Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
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I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
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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!
OBJECTIVES
Recognize patients who may have each of the following, and describe
the anatomic pathology and what we know of the etiology and
pathophysiology of each:
Describe the appropriate lab workups for:
QUIZBANK Endocrine (It's impossible to separate pituitary, adrenal, thyroid, parathyroid, etc. Look at it all
now.)
INTRODUCTION
This is an easy unit, but you have to do some thinking.
The thyroid begins as a patch on the back of the tongue (at the "foramen cecum"). It descends
(down what may become the "thyroglossal duct") into the neck.
The former track may be filled with thyroid tissue, imparting a "pyramidal lobe" to the thyroid (40%
or so of thyroids have at least a little one).
Occasionally some or all of the gland ends up in the mediastinum instead, explaining the occasional
"retrosternal goiter".
The thyroid sits close to the four (or however many) parathyroid glands
(and sometimes encases and thus hides one or more of them), and to the recurrent
laryngeal nerves. These structures may be damaged during surgery.
The healthy adult thyroid weighs around 15-25 gm. If you don't remember its histology and physiology
(follicles full of colloid, iodine traps, microvilli, parafollicular C-cells, thyroxine=T4, iodotyrosine
precursor compounds, triiodothyronine=T3, calcitonin (remember it's
from the parafollicular cells that are
mostly in the upper lobes), synthesis and endocytosis of thyroglobulin,
TRH, TSH=hTSH=thyrotropin, etc.), please review. HINT: C-cell function is vestigial in
humankind, completely dominated by parathyroid function. And don't expect to be able to
distinguish the C-cells unless they are hyperplastic (i.e., MEN II, response to chronic hypercalcemia)
or immunostained.
When thyroid is active (i.e., winter, puberty, pregnancy, stress, Graves's disease, Jod-Basedow) or
just overstimulated (propylthiouracil or other thiourea that inhibits peroxidase,
thiocyanate that inhibits the iodine pump), the cells will become taller and
thyroglobulin will be reabsorbed. You may even see the overabundant
cells piled up as little papillae
(really "pseudopapillae", as they lack fibrovascular cores; why?)
{08959} propylthiouracil effect
When thyroid is inactive (i.e., no TSH or other stimulation, or
there is excessive iodine that as you remember strongly inhibits lysis of thyroglobulin), the cells
flatten down and the amount of colloid increases. {24719} high-dose iodine effect
Most thyroids removed surgically have "palpation thyroiditis",
a mix of fibrosis and granuloma typically inside follicles. It's a non-problem.
Any enlarged thyroid (i.e., over maybe 50 gm) is a GOITER (or STRUMA). Areas of thyroid that are
mostly colloid (i.e., colloid-rich adenomas, colloid-rich nodules, glands poisoned by excess iodine)
will look gelatinous. Areas of thyroid with active cells and colloid-poor follicles look like raw beef.
Mitochondria-packed Hürthle cells in a thyroid (i.e., Hashimoto's, some multinodular goiters, some adenomas) impart a brown
color (why?)
Lone colloid nodules -- easily diagnosable because their contents are too viscous
to be aspirated by an 18-guage needle -- can be huge; they're now
ablated by ethanol injection (AJR 191: 1730, 2008).
Nuclear medicine plays an important role in thyroid testing. Active glands (or active nodules in a
less-active gland) appear "hot" on scintiscan. Inactive glands (or inactive nodules within a gland)
appear "cold".
{09362} normal scan
Hopefully you remember what thyroid hormones do. Thyroid disease is common and easy to treat
effectively, but its onset is insidious and it is often overlooked. "Idiopathic goiter" affects maybe one
older adult in 20 and is of negligible significance. Serious thyroid disease mimics "psychiatric
disease". This is unfortunate. Hopefully you won't fall into this trap.
Thyroid cancer is the most common endocrine cancer
and causes around 1000 deaths per year (current textbooks give figures that are too
high). Papillary carcinoma is the most common but the least deadly; most cases are never detected in
life. Follicular carcinoma is aggressive. Medullary
carcinoma is aggressive. Anaplastic carcinoma
is the least common but ultra-aggressive. Many thyroid tumors, both benign and malignant,
are incidental autopsy findings (Cancer 64: 1888, 1989).
* The non-disease "black thyroid" is deposition of a pigment (no one knows exactly what) in the
thyroids of patients treated long-term with minocycline (Arch. Path. Lab. Med. 118: 79, 1994).
CRETINISM
{49456} cretin, age 4 months
Hypothyroidism, presenting first in infancy or childhood. It may be due
to hypothyroidism during pregnancy (permanent brain damage), or to
a problem with the child's thyroid gland.
Often there is an inborn error of metabolism (most often a mutation
in the thyroid peroxidase gene). Or the thyroid may simply fail to form -- an
inquiry into the epidemiology of "thyroid dysgenesis" revealed not a clue
as to why this happens.
These people remain like small children
both mentally and physically throughout their lives. Replacing thyroid hormone later in life helps,
but does not reverse the damage (J. Clin. End. Metab. 70: 336, 1990); for best results,
you must treat before the third week (J. Ped. 136: 292, 2000).
The severity of the disease varies. If a mother is severely iodine-deficient, the child will be
profoundly retarded, deaf and spastic ("neurologic cretinism"). Less-severely affected children, such
as those who cannot make their own thyroid hormone after birth, fail to thrive and remain stunted.
They are likely to show any or all of the problems of adult myxedema.
Unless the cause is absence of thyroid hormone receptors, cretinism should never, ever develop. In
the U.S., all babies are screened shortly after birth, and impending cretinism is treated. (Even the
most fiscally-conservative politicians understand this: Each test costs a few dollars, and treatment
is cheap and simple, but lifetime care of a cretin costs megabucks. Ditto for phenylketonuria.)
* The early screening will often miss iodotyrosine dehydrogenase deficiency,
which will produce a goiter and hypothyroidism with the danger of neurologic
damage if it is missed: NEJM 358: 1856, 2008.
EPIDEMIC CRETINISM is the result of endemic dietary deficiencies in iodine. I would conclude from this that iodine deficiency has been a limiting factor on human populations,
and the ability of people to function as they should, throughout much of the world throughout most
of history. I would also consider ready-available iodine to be one undeniable blessing of science.
SPORADIC CRETINISM is the result of some kink in development or metabolism.
Causes of sporadic cretinism:
You need to treat these kids aggressively with thyroid supplements; undertreating cretinism is
disastrous: J. Ped. 125: 147, 1994.
ACQUIRED HYPOTHYROIDISM (Lancet 363: 793, 2004 -- it's often missed even though this should never happen)
CATEGORIES
PRIMARY HYPOTHYROIDISM means the thyroid gland is under-functioning because of some problem
other than insufficient hTSH.
SECONDARY HYPOTHYROIDISM ("central hypothyroidism")
means the gland is hypo-functioning because it is being under-stimulated
by too little hTSH, reflecting a primary problem in the pituitary gland.
Please don't miss this.
TERTIARY HYPOTHYROIDISM (the other "central hypothyroidism") means there is too little hTSH because
there is too little TRH, i.e., a primary problem in the hypothalamus.
Uncommon but not ultra-rare (Pitutiary 11: 181, 2008); it will come up
most often in patients who actually have "euthyroid sick syndrome"
SIGNS AND SYMPTOMS OF HYPOTHYROIDISM
SLOWING OF MIND AND BODY is the prime problem. Mental slowness,
fatigue, irritability, and loss of interest
may be mistaken for, and treated as, "depression" (they should revoke somebody's
license, but it
happens every day), or there may be hallucinations and delusions ("myxedema madness"). This
progresses to profound disability, MYXEDEMA COMA and death.
NOTE: Down's syndrome (trisomy 21) folks often (at least 50% of the time) get at least a
chronic lymphocytic
thyroiditis, and they may end up hypothyroid. Don't overlook this, or assume the mental
slowness is just part of Down's. In fact, there is now a trend to supplement Down's children
with thyroxine while they are young; this seems to help growth and development
(J. Clin. Endo. Metab. 90: 3304, 2005).
MYXEDEMA properly refers to accumulation of hydrophilic ground substance throughout the
connective tissues of the body; this leads to coarsening of the facial features, enlargement of the
tongue, puffiness around the eyes, and deepening and croaking of the voice.
* Future pathologists: Mucoprotein in the ducts of sweat
glands is a tipoff to myxedema.
{24611} myxedema
LDL CHOLESTEROL increases strikingly, and this promotes atherosclerosis.
CARDIAC DYSFUNCTION ("hypothyroid cardiomyopathy") leads to low heart rate and loss of cardiac
strength. The end-stage myxedema patient's heart is a typical dilated cardiomyopathy. The
accelerated atherosclerosis doesn't help, either. This is another reason to treat hypothyroidism
gingerly.
CONSTIPATION is common.
WEIGHT GAIN is usual, and beware of sleep apnea.
DRY SKIN and COARSE, BRITTLE HAIR that may fall out in patches or all over.
YELLOWISH DISCOLORATION OF THE SKIN (for some reason, these people tend to get more carotene in the
bloodstream -- actually true * Int. J. Vit. Nutr. 69: 132, 1999)
COLD INTOLERANCE (poor perfusion of the extremities, sluggish mitochondria)
DELAYED DEEP TENDON REFLEXES ("hung reflexes") is a helpful physical sign.
CAUSES OF HYPOTHYROIDISM LATER IN LIFE
BIRTH DEFECTS
THYROGLOSSAL DUCT CYSTS are bits of the old thyroglossal duct. The cysts may be lined by thyroid
and/or squamous epithelium (why?), always with some lymphoid tissue (why?) Protruding the tongue
as far forward as possible will cause the cyst to rise. Savvy surgeons
treat these midline cysts by removing them along with the center of the hyoid bone to prevent
recurrence (why?)
{49471} thyroglossal duct cyst, patient
Bits and pieces (or all of) the thymus and/or parathyroids may lie within the thyroid capsule. Bits of
extra thyroid may be found elsewhere, notably on the tongue (the annoying "lingual thyroid").
{21529} lingual thyroid
In some folks, the thyroid gland just never develops. Unless the hormone is replaced, these people
will become cretins. Gene J. Clin. Endo. Metab. 86: 234, 2001.
HASHIMOTO'S THYROIDITIS ("chronic autoimmune thyroiditis": NEJM 335: 99, 1996)
{09241} Hashimoto's, gross
A common, chronic, progressive thyroid disease. There are
maybe 1,000,000 Hashimoto cases in
the U.S. Most patients are adults, and as with most autoimmune disease there is a female
preponderance, but no age or sex is immune. The autoantigen is thyroglobulin and/or
peroxidase in the microsomes.
Patients are likely to have a goiter. Most are euthyroid, many are hypothyroid, and a few are at least
temporarily hyperthyroid ("Hashitoxicosis", "Toximoto's disease").
If you biopsy it (and you usually don't), patients with Hashimoto's disease will exhibit (1) lots and
lots of lymphocytes in the thyroid gland; (2) germinal centers; (3) plasma cells; (4) Hürthle cells
(i.e., cells packed with mitochondria, also called "oncocytes"; they probably don't make thyroid
hormone).
The unusual "fibrosing variant" features more fibrosis, more scar contraction, and less of everything
else. Unlike Riedel's, it stays within the gland.
* Some physicians distinguish a non-Hashimoto "primary thyroid atrophy"
with a very small thyroid gland with most of the cells lost ("Ord's disease")
but this is probably just a Hashimoto's variant, as both feature
the same autoantibodies, and the size range isn't bimodal (J. Clin. Endo. Metab. 94: 833, 2009.)
We've already seen this disease as the prototype of antibody-dependent cell-mediated cytotoxicity.
More in keeping with some of
the newer work on Sjogren's, type I diabetes, etc., etc., we now know that Hashimoto thyroids
express HLA-DR antigens on their follicular cells, and this might get the process going.
These people have increased rates of autoimmune addisonism, pernicious anemia,
Sjogren's, vitiligo, and type I diabetes. We'll talk about the autoimmune
polyendocrine syndromes when we discuss
the adrenals.
PITFALL: You remember that many Hashimoto patients have SCHMIDT'S SYNDROME -- coexisting
autoimmune adrenalitis with addisonism. Further, if
there's a problem with the pituitary or hypothalamus causing the hypothyroidism, there's likely to be
concurrent secondary adrenal insufficiency. So... before you give that patient in myxedema coma a
nice booster of thyroid hormone, first administer glucocorticoid so as not to cause death from acute
adrenal insufficiency!
We will review Hashimoto's encephalopathy, a vasculitis involving the
subcortical white matter, under "CNS". Thankfully only about 1% of Hashimoto's
patients get this. Don't forget about it, or assume the patient has "MS" or "Alzeimer's"
or "idiopathic epilepsy". Autopsy findings Neurology 61: 1124, 2003.
NON-HASHIMOTO LYMPHOCYTIC THYROIDITIS
Abundant lymphocytes in the thyroid gland, but without germinal centers, plasma cells, or Hürthle
cells (Cancer 68: 1944, 1991). This is extremely common, especially in older
women.
In the very common "chronic lymphocytic thyroiditis",
there may be a small goiter, and there may be transient hyperthyroidism. Nobody really knows the
cause or the relationship to DeQuervain's, Hashimoto's, etc.
Postpartum thyroiditis, one variant of "subacute lymphocytic thyroiditis", has been studied well and has
increased expression of HLA-DR antigens on the surfaces of the follicular cells (no surprise; Am. J.
Clin. Path. 100: 200, 1993).
This pathologist suspects the histopathology covers several diagnostic entities, including the ill-defined
PRIMARY AUTOIMMUNE MYXEDEMA, often seen in Down's. To date, there is no international classification of thyoriditis, and
nowadays you'll probably just hear both Hashimoto's and non-Hashimoto's
called "chronic autoimmune thyroiditis" (NEJM 335: 99, 1996).
Be this as it may, lots of kids have goiters because of lymphocytic
infiltration, some will be euthyroid, some will be
hypothyroid, and you'll make these goiters shrink with thyroid hormone
therapy (J. Clin. Endo. Metab. 91: 1729, 2006; J. Clin. Endo. Metab. 92:
1647, 2007).
DEQUERVAIN'S SUBACUTE GRANULOMATOUS THYROIDITIS ("thyroid virus infection")
{09247} DeQuervain's
Thyroiditis review for the primary care physician: Am. Fam. Phys. 61: 1047, 2000;
Am. Fam. Phys. 73: 1769, 2006.
Despite "Big Robbins", infections involving the thyroid gland are extremely uncommon, with the
outstanding exception of DeQuervain's, a common, usually-missed, usually-mild disease.
In "DeQuervain's", the thyroid follicle cells die off in patches, almost certainly the result of some
virus or other. Known culprits include
mumps As you'd expect, the gland becomes large and painful. If you are foolish enough to biopsy the gland,
you will see a spectacular granulomatous response to the released colloid (probably
not "sequestered antigens"; it looks like a typical foreign-body reaction to glop).
Most patients are young adult women, but nobody is immune. The major problem is generally the
pain (neck, or referred to ear; "take two aspirins"), though sometimes the process is painless.
Occasionally, enough thyroglobulin may be broken down to produce transient hyperthyroidism, or
enough of the gland may be destroyed to produce hypothyroidism. The sed rate goes way up (why?)
In weeks to months, things settle down and the disease goes away by itself. Despite the impressive
histology during the illness itself, I've never seen what I thought was "old scarring from
DeQuervain's" at autopsy.
* DeQuervain's producing "acute mental illness": South. Med. J. 100: 837, 2007.
RIEDEL'S THYROIDITIS ("Riedel's struma"; review J. Clin. Endo. Metab. 87: 3545, 2002;
Am. J. Clin. Path. 121: 550, 2004)
{49460} Riedel's
A thankfully
rare process in which fibroblasts proliferate and lay down collagen, usually as broad, keloid-like bands. Most patients are older
women, who present with a rock-hard ("woody", etc.) neck mass.
Riedel's does not respect the thyroid capsule, or anything else. (This makes
it easy to tell from fibrosing Hashimoto's.)
It mimics an invasive sarcoma, but there is no anaplasia or necrosis.
Enough of the gland may be destroyed to produce hypothyroidism.
Surgical exploration may be
required to relieve pressure on the trachea. Fortunately, the disease generally stops before the
patient asphyxiates.
CATEGORIES
PRIMARY HYPERTHYROIDISM means the thyroid gland is over-functioning because of some problem
other than excess hTSH.
SECONDARY HYPERTHYROIDISM means the gland is hyper-functioning because it is being overstimulated
by too much hTSH, reflecting a primary problem in the hTSH-producing organ. (The most common
cause may be ectopic hTSH production by a choriocarcinoma).
TERTIARY HYPERTHYROIDISM means there is too much hTSH because there is too much TRH. It is almost
never mentioned in the literature and is probably very rare.
SYMPTOMS AND SIGNS OF HYPERTHYOIRIDISM
HYPERMETABOLISM is manifest by weight loss, muscle atrophy, heat intolerance, increased appetite.
Basic thermodynamics tells what's happening: Food is being burned for heat rather than for ATP
(i.e., oxidative phosphorylation is being uncoupled). Patients sweat (and their skin feels moist) and
develop hyperdynamic pulse.
INCREASED MENTATION may or may not make the person smarter, but it'll make them more anxious and
labile ("You're not sick, it's nerves.") In the very elderly, APATHETIC
HYPERTHYROIDISM may appear
instead, and be mistaken for Alzheimer's.
ENHANCED EPINEPHRINE EFFECT shows as tremulousness and "anxiety". (Try this: Take a sheet of paper
and lay it over the backs of the patient's outstretched hands. A very fine fluttering speaks for
hyperthyroidism). Blocking the epinephrine receptors with
propranolol is a big help while you're stabilizing a Graves's patient prior to
definitive treatment.
LID LAG is a delay in downward movement of the upper eyelid as the patient looks down. The
upper eyelid tends to be held too high anyway. (This "bug-eyed" appearance is common to all
hyperthyroid patients; it is enhanced by the ophthalmopathy of Graves's disease.)
ATRIAL FIBRILLATION (or other atrial arrhythmia) is particularly likely to result from hyperthyroidism.
(George Bush Sr.'s disease.) There is no consensus on the nature (or even the existence) of
HYPERTHYROID CARDIOMYOPATHY.
MILD DIARRHEA may be present.
OSTEOPOROSIS is a very serious long-term complication of hyperthyroidism.
LDL CHOLESTEROL goes down, which is nice as far as the arteries are concerned.
THYROID STORM ("thyrotoxic crisis") is the most dreaded problem in hyperthyroidism. This is
development of extreme hypermetabolism, leading to coma and death, when the hyperthyroid patient
is subjected to some other major physiologic stress.
THE CAUSES OF HYPERTHYROIDISM
GRAVES'S DISEASE (NEJM 358: 2704, 2008)
{09235} Graves's
This is a common problem caused by autoantibodies directed against the hTSH receptor. The
receptor mistakes them for TSH.
Nobody knows the cause of the autoantibody production.
The nature of the disease has been clarified by a good mouse model using either of two monoclonal antibodies
that produce somewhat different pictures
(J. Immuno. 176: 5084, 2006).
Patients also usually exhibit ophthalmopathy (the usual "lid lag", etc., of hyperthyroidism, plus
weak eye muscles plus excess collagen and ground substance behind the eyeball ("orbitopathy"), causing
PROPTOSIS-EXOPHTHALMOS).
There are usually antibodies against both eye muscles and against the fibroblasts
behind the eye and on the shin.
{09355} Graves's exophthalmos
To complete the triad, patients often exhibit myxedema-like nodules confined to the anterior aspects
of the lower extremities ("pretibial myxedema").
* Try a generous dose of a topical glucocorticoid for the pretibial myxedema
(J. Clin. Endo. Metab. 87: 438, 2002).
{09360} pretibial myxedema
Whether or not the complete triad is present, "Graves's" is the usual cause of
DIFFUSE TOXIC GOITER
(weight up to 100 gm, seldom more, since there's little colloid). You're likely to hear a bruit over
the gland (why?), and at surgery (oops), untreated Graves's will be beefy red.
If you examine an untreated Graves's thyroid gland under the microscope ("oops!"), you'll see scanty
colloid, typically being actively resorbed ("bite marks", "scalloping") around its edges.
{24717} Graves's with scalloping
If the patient has been pre-treated with a goitrogen, you'll less colloid and more papillary formations
(why?) If the patient has been treated with a huge dose of iodine to suppress thyroid hormone
formation, you'll see a colloid goiter (why?)
Today, most patients prefer to take a drink of I131, though they know this will eventually make them
hypothyroid. The ophthalmopathy may require an ophthalmologist's care.
NOTE: Sometimes antibodies merely block the effects of hTSH. This may be seen in both
Hashimoto's disease and in "primary idiopathic hypothyroidism". Not rare, and may self-cure.
NEJM 326: 513, 1992.
ATROPHY OF THE THYROID
{17447} burned-out thyroid; this could be anything from old I131 injury to old Hashimoto's to
Riedel's to a really gone patch in a nodular goiter.
Every so often, at autopsy of an adult, the thyroid is shrivelled to a miniature thyroid-shaped nubbin
of white scar tissue, weighing perhaps a gram. Trying to guess the cause is fun but usually
futile.
If you see giant nuclei and hyalinosis of small arteries, perhaps the patient forgot she had once taken
a drink of I131. Other cases may be burned-out Hashimoto's or DeQuervain's. Of course, if there's
no pituitary gland, the thyroid may have died of under-stimulation.
* Future pathologists: the rare AMYLOID GOITER
features amyloid AA and often extensive fatty ingrowth. It remains
a minor mystery of medicine. See Arch. Pathol. Lab Med. 124: 281, 2000.
{21053} colloid goiter
Diffuse enlargement of the thyroid gland was historically due to
EPIDEMIC GOITER, caused by lack of
iodine in the diet (i.e., any community far from the seashore). This was often exacerbated (or even
primarily caused by) goitrogens in the diet.
WARNING: The iodine-deficiency thyroid gland is under heavy TSH stimulation (why)? When an
iodine-deficient patient is treated with a large amount of iodine, acute hyperthyroidism and even
hyperthyroid crisis can supervene. This is the dread
JOD-BASEDOW phenomenon.
When iodized salt is introduced into a region that is significantly iodine-deficient,
the number of people being treated for hyperthyroidism seems to increase,
then drop to the usual within six years (the Danes: J. Clin. Endo. Metab. 94:
2400, 2009) as goitrous thyroids that have been in overdrive for years settle back down.
Beyond this, I am not aware of any reason to believe that the obscure WHO claim that too much iodine in the
diet cases hyperthyroidism is true.
* SPORADIC DIFFUSE GOITER, once mysterious,
is now known to be (at least in many cases)
the result of incomplete inborn errors
of metabolism. These include (1) partial inability of stomach or thyroid to take up
iodine; (2) partial lack of peroxidase to link iodine to tyrosine (fairly common... J. Clin. Endo. Metab. 93: 627, 2008); (3) partial inability to recycle iodine in the thyroid
gland; (4) partial inability to crunch the two iodotyrosine moieties together to make T4. Others are
described.
A small diffuse goiter is almost the rule rather than the exception around menarche.
Early in its development, the colloid goiter shows hyperplasia (i.e., tall cells, maybe piling-up) under
the influence of TSH. Later, the cells appear to give up, and the gland becomes a mass of oversized,
colloid-packed follicles. Of course, the process is never really uniform, and eventually the diffuse
nontoxic goiter turns into a MULTINODULAR GOITER. By the time the gland reaches over 100 gm, the
multinodular stage is usually well-underway.
In a multinodular goiter, there are many nodules, most composed of follicles more or less filled with
colloid ("adenomatous nodules"), others representing sites of old hemorrhage and fibrosis ("Feel my goiter!" "Oops, I bumped
my neck!") You can see squamous metaplasia, foam cells, masses of hemosiderin,
foreign-body granulomas,
and many other interesting things.
Rule: If the excised portion of thyroid contains two "adenomas", go ahead and call it a
nodular goiter.
A microscopic survey of a nodular goiter is enough to make anyone think about
selection of mutant clones in precancer seriously, and
this is supported by the finding that many genetically distinct clones of cells with various functional
problems. (Clonality in the nodular goiter revisited: Am. J. Path. 134: 141, 1989; hot-spot
ras
mutations in goiter nodules: Mol. End. 4: 1474, 1990). However,
the common genetic basis remains obscure. (J. Clin. Endo. Metab. 87:
4264, 2002).
Multinodular goiter often arises de novo,
either sporadically or in certain anti-oncogene deletion syndromes (notably Cowden's).
Usually there are no new functional problems with the thyroid gland in multinodular goiter, but
sometimes a clone of cells may turn "hot", causing hyperthyroidism. Fortunately, carcinoma very
seldom arises in multinodular goiter, and most "cold nodules" removed from thyroid glands turn out
simply to be sleepy nodules from multinodular goiters.
No one really knows how to manage cancer risk in a thyroid with several
nodules. Of course, if there are just a few, there will be a lot of fine-needling,
but when there are massive numbers, controversy remains (J. Clin. Endo. Metab. 91:
3411, 2006).
THYROID ADENOMAS
{24724} thyroid adenoma, gross
Thyroid neoplasia is an area in pathology that is fraught with problems
(review Arch. Path. Lab. Med. 132: 622, 2008).
"Experts" still disagree about many lesions. The World Health Organization
recently issued another histologic classification; don't worry about it.
It is certain that in the not-too-distant
future, thyroid lesions will be classified largely by their genetic signatures,
as leukemias and lymphomas are today (J. Clin. Endo. Metab. 93: 3286, 2008).
The vast majority of dominant thyroid nodules are either benign adenomas or just big
nodules in a multinodular goiter. This is good, because thyroid nodules are very common (around
5,000,000 in the U.S.) You'll learn to manage these clinically. Most patients are adults, and there is
a modest female preponderance.
As you would expect, thyroid adenomas are composed of thyroid follicles ("follicular adenomas").
The follicles may be tiny (* "fetal" / "microfollicular"),
shelf-like ("trabecular" / "embryonal"), or solid.
Don't worry about the useless subclassification given in "Big Robbins"; they all behave pretty much
the same, i.e., they are harmless or might perhaps make excess T4 and/or T3.
* A lone patch of "adenomatous hyperplasia" of multinodular goiter
can't really be told from follicular adenoma. If there's just a couple...
hyperplastic nodules supposedly don't compress surrounding thyroid
like adenomas do, and hyperplastic nodules
often have fibrous bands crisscrossing them.
It makes no real difference to the patient.
* The major pathologist-fooler is the "hyalinizing trabecular adenoma", with balls
of cells embedded in shelves of basement membrane;
it can include psammoma bodies and orphan-annie eye nuclei, and
has an immunostaining profile similar to papillary carcinoma. Leave diagnosing it to us
(stain Am. J. Clin. Path. 122: 506, 2004; there are metachromatic blobs). It has both a benign and malignant (i.e., capsular invasion)
form -- or perhaps all of them are "malignant neoplasms of low
metastatic potential" (Am. J. Surg. 193: 707, 2007).
* Hyperfunctioning nodules, not surprisingly, often have (Nowell's law) gotten mutated TSH
receptors stuck in the "on" position: J. Clin. End. Metab. 81: 1584, 1996; we can assume the ones
that don't have something else wrong in the cAMP signal pathway.
T3 toxicosis usually means adenoma. Why? Hint: Think of Nowell's Law.
Less often, one gets unusually big, or causes pressure symptoms.
* Molecular profiling of cells in fine needle aspirates
to predict malignancy is a promising area (J. Clin. Inv. 113: 1234, 2004, and see the
markers below),
but we're not going to give up microscopy or risk leaving something bad in place
anytime soon. Fine-needle aspiration and molecular profiling together
have made frozen-section
examination of thyroid nodules during surgery obsolete (Arch. Otol. 133: 874, 2007).
Fortunately, the genes that cause adenomas don't seem to be the same ones that produce thyroid
carcinomas, and thyroid adenomas have virtually no tendency to turn malignant. (* You may see
slight atypia in these tumors. Let the pathologist worry about it.)
You can remove adenomas surgically, or suppress them by using thyroxine
to suppress TSH. (Ignore "Big Robbins" about
how adenomas should "theoretically" be "autonomous"; the idea that "tumors are free of controls on
their growth" is rank superstition.)
* Ask a pathologist whether he or she has ever seen a C-cell adenoma. No follicles, cells may
spindle, and stain for calcitonin.
PAPILLARY ADENOCARCINOMA ("Orphan Annie's Tumor"; Arch. Path. Lab. Med. 130: 1057, 2006)
{24725} papillary carcinoma, gross
This is a common (the commonest endocrine cancer), often-multifocal (separate primaries NEJM 352: 2406, 2005) cancer, fairly common in adults with
a female predominance (maybe 75%), and not
unknown in children.
The harder you look for papillary carcinoma of the thyroid, the more you find. The "greatly
increased rate" seen in autopsies of Hiroshima survivors was probably real, though these glands
were meticulously sectioned in search of small cancers.
There's no question that irradiating the thyroid gland (for a good reason or for "big thymus", tonsils,
acne, or what-have-you) gives an increased rate of papillary (and probably follicular) carcinoma; the
increased risk from radioactive iodine therapy of Graves's is very small. The risk from external beam
radiation continues for life (Endo. Metab. Clin. N.A. 19: 495, 1990), with cancers typically appearing
decades later.
In the past, radiation-induced
cancers (as from thymic radiation) seemed to be tame (Arch. Ped. 148: 260, 1994).
, but don't expect them to
remain dormant (Ann. Surg. 239: 536, 2004). Chernobyl's children and their papillary
thyroid cancers: Cancer 74: 748, 1994; nobody knows exactly why, but it's a real problem, maybe
Nowadays, they seem a bit more aggresive
than the others (Arch. Otol. 135: 355, 2009).
Chernobyl showed that kids are more susceptible to hot iodine. Thankfully most of these are non-lethal.
The cancers are continuing to develop, and a few are proving aggressive (Cancer 107: 2559, 2006).
It's finally been pretty well established that Hashimoto's disease, with ongoing
destruction and regeneration of the epithelium, triples one's risk for
well-differentiated thyroid cancer (J. Am. Coll. Surg. 204: 764, 2007).
The most-often-mutated gene
in papillary cancers turns out to be the serine-threonine
kinase BRAF (Hum. Path. 36: 694, 2005; maintains malignancy J. Clin. Endo.
Metab. 92: 2264, 2007);
there is a signature mutation (notably in radiation-induced tumors -- J. Clin.
Inv. 115: 94, 2005), and regardless of history, the mutation
imparts a much worse prognosis and probably the need
for more aggressive early therapy (J. Clin. Endo. Metab. 90: 6373, 2005;
Cancer 110: 38, 2007;
Cancer 110: 1218, 2007).
In the near future, we will probably see BRAF-positive thyroid cancers
treated with the new tyrosine-kinase inhibitors (Br. J. Cancer 96: 16, 2007).
In the 1990's, it was discovered that the cancer has its
several distinctive oncogenes, PTC-1, -2, and -3, which turned out to be particular
rearrangements of the tyrosine kinase receptor RET (Endocrinology 137: 375, 1996; J. Clin. End. Metab. 81: 3360, 1996;
update Cancer 104: 943, 2005). Watch these also as therapeutic markers / targets.
* The less-well-known oncogene hPTTG is also commonly mutated
and imparts a worse prognosis in both papillary and follicular carcinoma; staining
for the activated form is available (J. Clin. Endo. Metab. 91: 1404, 2006).
Fusion genes are better-known from sarcomas and lymphomas,
but the CCDC6-RET fusion gene is seen in many papillary thyroid carcinomas
(update J. Clin. Path. 63: 4, 2010).
In most cases of papillary thyroid carcinoma, the genome is not
destabilized (Arch. Path. Lab. Med. 131: 65, 2007). We might
reasonably think that in those unusual cases in which it does destabilize, anaplastic carcinoma results. See below.
In the thyroid, malignancy is based on nuclear changes, and ironically,
the cell arrangement of a "papillary carcinoma" is not a factor in making
the call.
The usual histology is that of a papillary adenocarcinoma (i.e., inside-out glands growing like a tree, the
stalk being the trunk and branches, the cells being the leaves.) A good rule: Any reasonably well-differentiated thyroid tumor
with any papillary area will act like a papillary carcinoma of the
thyroid. (Even if there are also follicles: Arch. Surg. 138: 1362, 2003; Cancer 97: 1181, 2003;
and many more).
Pathologists usually (but not always) see the "Orphan Annie eye" nuclei, with the
heterochromatin all pushed to the edge and the central areas of the nuclei optically clear.
(Annie was, of course, a
character in a comic strip where no one had irides or pupils.) These nuclei have marginated chromatin and optically
clear centers. It's a fixation artifact. Another good rule: Any reasonably well-differentiated thyroid tumor with Orphan
Annie nuclei (or the other features mentioned below) will act like a papillary carcinoma of the thyroid.
Other helpful features include
cytoplasmic invagination into a nucleus. This is impressive, especially
on electron microscopy. This is another criterion for malignancy, though contrary
to what you may hear, it is not the cause of
"Orphan Annie Eyes". Yet another is several micro-nucleoli right underneath the nuclear membrane; still
another is nuclear grooving ("coffee beans").
* Future pathologists: Any cell (and notoriously, endocrine cells
and healthy lymphocytes) that is poorly-fixed prior to tissue sectioning
can exhibit an "orphan annie eye nucleus".
Another favorite finding is psammoma bodies.
Again, these suggest the tumor will behave like papillary carcinoma. * Future pathologists:
You see these in normal chorioid plexus, normal pineal, papillary
carcinoma of the thyroid, serous cystadenocarcinoma of the ovary, meningioma, and
somatostatinoma.
Except for a few uncommon subtypes, these lesions are noted for being non-aggressive,
especially in patients young than age 40. Even when first
diagnosed as a metastasis in a cervical node, survival is likely (Surgery 143: 35, 2008).
Like most carcinomas, it prefers
the lymphatic route, and can ultimately spread by the bloodstream.
Despite its usually gentle nature, papillary carcinoma does occasionally kill people, typically by
asphyxiation. It is also the breeding ground for anaplastic carcinoma of the thyroid.
The diffuse sclerosing form presents as a goiter composed entirely of papillary
cancer. The abundant psammoma bodies impart a remarkable gritty feel
when cut. It's more likely to be in the lymph nodes at presentation than
other forms of papillary cancer, but the prognosis is still generally good
(Eur. J. Surg. Onc. 29: 446, 2003).
The tall-cell variant (around 10% of tumors)
features very tall pink cells, oncogenic met, and a greater
metastatic potential (Cancer 98: 1386, 2003).
* The columnar-cell variant is also aggressive. It's seen in older folks
and unlike the other variants doesn't have the classic orphan-annie nuclei.
* The solid variant (rare, but with
obviously infiltrating borders) is also more somewhat aggressive but has the
same genes (Am. J. Surg. Path. 25: 1478, 2001).
* Future pathologists only: The picturesque cribriform-morular variant
of papillary carcinoma
warns that the patient likely has familial polyposis coli (Am. J. Path. 115:
486, 2001; Am. J. Clin. Path. 128: 994, 2007); it is mutant-BRAF negative (Arch.
Path. Lab. Med. 133: 803, 2009).
* Sclerosing variant: Cancer 66: 2306, 1990.
Other variants that probably have no prognostic significance include clear-cell,
Hurthle-cell, and Warthin-like.
Keratin 19 as marker for papillary carcinoma (Am. J.
Clin. Path. 92: 654, 1989) and histologic grading (aggressive vs. non-aggressive): Am. J. Clin. Path.
101: 651, 1994) have given way to molecular markers.
* There is a familial sundrome; the gene has still not been found (World Surg. J. 24: 1409, 2000;
J. Clin. Endo. Metab. 90: 5747, 2005; Surg. 145: 100, 2009), but contrary
to older reports the familial variant isn't more aggressive than the sporadic.
in any case having a family member affected increases your own risk by about a factor of ten
J. Clin. Endo. Metab. 90: 5747, 2005).
Several classic anti-oncogene deletion syndromes supposedly place one at increased
risk, but these account for only a very small minority of cases.
* Watch for Tc99-sestamibi as a new way to detect metastatic
papillary thyroid carcinoma (also breast, oat cell, and of course parathyroid).
Relative frequency of detected thyroid carcinomas (older data):
Papillary... 65-80% of primary thyroid carcinomas; the large majority (~90%) will not die of it
Follicular... 10-25% of primary thyroid carcinomas; maybe 50% will eventually die of it if it is "frankly invasive" at diagnosis, though it may be much later than 5 years
Medullary... 5% of primary thyroid carcinomas; 50% 5-year mortality if sporadic (probably less nowadays), much better if you
picked it up early as part of workup of a family
Anaplastic... 5% of primary thyroid carcinomas; almost all will die of it in a few months
* A reputed increase in thyroid cancer in the United States over the past 30 years
seems to be due to increased detection of small papillary carcinomas that probably
wouldn't have killed the person anyway.
The percentage of all deaths that are deaths
due to thyroid cancer remains the same (JAMA 295: 2164, 2006 -- remember that
we're probably curing more thyroid cancers and people are surviving other once-fatal diseases as well, so things balance.)
* Future
pathologists: It's claimed that dipeptidyl aminopeptidase IP stain of cytology preparations
distinguishes benign follicular cells
(negative) from malignant ones (positive): Am. J. Clin. Path. 96: 306, 1991;
Diag. Cyto. 19: 4, 1998; still holding up Arch. Surg. 139: 83, 2004.
this seems to work but isn't in widespread use.
However, there's a consensus that CK19 (cytokerain 19) positivity is sensitive for malignancy,
and that HBME-1 positivity is specific, but not particularly
sensitive, for carcinoma when staining thyroid lesions; galectin-3 (GAL3)
(Am. J. Clin. Path. 126: 700, 2006) is in-between. They also work for
fine needle aspirates (Cancer Cytopath. 105: 87, 2005).
FOLLICULAR ADENOCARCINOMA (pathologists see Cancer 100: 1123, 2004)
This is a more aggressive thyroid carcinoma that generally makes follicles. Grossly, it may be
obviously malignant, or there may be metastases. More often, malignancy is established by
demonstrating that a thyroid nodule contains groups of cells invading BLOOD
VESSELS (not lymphatics); for
some reason, this particular cancer prefers the vascular route of invasion.
The rules also specify that the invaded blood vessel be within or just outside the capsule.
Since the surgeon will take one lobe for a follicular adenoma
(common), and probably do a total thyroidectomy for a follicular
carcinoma (much less common), there's been much discussion
of "the best way to tell at surgery".
The genetics are being worked out; the fusion gene known from
follicular carcinomas is PAX8-PPARG1 (J. Clin. Path. 63: 4, 2010).
Unlike papillary carcinoma of the thyroid, with its distinctive weird nuclei,
the nuclei of a follicular carcinoma tend to be bland-looking. The distinction
between benign and malignant is made on the apparent pattern of growth (i.e., invasiveness), and is
notoriously difficult.
If the tumor invades through (not just into) its "capsule",
this is also a criterion for malignancy, though it is far less
ominous than
vascular invasion.
There are no good fibrovascular papillae, Orphan Annie nuclei, or psammoma bodies. The tumor
cells often take up radioactive iodine, which is useful both in scanning for metastases and for
treating them (clinical review Cancer 95: 488, 2002; especially in the young,
radio-iodine therapy is often curative even in metastatic disease J. Clin. Endo. Metab. 91:
2892, 2006).
This tumor (and papillary carcinoma) may be modestly hTSH dependent, and thyroid
hormone administration may suppress them temporarily.
* The Hürthle-cell variant isn't much different from
the more common form (Cancer 106: 1669, 2006). However, telling
benign from malignant can be tricky; one group suggests that those with the ret/PTC
gene rearrangements specific to papillary carcinoma of the thyroid be
treated by full thyroidectomy regardless of histology (Arch. Otol. 132:
54, 2006).
Of course, pathologists hate this lesion, as it's difficult to tell from one of the
much-more-common follicular adenomas / hyperplastic nodules (or for that matter,
medullary carcinoma with a follicular growth pattern). There is a "minimally invasive subtype",
detected by its pushing all the way (or part-way, there's disagreement) through a very thick capsule; it has
a very good prognosis (Cancer 91: 505, 2001) that the Chernobyl
group proposes calling "well-differentiated thyroid tumor of uncertain
malignant potential" (Int. J. Surg. Path. 8: 181, 2000). Again, if the nuclei
say "papillary carcinoma", that's what you diagnose.
Criteria for handling follicular lesions
Am. J. Clin. Path. 117: 143, 2002. The ongoing difficulty diagnosing the
follicular lesion of the thyroid: Arch. Path. Lab. Med. 130: 984, 2006.
The prognosis for any lesion that you think might be follicular carcinoma
is always guarded. This tumor tends to metastasize to lungs
(via veins, of course) and bone.
{09255} follicular carcinoma of thyroid, histology. Trust me, this was invading a vessel
MEDULLARY ADENOCARCINOMA (Surg. Clin. N.A. 75:
405, 1995; Am. J. Med. 103: 60, 1997).
This is cancer of the C-cells (or at least differentiating as C-cells; see Cancer 74: 928, 1994). Its
stroma is usually (* not always)
laced liberally with calcitonin pleated into amyloid.
As you remember, this cancer is caused, at least in part, by loss of both copies of the MEN-II anti-oncogene on chromosome
10. As you'd expect, in MEN-II it is very common and often multifocal,
and occurs at any age.
Sporadic cases (older folks) also lack the protective genes. With the cloning of the RET gene (the
MEN-II gene), we've discovered different alleles producing different complexes (J. Clin. End. Met.
79: 590, 1994; J. Clin. End. Metab. 81: 1780, 1996), some families get only medullary carcinoma
(Nature 367: 319, 1994; J. Clin. Endo. Metab. 87: 1674, 2002). We can test people for the gene (Surgery 116: 124, 1994)
and prophylactic thyroidectomy is now routine (J. Am. Coll. Surg. 195: 159, 2002).
Pathologists enjoy looking at the hyperplastic C-cells, and the patients do extremely well
(Arch. Path. Lab. Med. 132: 1767, 2008).
The cancer tends to be indolent, with stage at surgery and
calcitonin levels shortly after surgery the
only prognosticators: Cancer 77: 1556, 1996.
As befits cancer of the C-cells, the tumor often makes calcitonin. In extreme cases, tetany may
result.
Today's diagnosticians typically rely on seeing how high the serum calcitonin
can be made to go following pentagastrin administration ("stimulation test"): Surgery 142:
1003, 2007.
You may also gets ACTH (Cushingism), VIP (diarrhea), serotonin (instant carcinoid syndrome),
and a variety of other things.
{49355} medullary carcinoma of thyroid, gross
Future endocrinologists: Anybody you suspect of harboring MEN-II gene (i.e., they have a personal
or family history of hyperparathyroidism, pheochromocytoma, mucosal neuromas, and/or medullary
carcinoma of the thyroid) needs a check.
The old technique was to infuse calcium and/or pentagastrin; a
brisk rise in blood calcitonin means pre-malignant hyperplasia of C-cells, and you need to do
something about it. All about provocative calcitonin testing: Am. J. Hum. Genet. 52: 335, 1993;
nowadays of course we check for the mutated RET gene.
* People with C-cell hyperplasia are likely to have elevated serum
calcitonin (usually asymptomatic). The RET mutation is the usual
cause; mutated succinic dehydrogenase can also do this but does not seem
to lead to actual neoplasia (J. Clin. Endo. Metab. 88: 4932, 2003)
Nowadays, anyone found to be at risk because of a mutated
RET gets a total thyroidectomy, and removal of the regional
lymph nodes if the calcitonin stays up (Surgery 146: 906, 2009).
This seems to be the right approach.
POORLY DIFFERENTIATED THYROID CANCER is a proposed new category convincingly defined in 2006 (Cancer 106: 1286, 2006).
The best known type is "insular thyroid carcinoma". composed
of cancer cells with prominent nucleoli, surrounded by fibrous tissue
(Am. J. Surg. Path. 8: 655, 1984). All stain positive for
thyrogloblin.
There's also a trabecular variant.
ANAPLASTIC ADENOCARCINOMA ("undifferentiated carcinoma")
Very, very ugly, both histologically and clinically. We believe that most of these tumors arise in a
previous papillary or follicular thyroid carcinoma (Nowell's law triumphant);
this has been confirmed by genetic studies (Cancer 103: 2261, 2005).
Thyrotoxicosis (from overproduction of thyroid hormone by the cancer)
is uncommon but does happen (J. Lar. Ot. 121: 695, 2007).
* Ignore the subclassification of the old WHO system.
Most of the "small cell anaplastic carcinoimas"
were really lymphomas; most of the
"large cell anaplastic carcinomas"
were for real.
Today, we distinguish "spindle cll"
(looks like sarcoma but still lights up with keratin),
"giant cell", and
and "squamoid". All are obviously malignant.
There are many variations of the theme of anaplasia (Arch.
Path. Lab. Med. 111: 1169, 1987; these tumors generally light up with both keratin and vimentin).
Fibrotic anaplastic carcinoma mimicking Riedel's: Am. J. Clin. Path. 105: 388, 1996.
* A Canadian group's experience with very aggressive
treatment; Cancer 91:
2335, 2001. This is the only optimistic report ever.
{09264} anaplastic carcinoma of thyroid, histology
PRIMARY THYROID LYMPHOMA is an uncommon B-cell neoplasm arising usually in Hashimoto's
(molecular precursor lesions in the Hashimoto lymphocytes: J. Clin. Path. 61: 438, 2008). Look
for malignant lymphocytes inside the follicles. Hashimoto's often has clones of lymphocytes, and these tend to be
the ones that give rise to lymphoma (no surprise: J. Clin. Path. 61: 48, 2008).
{10934} lymphoma of the thyroid
THYROID TESTING (see Lancet 357: 619, 2001) Serum T4 will give you the total bound plus unbound. Serum free T4 will give you the unbound,
but it is more expensive. Serum T3RU (T3 resin uptake) is an unfortunately-named test that gives
you a value inversely proportional to the number of unbound sites on the serum thyroid hormone
carrying proteins (remember them?) Multiply T4 and T3RU to get "free thyroxine index", a
measure of the biologically active hormone.
Quiz: Who remembers what proteins carry T4 and T3? Answer: Thyroxine-binding protein (TBG,
lion's share), transthyretin ("prealbumin"), and albumin. What's the best way to raise TBG? Take
estrogen. What does this do to total T4? T3RU? Free T4? TSH?
Serum T3 of course measures the active hormone. You can get a serum free T3 also. Some toxic
nodules make T3 instead of T4, so it's often worth checking (Am. J. Med. 96: 229, 1994).
Quiz: Suppose somebody took T4 to lose weight and got sick it ("factitious hyperthyroidism").
How would the tests be affected? Suppose the person took pure T3 instead?
The newer, super-sensitive TSH assays are a good way to screen for hyperthyroidism (TSH in
primary, in secondary or tertiary) and hypothyroidism ( in primary, in secondary or tertiary).
Some people say that patients may actually be suffering from symptomatic thyroid disease if hTSH
is abnormal but T7 is in the normal range (i.e., "not everybody has the same 'normal' thyroid
hormone levels".) hTSH has long been the best screen for cretinism. (There are now calls
for additional screening to detect congenital secondary hypothyroidism, which of course
looking for a high hTSH will miss: J. Clin. Endo. Metab. 90: 3350, 2005).
Nowadays, we talk about "subclinical thyroid disease" defined to be a hTSH
outside the normal range, free thyroxine and free triiodothyronine in the normal
range, and no symptoms or signs. It often declares itself as real thyroid
disease in a few years, but so far, no one knows what to do about it (Am. Fam. Phys.
72: 1517, 2005).
On thyroid scans, cold nodules are the ones most likely to be malignant (why?) Hot nodules are the
ones most likely to produce hyperthyroidism. You'll learn how to manage both on rotations. In
hyperthyroidism due to most causes, the gland will be hot, but in struma ovarii, DeQuervain's, or
factitious hyperthyroidism, it will be cold (why?)
Serum thyroglobulin will often be increased in thyroid cancers (papillary, follicular) or in
DeQuervain's (why?). For use of thyroglobulin in detecting the spread of well-differentiated
thyroid carcinoma, see the update from Mayo's at J. Clin.
Endo. Metab. 92: 4278, 2007; also J. Clin. Path. 62: 402, 2009 (the assay is a difficult and problematic one).
When you are monitoring thyroid hormone replacement in somebody who has been hypothyroid,
the conventional wisdom is to try to avoid their becoming even a little bit hyperthyroid, since this will supposedly lead to
osteoporosis in the long run. However, some people actually do not feel well until
the free T4 is somewhat above the upper limit of normal (Br. Med. J. 326:
295, 2003), and I'd trust the body's wisdom on this. Currently, clinicians
make sure that hTSH stays in the normal range. If, on the other hand, you are administering
thyroxine to suppress a hTSH-dependent thyroid cancer, be sure that you give enough so that hTSH
levels remain zero.
During serious
illness or injury, some people have diminished intracellular conversion of T4 to
T3 by the deiodinases.
EUTHYROID SICK SYNDROME ("low T3 syndrome"; "the non-thyroidal illness syndrome") is recognized, for research
purposes, in patients who are
seriously sick with something serious have low T3's and high rT3's (i.e.,
T4 is getting metabolized wrong). hTSH levels tend to stay in the okay range.
It is a real entity
(J. Clin. Endo. Metab. 90: 5613, 2005), is very common
in the very-sick and the malnourished if you look for it,
and (at least in ICU patients on the ventilator) somewhat ominous
overall (Chest 135: 1448, 2009). And it will confuse you
when you are caring for the very-sick. The conventional wisdom
is that you do not treat it (i.e., you do not administer
extra T4 or T3); not everybody agrees (Am. Heart. J. 135:
187, 1998; discussion is ongoing). There are so many proposed explanations
for "euthyroid sick syndrome" that I urge you not even to start trying to figure it out.
* Now, you are familiar with the selenium-dependent enzymes
that turn T4 into usable T3 in the tissues.
Deficiencies of course are known; these people seem to do okay
but of course have high rT3, low T3,
high FT4, and usually
normal hTSH (see for example J. Clin. Endo. Metab. 94: 4003, 2009.)
There are two schools of thought on managing thyroid replacement
therapy -- by the numbers or by how the patient feels.
I have often wondered whether (1) a "normal" serum T4 might still
be low for that person, and whether (2) a "normal" serum T4 might
not mean a normal T4 in the brain milieu.
Physicians who fear being sued decades later for "causing osteoporosis"
are reluctant to approve patients who feel best when they take a bit
more thyroxine than "the lab tests say they need". I'm not a clinician,
but we have a saying in pathology, "Listen to the patient, not
the numbers." I'm not alone (Br. Med. J. 320: 1332, 2000;
Br. Med. J. 326: 295, 2003)
* This brings us to
a late 1990's fad diagnosis, WILSON'S SYNDROME. Supposedly
this results from faulty metabolism of T4 into rT3
at the tissue level.
People interested in complementary medicine are invited
to take their body temperature repeatedly, and if it is "a few tenths of a degree
below 98.6" at any time of the day, and they have any of a huge list of
symptoms, then the diagnosis is considered established and the patient gets
a series of "complementary" remedies. Before you diagnose or treat yourself
or somebody else, please consider these facts: * Do you remember those deiodinases? Selenium takes the place
of sulfur in their cysteines!
In suspected Graves's disease and Hashimoto's disease, you can order a battery of anti-TSH receptor
autoantibodies ("thyroid stimulating antibody", "long-acting thyroid stimulator"=LATS), anti-thyroglobulin antibodies , and
anti-microsomal antibodies.) Interpretation is rather cloudy, though
very high titers of anti-microsomal antibodies (against the peroxidase autoantigen,
of course) is pretty specific for Hashimoto's.
If you've got a bump in your thyroid, a pathologist will be happy to FINE-NEEDLE ASPIRATE it, and look at the
cells on a slide.
Review of 4700 cases from Galveston: Cancer 111: 306, 2007 (it's accurate).
How to do it right: J. Cln. End. Metab. 79: 335, 1994;
Mayo Clin. Proc. 69: 44, 1994; some sub-subspecialty training
is advised for pathologists who want to do this (Cancer 107: 406, 2006). Using it with ultrasound to be sure you hit
the itty-bitty nodules: Otolar. 123: 700, 2000.
The procedure is not perfect, and there are still plenty of false-positives
and false negatives; the most common problem is the all-too-human attempt
to interpret an unsatisfactory specimen (Am. J. Clin. Path. 125: 873, 2006).
Patients may be concerned that the needling will spread the cancer;
this is very rare but does happen (J. Laryn. Otol. 121: 268, 2007.
This is really a screening technique to find out which bumps to cut
out, and it is the one instance in which a decision to perform
such serious surgery may be based on a few cells in a cytology smear.
The practice is now standard, and has greatly reduced the number
of people who need to be operated for diagnosis.
Update on this now-huge field: CA 59(2): 99, 2009
Please remember that we CANNOT tell benign from low-grade-malignant follicular
lesions of the thyroid using fine-needle aspiration.
A surgeon should remove the bump if the fine needle aspirate shows:
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about
thyroid 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!
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
Recognize the common signs, symptoms, causes, and anatomic pathology
of each of the following:
acquired hypothyroidism
Do a proper lab workup for each of these.
Generally maintain an appropriately high index of suspicion
for thyroid disease.
congenital hypothyroidism
hyperthyroidism
goiter
DeQuervain's subacute thyroiditis
Describe the etiology (as far as is known), pathophysiology,
anatomic pathology, and clinical picture for each of the major thyroid tumors:
Graves's disease
Hashimoto's disease
"Idiopathic" goiter
Jod-Basedow
Riedel's struma
thyroid adenomas
papillary thyroid carcinoma
follicular thyroid carcinoma
medullary thyroid carcinoma
anaplastic thyroid carcinoma
thyroid lymphoma
Recognize each tumor grossly and microscopically as appropriate.the patient with a palpable thyroid mass
the patient at extra risk for thyroid cancer
Endocrine
Taiwanese pathology site
Good place to go to practice
Tulane Pathology Course
Great for this unit
Exact links are always changing
Thyroid Exhibit
Virtual Pathology Museum
University of Connecticut
{11803} normal thyroid, gross
{00135} normal thyroid, histology
{11755} normal thyroid, histology
{00138} goiter
{24613} goiter
{39460} goiter
Endemic goiter
Mountaineers dew-lapped like bulls, whose throats had hanging at 'em wallets of flesh...
-- Shakespeare, "The Tempest"
{24718} propylthiouracil effect
* This was strikingly illustrated in a community in China with
a very high amount of iodine in the drinking water: everybody got a goiter
(Am. J. Clin. Nutr. 90: 1633, 2003).
* "Globus hystericus" ("a lump in my throat") is often emotionally-based but be sure not to miss
a goiter or thyroid nodule (J. Laryngol. Otol. 121: 242, 2007).
{09363} cold nodule, right upper pole
Cretin
Classic drawing
Adami & McCrae, 1914
These children may
get enough thyroid from Mom while in the womb, but after they are born, cannot make
their own. However, this is not always the case -- there may not be
sufficient thyroixine transferred across the placenta.
When a goiter is picked up on ultrasound before birth,
thyroxine may be administered by injection into the unborn child
(J. Clin. Endo. Metab. 94: 3731, 2009) to prevent developmental
defects and delivery problems due to the goiter itself.
It is scandalous that this
should exist anywhere in the world in the 21st century.
Yet it remains commonplace in the world's current goiter belts,
outstandingly western Mainland China ("the people's paradise"), Tibet
(NEJM 339: 1112, 1998), central Java, Sikkim (India), Afghanistan
(horrible problem through the 1990's: World Health Forum 17: 209, 1996),
Nepal,
central Africa (Am. J. Clin.
Nutr. 52: 1087, 1990), and some jungle tribes (J. Clin. End. Met. 77: 878, 1993).
Iodine deficiency in children remains rampant ("the new South Africa" Am. J. Clin. Nutr. 86:
1040, 2007).
The fault is NOT with the world's poor -- they simply are not given
access to iodine.
{25468} myxedema
{25469} myxedema
{09245} thyroglossal duct cyst, histology
{08960} Hashimoto's, histology
{08961} Hashimoto's, histology
{09242} Hashimoto's, histology
{37881} Dr. Hashimoto
{37882} Dr. Hashimoto "after 40 years of teaching"
Hashimoto's Disease
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Hashimoto's thyroiditis
Germinal centers, damaged parenchyma
KU Collection
* This "cirrhosis of the thyroid"
was actually what Dr. Hashimoto's original
paper described.
* A classic rat model is based on an
immunogenic sequence within thyroglobulin (J. Immunol. 149: 1039, 1992); similar antibodies
may be seen in humans with Hashimoto's or "nonspecific" thyroid disease (Arthr. Rheum. 34: 1585,
1991).
{24721} DeQuervain's
DeQuervain's
WebPath Photo
,
coxsackie B (most common),
EBV,
ECHO, and
adenovirus. There are surely others. Epidemic DeQuervain's: J. Clin. End. Metab. 70: 396, 1990.
HYPERTHYROIDISM (Lancet 362: 459, 2003; Am.
Fam. Phys. 72: 635, 2005)
* "Subclinical hyperthyroidism", with low hTSH but "normal range" thyroid
hormone levels, seems to put a lot of older folks at risk for atrial fibrillation
and overall mortality. Screening and treating might be wise. Lancet 373: 1930, 2009;
children and teens (especially pudgy ones) J. Clin. Endo. Metab. 94: 2414, 2009.
{09237} Graves's
{09356} Graves's exophthalmos
* There are autoantibodies against fibroblasts located here
(J. Clin. Endo. Metab. 80:
3427, 1999). For some reason, fibroblasts on the shins, and only on the shins,
evidently have TSH receptors (!) J. Endo. Inv. 19: 365, 1996.
{25470} pretibial myxedema
{25471} pretibial myxedema
{25472} pretibial myxedema
Burned out thyroid
No history -- surprise at autopsy
KCUMB Team
DIFFUSE NONTOXIC GOITER ("colloid goiter") / (MULTI)NODULAR GOITER
{21054} colloid goiter
{19502} colloid goiter, around 100 gm
{09354} colloid goiter, gross
{19505} colloid goiter, histology
{19511} colloid goiter, histology
{10825} nodular goiter
{12710} nodular goiter (this was billed as "Hashimoto's"; I doubt it)
{39052} nodular goiter (dominant nodule was called "adenoma", heh heh)
{09238} nodular goiter, gross
{49451} nodular goiter, gross
{09240} nodular goiter, histology
{49465} nodular goiter, they decided to operate
Thyroid gland with diffuse hyperplasia
What could this be?
Wikimedia Commons
Big inactive follicles
Nodular goiter / Could be other things too
WebPath Photo
* "Jod" is German for "iodine", and "Basedow's disease"
their term for any hyperthyroidism.
{13363} thyroid adenoma, gross
{09248} thyroid adenoma, gross
{09250} thyroid adenoma, gross
{09777} thyroid adenoma, gross
{39965} thyroid adenoma, gross
{49453} thyroid adenoma (center has liquefied)
{49454} thyroid adenoma
{19523} thyroid adenoma, histology
{19529} thyroid adenoma, histology
* Future pathologists: TTF-1 is a marker for thyroid origin that
for some unknown reason also lights up most pulmonary adenocarcinomas.
* A recent claim that a three gene (PCSK2, PLAB, CCND2) assay could reliably
distinguish benign from malignant on fine needle aspiration proved something of a
disappointment (Cancer 113: 930, 2008).
{24723} papillary carcinoma, histology
{26792} papillary carcinoma, histology
{26795} papillary carcinoma, histology
{26798} papillary carcinoma, histology
{20291} world's smallest papillary thyroid cancer
* Well, maybe not. A thyroid cancer with the hallmarks of
papillary carcinoma but an entirely follicular pattern plus an obvious capsule
will according to an initial report probably behave as a follicular carcinoma.
No capsule, and the lesion is relatively
less aggressive, like a common papillary carcinoma (Cancer 107: 1255, 2006).
Stay tuned.
"Orphan Annie's tumor" reminds us of papillary carcinoma of the thyroid:
Follicular carcinomas tend to have thick capsules (thicker than follicular adenomas).
{39838} follicular carcinoma of thyroid, histology. Trust me, this was invading a vessel
{49356} medullary carcinoma of thyroid, gross
{49366} medullary carcinoma of thyroid, gross. Of course, you couldn't diagnose any of these four
without histology.
{09265} medullary carcinoma of thyroid, histology
{09266} medullary carcinoma of thyroid, histology
{37160} medullary carcinoma of thyroid, histology; Congo Red stain
{37163} medullary carcinoma of thyroid, histology; crystal violet stain (amyloid is scarlet, all else is
Navy Blue)
This is a thyroid cancer that shows follicular differentiation but either has necrosis
or has 5 or more mitotic figures per ten high power fields. So defined, the tumors
are quite homogeneous, and common enough to be mentioned here. Mortality is about 50%, and the prognosis seems
to depends solely on size of the primary and the stage of the cancer.
In the past, this has been lumped in with follicular carcinomas.
I believe this entity is distinct and has been missed, and will be included in the next classification scheme.
It is common to find remnants of the better-behaved cancer within the gland.
The immunostaining is of course different (spectacular photos: Am. J. Clin. Path. 125:
399, 2006).
{37004} anaplastic carcinoma of thyroid, cytology
Anaplastic carcinoma of the thyroid
Clear vascular invasion
Pittsburgh Pathology Cases
{10937} lymphoma of the thyroid
This is mediated by the cytokines of the acute phase
reaction, and to be usual, correlating with the drop in albumin
(Surgery 123: 560, 1998).
Nobody knows whether this is good (diminishing energy use during convalescence)
or bad, and replacement
Of course, labs can be normal or abnormal,
and the patients can feel well or ill.
Today's terminology:
Oxalate crytsals in the thyroid
Curiosity of no significance
KCUMB Team
LiVolsi's Endocrine Pathology
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silverberg's Surgical Pathology
Sternberg's Diagnostic Surgical Pathology
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 |
Thyroid
Iodine deficiency
Thyroid, follicular adenoma
Oxalate crytsals in the thyroid