Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
No texting or chat messages, please. Ordinary e-mails are welcome.
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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome.
DoctorGeorge.com is a larger, full-time service.
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at www.afraidtoask.com.
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With one of four large boxes of "Pathguy" replies. |
I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
pathology.org -- my cyberfriends, great for current news and browsing for the general public
EnjoyPath -- a great resource for everyone, from beginning medical students to pathologists with years of experience
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.
Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.
Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.
Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.
If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.
I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!
Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.
This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.
During the fifteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at KCUMB
for making it possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!
QUIZBANK Endocrine (It's impossible to separate pituitary, adrenal, thyroid, parathyroid, etc. Look at it all
now.)
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
MedEdPORTAL -- American Association of Medical Colleges. Primarily for medical school faculty.
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta Tumor Photos -- and lots more. Highly recommended.
Bristol Biomedical
Image Archive
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
U. of Virginia Case Studies
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Upstate NY Cases -- works only on some browsers
Society for ultrastructural pathology -- electron microscope cases
PathologyPics -- where pathologists share favorite images. Thanks!
WebPath:
Internet Pathology
Laboratory -- great site
My team:Ed Lulo's Pathology Gallery
Also:
Bryan Lee's Pathology Museum
Dino Laporte: Pathology Museum
Tom Demark: Pathology Museum
Path Consult -- great photos and text for more advanced learners
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
Endocrine
Taiwanese pathology site
Good place to go to practice
Mediastinum (Thymus)
Photo Library of Pathology
U. of Tokushima
Tulane Pathology Course
Great for this unit
Exact links are always changing
Adrenal Exhibit
Virtual Pathology Museum
University of Connecticut
Mention the normal gross and microscopic anatomy of the adrenal glands, parathyroid glands, and thymus gland. Describe their origins within individuals, and their functions.
Define hypoadrenocorticism, mention the etiologies of the chronic and acute forms, and tell what each looks like clinically. Explain hyperpigmentation in some of these patients, and tell why they are at risk for sudden death.
Describe the etiologies of Cushing's syndrome, from the most to the least common. Tell what symptoms and signs should alert you, the physician, to the possibility of Cushingism. Explain Nelson's syndrome, and why it is becoming uncommon.
Define primary hyperaldosteronism and Conn's syndrome. Distinguish these from secondary hyperaldosteronism. Tell what symptoms and signs point to excess aldosterone, and explain the danger of treating these patients with "safe" diuretics.
Describe in detail the pathogenesis of congenital adrenal hyperplasia, and distinguish the most common salt-retaining and the most common salt-wasting form. Describe the forme fruste that we now believe is very common.
Describe the behavior of carcinomas of the adrenal cortex.
Discuss pheochromocytoma and neuroblastoma with respect to their names, locations, etiologies, catecholamine production, gross and microscopic appearances, clinical picture, and prognosis. Mention the "primitive neuroectodermal tumors" that look like neuroblastomas, and describe "spontaneous cures" of neuroblastoma. Provide an educated guess of how many of your classmates had a "neuroblastoma" at birth.
Describe in some depth the prevalence, etiologies, symptoms, signs and treatment of hyperparathyroidism. Explain how to tell parathyroid hyperplasia from parathyroid adenoma, and why anyone cares. Describe how and when hypoparathyroidism develops, why it is serious, and how to recognize it.
Describe how the size of the thymus gland changes with age. Define thymic hyperplasia and thymoma, tell what they look like, and mention the diseases with which they are associated.
List the components of the important anti-oncogene deletion syndromes MEN I, IIa, and IIb.
MAINTAIN A HIGH INDEX OF SUSPICION FOR ENDOCRINE DISEASE. This lecture ought to scare you.
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THE ADRENAL CORTEX: "An organ essential to life." Pathology of the adrenal cortex: Arch. Path. Lab. Med. 132: 1263, 2008.
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{11204} adrenal and its nerve, normal
{11207} adrenal and its nerve, normal {11210} adrenal and its nerve, histology, normal {15035} normal adrenal gland, showing zones (can you figure them out?) |
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Unlike the pancreas, it isn't obvious where the "head", "body", and "tail" of an adrenal is located. The head is medial, the tail lateral.
The cortex, of course, has three "zones":
(1) ZONA GLOMERULOSA: mineralocorticoid production. Thin and patchy, small cells.
(2) ZONA FASCICULATA: glucocorticoid production (now seems settled), resting cells (the reserve cells are at the ZG-ZR interface). Yellow.
(3) ZONA RETICULARIS: glucocorticoid production, androgen and estrogen production, grossly darker than outer layers. Brown.
(Mnemonic: Salt, sugar, and sex: the deeper you go, the sweeter it gets.)
Under the microscope, the borders are fairly easy to see.
In newborns, the future adult cortex is a thin layer under the capsule, and most of the gland is "fetal zone". This regresses in a few weeks and is usually gone altogether by the first birthday.
Future pathologists:
The normal adult weight of each adrenal gland is 4 gm.
If an adrenal gland weighs 6 gm or more (without a tumor), it is usually hyperplastic. The stress of the final illness increases the weight of the adrenals, which is why "normal autopsy weight" is sometimes given at 6-8 gm. Most violent suicides have adrenals weighing 9-11 gm (Am. J. Psych. 144: 1214, 1987; confirmed AJFMP 19: 72, 1998.)
* More for future pathologists: A bit of ectopic marrow, a few pigmented cells, or theca cells (especially in menopausal women) are normal.
* Ask a physiologist about the role of dehydroepiandrosterone in health; about 30% of a man's androgens are derived from this, and 90% of a post-menopausal woman's estrogens.
{49431} hyperplasia of adrenal cortex, etiology undisclosed
{09217} adrenal cortical hyperplasia, etiology unknown
* Around 2% of folks have adrenals with black nodules, usually without any evidence of dysfunction.
CONGENITAL ADRENAL HYPOPLASIA
Two types, both uncommon:
(1) Anencephalic type: thin cortex, no fetal zone; no ACTH during development
(2) Cytomegalic type (X-linked recessive?): thin cortex composed entirely of large, bizarre cells (foci of such cells are common in normal newborns but regress).
It now turns out that a forme fruste allele at the DAX1 locus causes adrenal insufficiency in boys (no adults yet), i.e., this is a common, previously-unrecognized cause of adrenal insufficiency (J. Clin. Endo. Metab. 91: 3048, 2006).
Both present as hypoglycemic seizures in infants. Glucocorticoid replacement saves these children's lives.
ECTOPIC ADRENAL CORTICAL TISSUE (sometimes ectopic adrenal medulla too)
This is most common in the capsule ("capsular extensions")
and at the origin of the celiac artery, but it can occur anywhere in the
retroperitoneum, or under capsules of liver, kidney, ovary, or testis.
Ectopic adrenal caused problems when surgical adrenalectomy was very popular. ("A new adrenal
gland grew back in a different place....")
CHRONIC HYPOADRENOCORTICISM (ADDISON'S DISEASE, now regardless of etiology). Troubles start when
80% of the gland tissue is gone. Review Br. Med. J. 312: 1085, 1996.
You need to know the etiologies of chronic hypoadrenocorticism:
INFECTIONS
Most of Dr. Addison's patients had bovine TB {09223} adrenal tuberculosis, gross
Worldwide, fungal infections (remember histoplasmosis AUTOIMMUNE
The most prevalent non-iatrogenic cause of Addison's disease in the US today. The adrenal
remnants are typically loaded with lymphocytes, etc., etc. Jack Kennedy suffered
from this illness in his youth, and it was missed for several years (JAMA 201: 115, 1990).
Long-mysterious, it's now clear that most of these patients have autoantibodies against 21-hydroxylase (Lancet 339:
1559, 1992). These are now generally called "adrenal cortex antibodies."
Presumably this is antibody-dependent cell-mediated
cytotoxicity, as in Hashimoto's disease.
Autoimmune adrenalitis often occurs jointly with Hashimoto's thyroiditis, type I diabetes mellitus,
vitiligo, gluten enteropathy, and/or pernicious anemia "autoimmune polyendocrine deficiency
syndrome II", "Schmidt's syndrome", etc.)
Schmidt's is only the best-known of
the autoimmune polyendocrinopathies in which
there are various immune and non-immune disturbances
tending to run together. Remember them especially when
a patient with vitiligo or prenicious anemia seems unwell.
The more common Schmidt's (autoimmune polyglandular syndrome type II)
is diagnosed when there is autoimmune addisonism plus either autoimmune
thyroid disease or autoimmune diabetes (Am. Fam. Phys. 75: 667, 2007).
* Autoimmune polyglandular syndrome type III is diagnosed
when there is autoimmune thyroid disease plus one or more other autoimmune
diseases other than addisonism or hypoparathyroidism (Am. J. Med. Sci. 333:
178, 2007).
IATROGENIC
This results from too-rapid withdrawal of glucocorticoid medication, post-adrenalectomy for breast
cancer or Cushingism, etc., ketoconazole or fluconazole antifungal drug therapy
(Crit. Care Med. 29: 668, 2001), removal of a "non-functioning adenoma"
(rare).
CORTICOSTEROID INSUFFICIENCY OF CRITICAL ILLNESS is a newly-characterized
entity, seen especially in severe systemic infections, in which the
body does not put out enough glucorticoid to handle the extra stress.
The pathology's not worked out yet, but the impact on clinical
practice in the ICU will be huge, since one must know whether to give supplementary cortisol.
Consensus statements from the American College of Critical Care Medicine: Crit. Care Med. 36:
1937, 2009. See also Chest 135: 181, 2009.
OTHERS: Worth remembering are
{25394} adrenal cortical atrophy (key says "hypoplasia", I doubt this)
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.)
{09371} Addison's disease; pigmentation and vitiligo (mother and daughter)
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 the meningococcus, though
staphylococci 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.
{24606} Waterhouse-Friderichsen adrenal, gross
CUSHING'S SYNDROME: too much glucocorticoid. Review NEJM 332: 791, 1995.
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 usually be diffusely enlarged, but may 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.... Again, the hyperplasia is usually
diffuse but may be nodular.
{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):
* Genetic syndrome with too many cortisol receptors, low plasma cortisol: J. Clin. Endo. Metab. 85:
14, 2000.
* 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:
{09367} Cushingism, face
* 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; Lancet 371: 1921, 2008)
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. The most recent work (Lancet 2008)
uses the retrospectoscope to show that Conn's is probably not so common
as has recently been claimed, but still an important concern.
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. Some 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 familiar 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, go back
and review your endocrine physiology.)
* 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
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).
* Consider screening
folks with incidentalomas 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 recognized
entity: J. Clin. Endo. Metab. 88: 5808, 2003.
NIH Consensus Conference: Ann. Int. Med. 138: 424, 2003.
The case against fine-needling incidentalomas, made by surgeons: Surgery 142: 497, 2007.
* 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
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
ADRENAL CORTICAL CARCINOMA (Am. J. Clin. Path. 105: 76,
1996; J. Urol. 169: 5, 2003)
These are rare cancers that are often lethal. Many are
are hormonally active and produce Cushing's, Conn's, and/or virilization.
Future pathologists: These are usually obviously malignant,
grossly and microscopically, with ten or more mitotic figures per high
power field.
The most reliable way of spotting malignancy is still the mitotic figure count;
other systems have not proved very reliable (Am. J.Clin. Path. 127: 398, 2007).
* 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. (It will also destroy and scar any remaining normal adrenal gland.)
* 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.
{24087} adrenal cortical carcinoma, gross
NOTE: Cancer in the adrenals is usually metastatic carcinoma. Half of all lung cancers
eventually metastasize
to the adrenals. Adrenal insufficiency sometimes results when replacement is massive, but is usually missed clinically.
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.
"Adrenal medullary hyperplasia" (i.e., the medulla is too big; one way to tell is that
it extends into the tail, where it's not supposed to go) is a marker for MEN II and a few
rarities. It can be diffuse or nodular, and it may be best to call any nodule bigger
than 1 cm a pheochromocytoma.
The only bona-fide 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", formerly "ten percent tumor";
big NIH consensus review Ann. Int. Med. 134: 315, 2001; big review for pathologists
Arch. Path. Lab. Med. 132: 1272, 2008).
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).
Pathologists confirm that a likely-looking tumor is a pheochromocytoma
by staining it up for chromogranin and/or synaptophysin.
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.
Today, "pheochromocytoma" is defined to arise in the
adrenal medulla.
Similar tumors (less common)
arising elsewhere are called "extra-adrenal paragangliomas."
These sites include the
organs of Zuckerkandl ("para-aortic bodies", i.e., the little nubbins of chromaffin tissue
at the origin of the inferior mesenteric artery and/or aortic bifurcation -- prominent and surely important
in the unborn child, but regressed by birth), paravertebral sympathetic
chain, urinary bladder (patients get terrible headaches whenever they urinate), or "paraganglia" such
as the carotid body.
The old business about "ten percent of pheo cases involve both adrenals,
10% are familial, and 10% metastasize" is history. Today, everything's
about the new genetics.
* "Composite pheo" contains some neuroblastoma, ganglioneuroblastoma, or
nerve-sheath tumor; think of MEN II or neurofiromatosis. If there's no
neroblastoma, the presence of other elements is probably not a bad prognostic indicator.
Update Am. J. Clin. Path. 132: 69, 2009.
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)
* The pituitary-and-parathyroid-only variant usually is from a
different locus that remains to be discovered: J. Clin. Endo. Metab. 92:
1948, 2007.
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 (MEN III):
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.)
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.
Nowadays, a tumor that stains for phenylethanolamine-N-methyltransferase (PNMT)
has the "adrenergic phenotype", one that doesn't has the "noradrenergic phenotype".
Of course, that's history now. Pheos light up with chromogranin A and
tyrosine hydroxylase. Extra-adrenal paragangliomas light up with chromogranin A
but often not with tyrosine hydroxylase.
For pheos, the traditional teaching has long been
that there are no histologic criteria for malignancy, not even vascular invasion. The honest
pathologist cannot predict the tumor's behavior.
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.
They must be thanatosomes.
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 (and likely permanently, as with cocaine) 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).
* 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
(J. Clin. Endo. Metab. 89: 2859, 2004); I am not sure I agree,
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
NEUROBLASTOMA (Ped. Clin. N.A> 55: 97, 2008)
Either Wilms tumor or neuroblastoma is the most
comon extracranial solid cancer of children. 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.
They seem to strike at random. * Three risk loci, all at 6p22, have been spotted (NEJM 358: 2585, 2008).
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 often
neurites too. (* True "Flexner" 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). "MKI" is the "mitosis-karyorrhexis index", i.e., what percent
of cells exhibit these; more than 4% is bad (2% if the child is over 1.5 years).
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
have screened their babies 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 indicated it's a
bad
idea NEJM 346: 1041 & 1047, 2002.
There are also a variety of curious (probably autoimmune)
paraneoplastic syndromes that result from neuroblastomas,
including neurodegenerative disorders similar to those in oat-cell carcinoma.
Prognosis in neuroblastoma:
And of course, it's good if the cells are differentiating...
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
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).
Retinoblastomas (cones of the eye), medulloblastomas (cerebellum),
pinealoblastomas (pineal), and adult neuroblastomas (lots of places -- many of these are probably
Ewing variants) 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.
* Neuroblastoma of the olfactory epithelium is a special entity.
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:
After 30-60 minutes, the serum cortisol should spike to at least 500 nanomoles/Liter =
18 micrograms/dL.
If it doesn't, you have adrenal insufficiency, either primary
(the glands are diseased) or secondary (the glands atrophied from
lack of ACTH stimulation).
In the past, we used to give an ACTH stimulation test each day
for a week; patients with secondary adrenal insufficiency would
grow their adrenals back from the test (and probably want to come back for more!)
Injected ACTH clears in a few minutes.
Nowadays, just take your 30-minute blood sample
and check serum ACTH (it'll probably still be high in primary
adrenal disease, low-ish in pituitary insufficiency).
Also check serum aldosterone in the same sample; the ability of the
adrenals to produce aldostone isn't lost as much as the ability to produce
cortisol when the problem is in the pituitary gland.
A lack of a normal spike after ACTH administration
confirms primary adrenal insufficiency.
A "spot serum cortisol" is worthless (the stress of venipuncture
can cause a false negative.) A "24 hour urine cortisol" is worthless
(it can be zero in health.) A "spot serum ACTH" is worthless. It's
secreted in pulses.
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.
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.
Current thinking: J. Clin. Endo. Metab. 91: 2618, 2006.
Administer ACTH and measure blood 17-OH-progesterone.
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.
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?
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 pericardial sack, 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 ("oncocytes"): 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.)
Historically, I've suggested
measuring both. With high PTH, high calcium, and low phosphorus,
you have your diagnosis. Today's i-PTH (intact PTH)
might be more expensive but is available stat for use during surgery.
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 non-pagetic, non-injured 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.
Pathologists see Arch. Path. Lab. Med. 132: 1251, 2008).
80-85%... parathyroid "adenoma" ("single gland disease")
<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), or very rarely real PTH. 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. When serum calcium was added to the chemical
profiler in 1974, a huge number of patients were found and much good was done by
removing their tumors.
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.)
Most extreme: Calciphylaxis (metastatic calcification of the skin,
with horrible ulcers and breakdown): South. Med. J. 102: 318, 2009.
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).
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 (old-fashioned test)
high serum parathyroid hormone (PTH) 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. Well usually.
And often the hyperplasias are clonal. It's blurry.
These tumors are most common in older women, but may occur in anyone. They average around a
gram but are sometimes bigger.
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, much more since).
* When I first begin preparing these notes in the 1980's, I mentioned
that I'd seen several at autopsy that were probably non-functional.
In the scanning era, surgeons are now making the same discovery (Surgery 138: 1111, 2005).
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).
* 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 CARCINOMA (Cancer 100: 900, 2004; Surgery 142: 936, 2007)
A rare cause of primary hyperparathyroidism.
By definition, this cancer arises in a parathyroid gland and produces parathyroid hormone.
A familial syndrome
of parathyroid adenomas and carcinomas
involves mutant HRPT2 (parafibromin: NEJM 349: 1722, 2003);
this gene is not mutated in parathyroid adenomas, either familial or sporadic (J. Clin. Endo. Metab. 90: 5015, 2005).
* Loss of Rb, reportd in the 1990's, was a disappointment; loss of heterozygosity
for this and other anti-oncogenes is noted in some tumors showing
bizarre mitoses, invasion, or metastases (Surgery 144: 949, 2008); we await
studies with adenomas as controls.
* Today, the "other" marker stain that indicates malignancy in a parathyroid
tumor is PGP9.5 (J. Clin. Endo. Metab. 94: 434, 2009).
These cancers are somewhat aggressive. About a third are cured with simple excision,
another third recur and require re-operation for cure, and only a third eventually
metastasize and ultimately cause death, usually from
refractory hypercalcemia. Sestamibi scanning has greatly
improved the management of these tumors (Clin. Nuc. Med. 32: 358, 2007).
* Please leave the distinction among "parathyroid carcinoma",
"atypical parathyroid adenoma", and "parathyromatosis" to us pathologists.
Thanks. Cancer 110: 255, 2007.
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.
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.
Older techniques to tentatively distinguish a
hyperplastic gland from an adenoma on morphology have fallen into disuse.
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.
{27260} parathyroid hyperplasia (arrow sign helps)
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.)
NOTE: The honest pathologist CANNOT distinguish a hyperplastic gland from an adenoma! The
surgeon MUST send samples of two glands. (Why? Confirmed yet again.... Surgery 142: 930, 2007)
The pathologist will report "hypercellular parathyroid tissue". We can tell the second (normal)
gland easily using a touch-prep cytology.
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); serum parathormone levels are part of the screen especially by epidemiologists.
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 involved, it's "multiple gland parathyroid
neoplasia", with different genetic signatures for each. See Am. J. Path. 165:
565, 2004.
OTHER HYPERPARATHYROID SYNDROMES:
In the 1970's, many of these folks were operated in search of parathyroid disease... sorry!
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.
Worked out NEJM 335: 708, 1996.a
HYPERCALCEMIA: Differential diagnosis for beginners. Review Postgrad. Med. 115: 69, 2004.
HYPOPARATHYROIDISM
The most common cause is iatrogenic (following thyroid surgery).
Next is autoimmunity (remember the syndrome with addisonism, ectodermal dysplasia, and mucosal
candida * Zebras: Kearns-Sayre / mitochondriopathy (J. Clin. Endo. Metab. 83:
125, 1998), Wilson's, Riedel's struma; X-linked agenesis syndrome (J. Clin. Inv. 115:
2822, 2005); various genetic syndromes (for example J. Clin. Endo. Metab. 91:
4587, 2007).
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).
By the way... there's plenty of vitamin D deficiency (low calcium, low phosphate)
thanks to lack of sunlight (chosen lifestyles, veiling of women) and/or
malnutrition (fad diets, poverty, malabsorption) and/or vitamin D resistance (genetic
syndromes). Update on hypocalcemia: BMJ 336: 1298, 2008.
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 Gsα. There is a striking imprinting effect (Am. J. Hum. Genet. 68: 1283, 2001.)
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 -- now distinguished from true "myositis ossificans").
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. In the 1990's
I predicted it was caused by a different allele at the GNAS1 locus and this has now
been demonstrated (J. Clin. Endo. Metab. 87: 189, 2002; J. Ped. Endo. 19-S2: 635, 2006).
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.
THYMUS
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
* 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); one group thinks
it's too complicated and a simplified system would work just as well in answering
the real question (i.e., who should get chemo / radiation? Cancer 112:
2780, 2008).
Not classified yet... Fibrosing variant: Am. J. Clin. Path. 121: 867, 2004.
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.
{13952} thymoma, gross
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; update
on these thymomas Ann. Thor. Surg. 79: 219, 2005).
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; spotting them on needle
aspiration Arch. Path. Lab. Med. 130: 1612, 2006),
* CARCINOMAS (i.e., obviously
malignant on histopathology: Cancer 67: 1025, 1991), and * germinomas
(seminomas -- check for positive staining for placental alkaline phosphatase -- , less often embryonal-cell carcinomas or choriocarcinomas) arise in the thymus.
* Thymic TERATOMAS are relatively common.
* There's a popular "five T's" mnemonic for anterior mediastinal masses:
* 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
* THE MELATONIN BUSINESS: Older 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.
A meta-analysis found melatonin basically useless overall in sleep disorders,
even jet lag and shiftwork disorder (for which it was once famous: BMJ 332:
385, 2006).
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.
The most recent study showing an effect of the stuff showed it worked best
on patients who don't secrete normal amount of melatonin metabolite, and that
these were mostly older folks (Am. J. Med. 116: 91, 2004).
There are some hopeful results in irritable bowel syndrome (Gut 54:
1353, 2005) and a non-yet-reproduced report of improvement in
tardive dyskinesia (Arch. Gen. Psych. 58: 1049, 2001). An optimistic study in children (Clin. Ped. 42:
51, 2003) lacked controls.
For old folks with "cognitive decline, mood, behavioral and sleep disturbances",
melatonin seems to help as long as it's also given with bright light
(JAMA 299: 2642, 2008; I couldn't help but wonder if the old folks
weren't simply being given more attention, hence the benefit.)
In the meantime, the stuff seems extremely safe, and I wouldn't fault you
for wanting to experiment, assuming you give proper informed consent.
Adrenal -- cytomegalic fetal cortex
Beckwith-Wiedemann
Wikimedia Commons
* About 2% of men have adrenal cortex in their groins along the path
of the descending testicle (BJU Int 95: 407, 2005.)
HYPOADRENOCORTICISM ("Addisonism", etc.): Insufficient glucocorticoid (and usually
insufficient mineralocorticoid) production. Reviews Lancet 361: 1881, 2003;
NEJM 360: 2328, 2009.
of the adrenals (by way of the lymphoid tissue of the
duodenum).
{25399} tuberculosis of adrenal, histology
{27257} tuberculosis of adrenal, histology
TB of the adrenal
WebPath Photo
,
coccidioidomycosis
and South American blastomycosis)
and leprosy
are important
causes, and now AIDS is too.
Jack Kennedy, second from left
PT109 reunion, 1944
Notice weight and pigmentation
In a study with inevitable selection bias, about half of patients
with these antibodies eventually developed clinical addisonism (J. Clin. Endo. Metab. 91: 1637, 2006).
Autoimmune polyglandular syndrome type I
features (2 of 3)
hypoparathyroidism, addisonism and/or mucosal candidiasis
;
there's often
other autoimmune problems too).
It's an autosomal recessive, known locus AIRE (autoimmune regulator), that causes
patients to make an autoantibody against tryptophan
hydroxylase (TPH): Lancet 352: 255, 1998). Surprised that the tendency to get an autoimmune
disease can be simple-mendelian? I was.
Autoantigens are now being discovered (parathyroid NEJM 358: 1018, 2008).
Update on the autoimmune polyendocrinopathies: J. Clin. Endo. Metab. 91:
1210, 2006. Type II hasn't yielded up its basic biology
like type I has. There is also a deadly X-linked polyautoimmune endocrinopathy
of infants.
(in AIDS, it's almost the rule; Am. J. Clin. Path. 93: 651, 1990).
{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
* Some women feel better and have better sexuality if they get some DHEA.
Makes sense. Why? (NEJM 341: 1013, 1999).
{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
* Expect the unexpected. A lady dies because toluene inhalation
somehow produces adrenal necrosis: J. Tox. 36: 365, 1998.
(possible new
WF-producing strain NEJM 353: 1245, 2005), pneumococci, and H.
influenzae are other important causes (J. Clin. Path. 57: 208, 2004).
{09224} adrenal hemorrhage, consistent with Waterhouse Friderichsen
{07570} adrenal hemorrhage, gross, consistent with Waterhouse-Friderichsen syndrome
Waterhouse-Friderichsen
Cortex blood / necrotic, medulla (blue) spared
KCUMB Team
Etiologies,
from most to least common
{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
Adrenal cortical adenoma
Produced Conn's
Wikimedia Commons
* In "Conn's caused by idiopathic hyperplasia of the zona glomerulosa",
look for cords of glomerulosa-type cells creeping down into the zona fasciculata.
{24450} adrenogenital syndrome, virilized baby girl
{49432} 11-hydroxylase deficiency, 11 month old boy
About 75% of incidentalomas are adenomas; next most common is myelolipoma.
The folks at Brown had a series of almost 1000 patients with incidentalomas biopsied,
without one cancer (AJR 190: 1163, 2008); their surgeons also say, "Leave them alone" (Arch. Surg. 144: 465, 2009).
{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
{49443} adrenal myelolipoma, gross
{25413} adrenal myelolipoma, histology
Adrenal myelolipoma
Pittsburgh Pathology Cases
* Another tipoff is broad fibrous bands, but you usually
won't need this to know you're looking at cancer.
* The only real fooler is an adenoma, usually in a child under age 5,
made of bizarre cells with big nuclei, but the rarity of mitotic figures indicates
this is benign.
{40196} adrenal cortical carcinoma
{24090} adrenal cortical carcinoma, histology
Metastatic cancer in the adrenals
WebPath Photo
Cancer metastatic to the adrenal
AFIP
Wikimedia Commons
Up to 30% of affected people
seem to have a germline mutation -- see Arch. Path. Lab. Med. 132: 1272, 2008).
Syndromes include:
Sporadic pheos usually do NOT have any of these genes mutated.
Pheo patients need to be screened for germline mutations, and if positive, their
family members need to be screened as well (J. Clin. Endo. Metab. 94: 1701, 2009).
* Bronchial and thymic carcinoids too... the latter mostly in middle-aged men who smoke
a lot. Medicine 76: 21, 1997.
Patients with MEN II may first have adrenal medullary hyperplasia,
which can be nodular. Nodules over 1 cm are best considered pheos.
* The most recent effort (Surgery 143: 759, 2008), from Memorial Sloan-Kettering, provides
a scoring system based on twelve histologic parameters, including a bunch of
special stains (notably Ki-67 / MIB-1). Tumors with scores of four or less all proved to act benign;
those with higher scores were unpredictable.
Using 131-I-MIBG for metastatic malignant pheochromocytoma treatment, with
very good results: Cancer 98: 239, 2003; J. Clin. Endo. Metab. 90:
5888, 2005.
{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
{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
* Stay tuned for monoclonal antibodies as a mainstay in the treatment
of difficult neuroblastoma patients: Heme-Onc. Clin. N.A. 15: 853, 2001.
PARATHYROID GLANDS: ANATOMY AND PHYSIOLOGY
Order a rapid ACTH ("cosyntropin", "synacthen") stimulation test
Give an injection of 250 mg of synthetic ACTH, intramuscularly or intravenously.
Parathyroid Exhibit
Virtual Pathology Museum
University of Connecticut
Parathyroids
"Pathology Outlines"
Nat Pernick MD
Today's "i-PTH" (intact parathyroid hormone) assay is a long-time
pathologist's dream, and requires a two-antibody technique. It's replacing
the classic N-terminal and C-terminal assays.
10-15%... parathyroid "hyperplasia" ("multiple gland disease", usually all four glands)
maybe 1%... parathyroid carcinoma (I think this traditional number is high)
A person with MEN I has about an 85% lifetime chance
of getting primary hyperparathyroidism; a person with MEN II has about a 20% chance.
These are usually hyperplasias.
Brown Tumor of Hyperparathyroidism
Pittsburg Illustrated Case
The sestamibi scan lights up mitochondria,
so it's a good way to show up parathyroids.
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 glands do fail to "light up", especially if they are
very small or lack abundant mitochondria (Arch. Oto. 131: 493, 2005).
* All take up Tc99-sestamibi well; oxyphil-rich adenomas
are the best (Arch. Otol. 132: 779, 2006).
* 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 pheochromocytomas, hyperchromatic
nuclei ("endocrine atypia") don't mean cancer.
* Loss of parafibromin nuclear reactivity as a marker for malignancy:
Clin. Canc. Res. 10: 6629, 2004. Not surprisingly, and in contrast to other
genetic syndromes, it also disappears in involved parathyroids in familial
isolated hyperparathyroidism (HRPT2 / parafibromin locus, cited above).
* Watch for the name of "primary parathyroid hyperplasia" to change to
"multiple parathyroid gland neoplasia." The lesion in kidney disease is
a true hyperplasia.
Clear-cell lesions do not show well with sestamibi. 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).
{09271} primary parathyroid hyperplasia, histology
Parathyroid hyperplasia
You cannot tell this from adenoma by itself
WebPath Photo
Parathyroid hyperplasia
Note cell uniformity. Uremia.
KCUMB Team
This is now routine. You can use the sestamibi scan to see if the graft
is over-functioning: South. Med. U. 93: 215, 2000.
FAMILIAL HYPOCALCIURIC HYPERCALCEMIA, also called "familial benign hypercalcemia", a mild,
autosomal dominant disorder.
* Fun to know: CaSR is autoantigen in the parathyroid disease
in autoimmune parathyroid disease: J. Clin. Endo. Metab. 92:
2107, 2007.
* Long-overdue, pathologists and surgeons are now working
together to examine excised thyroid material intra-operatively to be sure
that parathyroid was not taken, and if so, to replace it (Arch. Otol. 133: 1105, 2007).
? --
J. Clin. Endo. Metab. 88: 4602, 2003).
In both familial and sporadic cases, the autoantigen is often CaSR (J. Clin. Inv. 97:
910, 1996; updates
J. Clin. Endo. Metab. 89: 4484, 2004; J. Clin. Endo. Metab. 94: 4655, 2009).
You also remember DiGeorge's syndrome.
In kidney (PTH-receptor), thyroid (TSH receptor),
ovary (FSH-LH receptors), 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.
Child with pseudo-pseudo-hypoparathyroidism
Courtesy of Mary Fay MD
Thymus Exhibit
Virtual Pathology Museum
University of Connecticut
{13958} Hassall's corpuscles stained for keratin (this appears to be normal thyroid)
* From best-to-worst prognosis, they are:
Type A: Spindle or oval epithelial cells, no atypia, no lymphocytes
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 epithelial cells growing in sheets, only a few lymphocytes
Type C: Obvious atypia, less recognizable as thymus. There are over a dozen variants described.
{25653} thymoma, gross
{13955} thymic tumor, possibly Hodgkin's
{49097} malignant thymoma, gross
Primary thymic lymphoma
Virginia
Good pictures
Carcinoid
Mediastinum
Pittsburgh Pathology Cases
{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
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
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about endocrine pathology to consult these standard textbooks.
In my notes, the most helpful current journal references are embedded in the text. Students using these during lecture strongly prefer this. And because the site is constantly being updated, numbered endnotes would be unmanageable. What's available online, and for whom, is always changing. Most public libraries will be happy to help you get an article that you need. Good luck on your own searches, and again, if there is any way in which I can help you, please contact me at scalpel_blade@yahoo.com. No texting or chat messages, please. Ordinary e-mails are welcome. Health and friendship!
| Visitors to www.pathguy.com reset Jan. 30, 2005: |
Ed says, "This world would be a sorry place if
people like me who call ourselves Christians
didn't try to act as good as
other
good people
."
Prayer Request
Teaching Pathology
If you have a
Second Life
account, please visit my teammates and me at the
Medical Examiner's office.
PathMax -- Shawn E. Cowper MD's
pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic
Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification
Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science
Trivia Quiz -- have a chuckle!
Rudolf
Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
 | Pathological Chess |
 |
Taser Video 83.4 MB 7:26 min |
Adrenal atrophy in
Waterhouse-Friderichsen
Paragangliomas
Neuroblastoma rosette
Child with neuroblastoma
Brown tumor
Brown tumor