some bone deformities. However, the urinary cAMP response to PTH challenge is normal, and The GNAS1 locus is not involved (i.e., there's a problem with the signal distal to cAMP). The genetics remains obscure.

* If you lack both copies of the real parathyroid hormone receptor, you die as a baby of a severe dyschondroplasia. Carriers are asymptomatic.

Child with pseudo-pseudo-hypoparathyroidism
Courtesy of Mary Fay MD

THYMUS

Thymus Exhibit Virtual Pathology Museum University of Connecticut

Thymus Histology Ed's Histology Notes

Originates from the third and (*  ?) fourth pharyngeal pouches (*  hence, a good location for an ectopic parathyroid gland.)

Large in neonates, it starts to involute after puberty, and is usually just a mass of fat in older people.

The cortex (many lymphocytes) and medulla (few lymphocytes) have as their basic structural unit an unusual stellate epithelial cell.

* A few of these cells differentiate as keratinizing squamous pearls, or Hassall's corpuscles.

You are already familiar with the severe underdevelopment of the gland in such illnesses as ataxia-telangiectasia, DiGeorge / Nezelof, and some (not all) forms of severe combined immunodeficiency. Usually these people lack good corticomedullary differentiation and Hassall's corpuscles, as well as lymphocytes.

Thymic cysts are fairly common (3rd branchial pouch), but don't assume all cysts are benign -- for some reason, cysts often form near a thymic cancer (Hodgkin's, germinoma).

* Ask a pathologist about the "myoid cells" in the medulla. They contain actin, myosin, and myoglobin. Maybe this has something to do with the whole myasthenia gravis connection.

{14760} normal kid's thymus; a=cortex, b=medulla, c=vessel
{13958} Hassall's corpuscles stained for keratin (this appears to be normal thyroid)

* Stress lesions in the thymus are of interest to pathologists, and help us tell how long somebody was seriously sick. Before 12 hours, there are no changes. At 12-24 hours, you start seeing macrophages eating lymphocytes. At 24-48 hours, you start seeing a starry sky. Over 48 hours, the corticomedullary junction becomes blurry as the gland atrophies. After 72 hours, the gland is atrophic and there will be no further changes.

Follicular hyperplasia is said to present when there are large germinal follicles in the organ.

Most folks do have a few tiny germinal follicles in the thymus gland. I'd ask you to reserve the term thymic follicular hyperplasia for situations in which the gland itself is oversized. This is common in folks with various autoimmune diseases (especially lupus and addisonism), and in early HIV infection.

Patients with myasthenia gravis, an autoimmune diseases caused by anti-NMJ antibodies, also show thymic hyperplasia (unless it is removed or destroyed by a thymoma), and thymectomy is the best treatment for myasthenia gravis.

* The less-common form of myasthenia gravis, caused by antibodies against muscle-specific kinase, is not helped by thymectomy (Brain 126: 2304, 2003).

* True hyperplasia of the thymus is simply a gland that's oversized for the person's age. For some reason that no one understands, this is fairly common in adults who have been cured of a malignancy by chemotherapy.

Thymoma is a histologically-benign tumor of the epithelial cells of the thymus gland. There are often lymphocytes mixed in, but these are non-neoplastic.

The gross appearance (i.e., whether or not the tumor invades the mediastinal structures) is most important for prognosis.

The World Health Organization (1999) classification of thymomas is now standard, and predicts outcome quite well (Ann. Thor. Surg. 77: 183, 2004).

* From best-to-worst prognosis, they are:
Type A: Spindle or oval epithelial cells, no atypia, no lymphoytes
Type AB: Like A, but with some areas rich in lymphocytes
Type B1: Areas that look like normal thymic cortex, and areas that look like normal thymic medulla
Type B2: Plump epithelial cells with vesicular nuclei and big nucleoli; big perivascular spaces; palisades around vessels
Type B3: Rounded / polygonal epithelail cells growing in sheets, only a few lymphocytes
Type C: Obvious atypia, less recognizable as thymus. There are over a dozen variants described.
A's can expect cures, AB's are usually cured (Ann. Thorac. Surg. 77: 1183, 2004). The rest are more dangerous, but the stage of the tumor at presentation is more important, and pathologists cannot distinguish the entities in type B very well: Chest 127: 755, 2005.

Fibrosing variant: Am. J. Clin. Path. 121: 867, 2004.

{13952} thymoma, gross
{25653} thymoma, gross
{13955} thymic tumor, possibly Hodgkin's
{49097} malignant thymoma, gross

Thymoma Pittsburgh Pathology Cases

Thymoma WebPath Case of the Week

Non-Invasive Thymoma Pittsburgh Illustrated Case

Among thymoma patients...

Myasthenia gravis occurs in around 50% (*  and around 30% of myasthenia gravis patients have a thymoma; thymomas express acetyl choline receptor epitope on their cells Lancet 339: 707, 1992)

Acquired "pure red cell aplasia" (stop putting out red cells, presumably autoimmune) occurs in around * 20%

Hypogammaglobulinemia occurs in a few percent and is called Good's syndrome (rare, but in the "diff" of nearly everything)

* Thymoma series from M.D. Anderson Cancer 73: 2491, 1994 (not surprisingly, they're for chemotherapy....)

Other thymus tumors:

Lymphomas (T-cell, of course), carcinoids (aggressive, and likely to produce ACTH or other troublesome hormones: Am. J. Clin. Path. 114: 200, 2000; Ann. Thor. Surg. 74: 133, 2003; the histology does not predict behavior Chest 124: 141, 2003), * carcinomas (i.e., obviously malignant on histopathology: Cancer 67: 1025, 1991), and * germinomas (seminomas, less often embryonal-cell carcinomas or choriocarcinomas) arise in the thymus.

* Thymic teratomas are relatively common.

Primary thymic lymphoma
Virginia
Good pictures


Mediastinal Masses
Queen's U., Kingston
Thanks Dr. Boag

* There's a popular mnemonic for anterior mediastinal masses:

• Thymoma


• Teratoma


• Testicular-type cancer


• T-cell or Hodgkin's lymphoma


• Thyroid enlargement (i.e., substernal goiter)



For some reason, there are famous as "the four T's", since one or another always gets omitted.

Carcinoid
Mediastinum
Pittsburgh Pathology Cases



* Brian Piccolo, of "Brian's Song" fame, had a thymic embryonal-cell type carcinoma, as did football player Dan Turk.

* "Status thymicolymphaticus" was an imaginary disease, dreamed up to explain SIDS and infanticide, for which several million newborns received radiation therapy. They are now at much increased risk for papillary carcinoma of the thyroid. (There's a lesson here -- self-deception is certain in the absence of proper controls.)

PINEAL ("the third eye"): Tumors of the pineal are troublesome because of their location. In children, pineal tumors are likely to produce sexual precocity.

Pinealoma, except for its location, looks exactly like a seminoma or dysgerminoma.

Other germ-cell tumors occur in the pineal also, so you could see a pineal teratoma, a pineal choriocarcinoma, or any other. (I've seen all three.)

Pinealoblastoma (see above) resemble neuroblastomas and medulloblastomas.

Pineocytomas are made up of cells like those in adult pineal. Both are aggressive cancers seen most often in children.

Gliomas, etc., can occur in the pineal. Pineal tumors: Cancer 72: 870, 1993. Cysts: Neurology 41: 1034, 1991 (fooled me once).

{03998} normal pineal gland, anatomy
{02815} normal pineal gland, gross
{01223} normal pineal gland
{01239} normal pineal gland histology, with brain sand
{05219} pineal cyst, gross
{01711} pineal germinoma, gross

Pineocytoma Pittsburgh Pathology Cases

* THE MELATONIN BUSINESS: Review Am. Fam. Phys. 57(8): 1783, 1998.

Since the stuff is dirt-cheap to make, occurs naturally, and isn't patentable, it's now widely available over the counter.

If you believed everything you heard about melatonin, you'd be reading uncritically. What is clear is that its effects on insomnia and jetlag have impressed people far more than most "supplement" stuff.

Since the pineal often calcifies in older folks, and perhaps fails as a result, look forward to melatonin as a sleep aid especially in geriatrics.

Expect in the next few years: Studies of the effect of melatonin in (1) seasonal affective disorder; (2) schizophrenia; (3) obsessive-compulsive; (4) narcolepsy; (5) bipolar disorder; (6) neurodegenerative diseases; (7) attention deficit disorder; (8) fibromyalgia. I'll predict strong favorable results in at least one of these categories.

In the meantime, the stuff seems extremely safe, and I wouldn't fault you for wanting to experiment, assuming you give proper informed consent.

THE MAN

A man said to the universe:
"Sir, I exist!"

"However," replied the universe,
"That fact has not created in me
A sense of obligation."

-- Stephen Crane


(1871-1900)

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