Ed Friedlander, M.D., Pathologist

Presentation: The Patient with a Neck Mass
Title:        Thyroid Disease and Testing
Date & Time:  Thursday, February 4, 2010 at 10 AM
Lecturer:     Ed Friedlander MD


Taiwanese pathology site
Good place to go to practice

Photo Library of Pathology
U. of Tokushima

From Chile
In Spanish

Endocrine Pathology
Virginia Commonwealth U.
Great pictures

Utah cases for path students
Juliana Szakacs MD

Iowa Virtual Microscopy
Have fun

Tulane Pathology Course
Great for this unit
Exact links are always changing

Brown Digital Pathology
Some nice cases

Thyroid Exhibit
Virtual Pathology Museum
University of Connecticut

Photos, explanations, and quiz
Indiana U.

Normal thyroid

WebPath Photo

Normal thyroid

WebPath Photo

Normal thyroid

WebPath Photo

Normal thyroid
C-cells stained
WebPath Photo

"Pathology Outlines"
Nat Pernick MD

Thyroid Histology
Ed's Histology Notes

{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"


{08959}    propylthiouracil effect
{24718}    propylthiouracil effect

{24719}    high-dose iodine effect

{09362}    normal scan
{09363}    cold nodule, right upper pole


{49456}    cretin, age 4 months

Classic drawing
Adami & McCrae, 1914

ACQUIRED HYPOTHYROIDISM (Lancet 363: 793, 2004 -- it's often missed even though this should never happen)


      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"


      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
{25468}    myxedema
{25469}    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.


    • Iatrogenic lack of thyroid tissue (surgical, radiation)
    • Excess iodine (poisons the gland, remember how?)
    • Iodine deficiency (endemic goiter)
    • Subsisting largely on dietary goitrogen (remember cabbage? also Brussels sprouts, turnips, cauliflower, and the thiocyanate-rich central African cassava that also causes CNS damage; lithium and cobalt can also be also goitrogens)
    • Hashimoto's autoimmune thyroiditis or severe chronic lymphocytic thyroiditis
    • DeQuervain's (the disease is common, but hypothyroidism as a result is rare and probably transitory)
    • * Autoimmune type II (some antibodies block but do not stimulate TSH receptors)
    • Amiodarone toxicity, as below -- another fact worth remembering about this triky medicine is that it inhibits entry of thyroid hormones into the peripheral tissues
    • Secondary hypothyroidism (i.e., disease of the adenohypophysis; this is much less common than primary hypothyroidism; there are also mutations of receptors that interfere with TSH production)
    • Tertiary hypothyroidism (i.e., disease of the hypothalamus; this is probably very uncommon)
    • Various medications (remember valproic acid: J. Ped. 151: 178, 2007)

Iodine deficiency
Epidemic goiter
KU Collection


Thyroid Malformations
From Chile
In Spanish

    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
{09245}    thyroglossal duct cyst, histology

    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
{08960}    Hashimoto's, histology
{08961}    Hashimoto's, histology
{09242}    Hashimoto's, histology
{37881}    Dr. Hashimoto
{37882}    Dr. Hashimoto "after 40 years of teaching"

From Chile
In Spanish

Hashimoto's Disease
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Anti-thyroglobulin antibodies
WebPath Photo

Hashimoto's thyroiditis
Germinal centers, damaged parenchyma
KU Collection


WebPath Photo


WebPath Photo


WebPath Photo

Anti-microsomal antibodies
WebPath Photo

    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.

        * This "cirrhosis of the thyroid" was actually what Dr. Hashimoto's original paper described.

        * 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.


    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.

      * 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).

    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).


{09247}    DeQuervain's
{24721}    DeQuervain's


WebPath Photo

    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, coxsackie B (most common), EBV, ECHO, and adenovirus. There are surely others. Epidemic DeQuervain's: J. Clin. End. Metab. 70: 396, 1990.

    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.

HYPERTHYROIDISM (Lancet 362: 459, 2003; Am. Fam. Phys. 72: 635, 2005)


      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.


      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.


    • Graves's disease (around 80%-95% of non-factitious U.S. cases, depending on your series)
    • Hyperactive multinodular goiter / Hyperactive adenoma ("hot nodule"; "Plummer's disease"; most of the rest of U.S. cases: Am. J. Clin. Path. 101: 29, 1994); not surprisingly, these tend to have mutant TSH-receptors stuck in the "on" position (J. Clin. Inv. 115: 1972, 2005; same in kids J. Ped. 154: 931.e2, 2009).
    • Jod-Basedow (very important in the iodine-poor nations, not so much in the US)
    • Well-differentiated thyroid cancer (occasional cases, uncommon)
    • DeQuervain's with rapid release of thyroglobulin (uncommon)
    • * "Silent thyroiditis" -- a few weeks of elevated thyroid, without any physical findings or known histopathology (wastebasket, but real; think of drug allergy)
    • Post-partum (mild, if you examine the gland, you'll see lymphocytes)
    • Amiodarone (at least 5 known effects on cells / enzymes here -- look for foamy macrophages full of this oily iodine-rich medicine in the follicles)
    • Pituitary TSH-oma (very rare)
    • Choriocarcinoma / hydatidiform mole (recall that TSH is chemically similar to hCG)
    • Excess TRH (tertiary hyperthyroidism, rare)
    • Struma ovarii (thyroid in an ovarian teratoma; rare)
    • Trauma to the gland during parathyroid surgery (Surg. 138: 1058, 2005)
    • Lithium releases colloid from the follicles -- look also for giant cells with oxalate crystals
    • Factitious (i.e., patient took thyroid pills trying to "get smarter" or "lose weight", or "as a holistic nutritional supplement" from the health food store J. Fam. Pr. 38: 287, 1994, or physician/pharmacist error; not included in the above %'s)
    • * Mutant TSH receptor stuck in the "on" position: NEJM 332: 151, 1995; J. Clin. End. Metab. 81: 547, 1996; now "familial nonautoimmune hyperthyroidism": J. Clin. Endo. Metab. 94: 2602, 2009. The many diseases caused by the TSH receptor: J. Clin. Inv. 115: 1972, 2005.
    • Hamburger thyrotoxicosis: Epidemic in Minnesota and South Dakota 1984-88. It was finally discovered that one meat packer company was "gullet trimming" the strap muscles of the neck and as a result, inept cutters were also throwing thyroid glands into the beef (NEJM 316: 993, 1987). Happened again in Nebraska Am. J. Med. 84: 10, 1988; reappears in Canada CMAJ 169: 415, 2003.
    * "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.

GRAVES'S DISEASE (NEJM 358: 2704, 2008)

{09235}    Graves's
{09237}    Graves's


WebPath Photo


WebPath Photo

    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
{09356}    Graves's exophthalmos

    To complete the triad, patients often exhibit myxedema-like nodules confined to the anterior aspects of the lower extremities ("pretibial myxedema").

      * 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.

      * Try a generous dose of a topical glucocorticoid for the pretibial myxedema (J. Clin. Endo. Metab. 87: 438, 2002).

{09360}    pretibial myxedema
{25470}    pretibial myxedema
{25471}    pretibial myxedema
{25472}    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.


Thyroid Atrophy
From Chile
In Spanish

{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.

Burned out thyroid
No history -- surprise at autopsy

    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
{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

Nodular goiter

WebPath Photo

Nodular goiter

WebPath Photo

Thyroid gland with diffuse hyperplasia
What could this be?
Wikimedia Commons

Big inactive follicles
Nodular goiter / Could be other things too
WebPath Photo

    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.

      "Jod" is German for "iodine", and "Basedow's disease" their term for any hyperthyroidism.

    * 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 filled with colloid, 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 Tumors I
From Chile
In Spanish

Thyroid Tumors II
From Chile
In Spanish

Thyroid Tumors
Histopathology and essay
For pathologists

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.

      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.

      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:

    • One E. Denis Wilson M.D. popularized this in "Wilson's Syndrome: The Miracle of Feeling Well", 1996

    • A medline search (1999) shows no scientific publications by anybody named Wilson on the subject of clinical hypothyroidism

    • The 1999 directory of US medical specialists does not list any Denis Wilsons, Dennis no-other-initials Wilsons, or E-- D-- Wilsons.

    • Average normal body temperature is 98.2, so most people would self-diagnose as having Wilson's syndrome

    • If the model is true, people with "Wilson's syndrome" would have relatively high rT3 levels at presentation. A medline search (1999) shows that no one has reported looking at this. If the proponents believed their own claims, they would do so. It would seem to me that the burden of proof is on them.

    • On the other hand, it seems entirely plausible that some people do not make as much thyroid hormone as is right for them, and they feel the effects of this lack. I cannot fault a physician for trying a small amount of thyroxine supplementation in a patient with vague complaints suggesting hypothyroidism.

    * 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.

    Today's terminology:

    • Anti-TSH receptor antibodies are called TRAb
    • Anti-microsomal / thyroid peroxidase antibodies are called TPOAb
    • Antithyroglobulin antibodies are called TgAb

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:

    • Orphan Annie eye nuclei
    • nothing but little tiny follicles or trabecula or sheets, without big follicles (follicular carcinomas very seldom have big follicles)
    • Hürthle cells (and it's not Hashimoto's)
    • anaplasia
    • even one mitotic figure.
    • telomerase (this is new; reportedly always means neoplasia and usually cancer: Cancer 105: 492, 2005)
    • positivity for CK19, galectin-3, HBME-1, and/or RET (see above)

Oxalate crytsals in the thyroid
Curiosity of no significance

Oxalate crytsals in the thyroid
Polarized shot