Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
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Cyberfriends: The help you're looking for is probably here.
Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please.
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I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
KCUMB Pathology Club
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.
This page was last updated June 30, 2009.
During the fourteen 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!
It is difficult to imagine the "politically correct" revision of Victor Hugo's work as "The Angular
Kyphotic of Notre Dame".
-- Joe Segen
Bone and joint #'s 1-56, 107-246 (tumors begin at 132)
{14645} osteoblasts, normal
You know bone supports you, protects you, and stores your calcium and phosphorus. You know
osteoblasts in their rows making the super-densely-woven collagen that is osteoid, osteocytes in their
lacunes (hard to study, but not inert),
multinucleated (usually; 3-20) osteoclasts with ruffled contact surfaces in their Howship's lacunes / resorption pits,
compact cortical bone, spongy cancellous bone, the inert (?) cells that line bone (osteoblasts that did not become
osteocytes), and so forth. You know that bone perennially
remodels itself. (This is why the orthodontist can straighten teeth, and how you replace your entire
skeleton each decade.) You also know that
unmineralized bone is called OSTEOID, which is mostly densely-woven type I collagen, with some
vitamin K dependent calcium-binding proteins mixed in.
* The great mystery of how osteoblasts and osteoclasts cooperate so that
there will be just the right amount of bone is on its way to being solved.
CBFA1 is the factor that osteoprogenitor cells
make to turn themselves into osteoblasts (Bone 25: 107-8, 1999); its levels decrease markedly with age.
Working osteoblasts make RANKL, a membrane-bound protein factor that binds to RANK
on osteoclast precursors and turns them into osteoclasts,
and also osteoprotegerin, which interferes with the interaction.
Obviously something is missing from the picture; since bone grows along
lines of stress, it may be an electrical phenomenon.
See JAMA 292: 490, 2004; NEJM 353: 918, 2005.
Update on osteoclasts: Am. J. Path. 170: 427, 2007.
Remember that interleukin-6 is a strong osteoclast activator; this probably
accounts for the bone wasting seen especially in rheumatoid arthritis.
All collagen is "woven", but here the term has a special
meaning. When bone is being made rapidly (unborn child, healing injury,
some diseases), collagen fibers tend to be laid down
as crisscross WOVEN BONE, made rapidly and able to withstand
stress equally well in all directions. When things are more sedate,
the new bone is laid down as LAMELLAR BONE, with collagen
fibers nearly parallel, which takes
longer to make but is much stronger. They are easy to tell apart using
polarized light; after age 3, woven bone indicates pathology. The
slim CEMENT LINES (blue on H&E) that you may see in bone got their extra calcium
from osteoblasts by processes that are still poorly-understood.
The osteoblasts are also
responsible for beginning the process of mineralization, but this can't be
the whole story, since a row of osteoblasts typically overlies an unmineralized
"osteoid seam", which then takes about two weeks to be mineralized under the influence of the same cells.
Bone is decalcified prior to histologic sectioning,
but bone that was calcified is less homogeneously dense-pink
than bone that was never calcified ("osteoid").
Since it takes about two weeks to mineralize osteoid well, wide osteoid seams beneath the
osteoblasts mean bone is being laid down fast or not being mineralized. Narrow osteoid seams mean
the osteoid is being laid down slowly.
You can label the osteoid that mineralized today by administering tetracycline. This will impart a
permanent yellow color and distinct fluorescence to the seam. (Yes, if you were on tetracycline for a
while for your acne, your skeleton was much more yellow and much more fluorescent than your
friends'.)
Diaphysis... The long shaft, remote from both growth plates
Epiphysis... Between the growth plate and the nearest joint
Metaphysis... Between the growth plate and the diaphysis. In kids, this is where most of the bone
growth is taking place, so this is where most pediatric bone disease (infections, tumors) will occur.
You remember that when osteoblasts are working (growth, healing fractures, bone disease),
they produce extra alkaline
phosphatase, which shows up in the serum. You can tell when new collagen is being laid down (i.e.,
healing bone, Paget's, others) by increased urinary hydroxyproline.
You can spot dead bone under the microscope because there are no osteocytes in the lacunes.
You remember that in scurvy, osteoid fails to form, while in rickets, osteoid fails to mineralize.
(Future radiologists: In kids, look for sawtooth rib-cartilage junctions in both
deficiencies.) You also remember the
"brown tumors" of hyperparathyroidism from any cause; these regress when the hyperparathyroidism is treated.
There's considerable bony variability among normal people. Stature, of course, is entirely the result
of bone growth (and, in age, of bone deterioration). Stature is mostly genetic; you know the effects
of poor nutrition, chronic disease, hGH excess and deficiency, and osteogenesis imperfecta;
precocious puberty will first make you taller than your peers, then your epiphyses close and you
may end up shorter in the long run. (It's actually the estrogens
that close the epiphyses: Lancet 357: 1723, 2001, which is why
we give an aromatase inhibitor when we treat boys with constitutional
delayed puberty). If you get your sex hormones late (or never -- XXY's for example), you're likely to be tall.
Rich people have been giving their sons growth hormone to make them taller
for over two decades -- there has been no obvious harm.
A missing or extra (i.e., cervical) rib is generally a mere incidental finding. A missing phalanx or
even radius isn't particularly disabling. Various anomalies of bone formation are a radiologist's and
geneticist's fascination. * Bone "cysts" are uncommon but do occur, usually as fluid-filled round cavities
near active growth plates.
They are lined by a simple layer of bone-lining cells;
old reports that they were not lined resulted
from these being missed after the lesions were curetted
out.
{18649} polydactyly
FRACTURE TERMS
STRESS FRACTURE: The bone fractures after repeated extra stress, i.e.,
there were some tiny microfractures first and the bone was already a bit sore
INCOMPLETE FRACTURE: The bone is cracked, but not broken into two pieces. The best-known
incomplete fracture is the fast-healing GREENSTICK FRACTURE from an impact to a child's supple
long bone.
CLOSED (SIMPLE) FRACTURE: The overlying tissues are intact
OPEN (COMPLICATED) FRACTURE: The bacteria have a route from the surface to the bone; perhaps the bone is even
sticking out the wound.
MULTIFRAGMENTED FRACTURE (formerly "Comminuted fracture"): The bone is broken into several pieces.
COMPLEX FRACTURE: A curious term for a fracture in which the ends of the bone fragments have done serious damage to the surrounding tissue.
PATHOLOGIC FRACTURE: Due to intrinsic disease of the bone; the force would not have broken a normal
bone. Seen in osteoporosis, cancer, osteogenesis imperfecta, others.
PROCALLUS: Fibrin / granulation tissue bump forming from the hematoma at the fracture site. "Provisional
callus".
CALLUS: Granulation tissue bump at the fracture site that is starting to turn into fibrous tissue and
cartilage, from which healed bone will arise. Eventually becomes BONY CALLUS and then remodels to
look more or less like the original bone.
PSEUDARTHROSIS: The ends of the bone did not heal back together with bone. At best, there is fibrous
scar connecting the ends, and a "false joint" is created.
If the fracture is comminuted, if the ends of the bones are much displaced, or if infection happens,
don't expect good healing. Likewise, poorly-nourished people or osteoporotic people are likely to
get bad results.
* Future pathologists: Don't be fooled by post-mortem "heat fractures"
of bones in burned bodies. These are caused by boiling of the bone marrow.
{07029} healing fracture, histology
Four days: Periosteal new bone formation beginning
Ten days: Fracture line no longer visible; soft callus present
Fourteen days: Hard callus present
Twenty-one days: Callus is all hard
Ninety days: Bone has remodelled
* Orthopedic nails and screws placed into bone become separated from the
bone itself by organized connective tissue continuous with the periosteum.
* Allogenic stem cells to enhance bone healing: Impressive animal study, no immunosuppression required J. Bone. Surg. 85: 1927, 2003.
OSTEOGENESIS IMPERFECTA ("brittle bone diseases", * fragilitas ossium; Clin. Ortho. 401: 6, 2002;
Lancet 363: 1377, 2004)
A family of diseases having in common defective synthesis of type I collagen.
* The molecular biology has been extensively worked out (Clin. Orth. 343: 23, 1997).
Here are the classic subtypes:
type I... Make too little pro-α1(1). Normal statue, lax joints, hard of hearing (another mutation:
J. Clin. Invest. 85: 282, 1990).
type II... Pro-α1(1) is too short, etc.
The collagen is made but poorly secreted.
Bones break in utero or during birth, killing the child (yet
another mutation: J. Clin. Invest. 83: 574, 1989)
type III... Triple helix doesn't form well. Short, many fractures, progressive kyphosis, hard of
hearing, bad cases are lethal in childhood
type IV... Pro-α2(2) is too short, etc. Short stature, somewhat fragile bones
And if you look hard, you find many "forme fruste" people whose bones
are just a bit more fragile (J. Clin. Invest. 97: 1035, 1996).
Most are autosomal dominant; type II's are either autosomal recessive or new autosomal dominant
mutations. (Explain.) In most cases, the teeth are deformed. Except for
type IV, all feature distinctive blue sclerae. (The "blue" color results from the translucence of the
collagen. Don't rely on this, and don't go calling every relatively dark sclera "blue").
Bisphosphonates (which suppress osteoclast function / induce osteoclast
apoptosis) for osteogenesis imperfecta: After some early flops, finally
success. NEJM 339: 947, 1998; Pediatrics 111: 573 & 601, 2003, Lancet 363: 1427, 2004,
others; pamidronate seems to be standard now and obviously works (J. Ped. 148: 456, 2006;
J. Ped. 149: 174, 2006; J. Clin. Endo. Metab. 91: 511 & 1268, 2006; Pediatrics
119(S2): S-163, 2007, lots more).
Bone marrow transplantation as a treatment for osteogenesis imperfecta: Nat Med. 5: 309, 1999.
This did not become widespread.
Gene therapy and somatic cell therapy
are under investigation (Clin. Orth. 379-S: S126, 2000).
Achondrogenesis II: Lethal mutation in COL2A1
* Osteogenesis imperfecta must be ruled out in children with
fractures attributed to abuse. This isn't difficult.
I used to be asked about "temporary brittle bone disease"
and after examining the evidence, decided that I don't believe in it.
Shortly afterwards, the physician who "discovered" this went
to court for making stuff up (Br. Med. J. 328: 187, 2004).
OSTEOPETROSIS ("marble bones", "Albers-Schonberg disease";
Am. Fam. Phy. 57: 1293, 1998)
This family of diseases features progressive obliteration of the marrow cavity by bone
because the osteoclasts don't work. This is bad
because (1) the bones become very brittle, and (2) the patient is likely to die of neutropenia or
anemia.
Most of these diseases are autosomal dominant (usually fairly mild)
or autosomal recessive (usually severe). The genetics
of both have not been fully worked out (J. Clin. Endoc. Metab. 84:
1047, 1999).
Other patients lack carbonic anhydrase II, and
the osteoclasts die of too much acid (Hum. Genet. 99: 634, 1997;
Blood 97: 1947, 2001).
The dominant form is caused by a faulty chloride channel, preventing
the cytoplasm from becoming sufficiently acidic to dissolve bone in the first place
(Am. J. Path. 164: 1537, 2004; J. Clin. Endo. Metab. 92:
771, 2007). Of course, the forme fruste is resistance to osteoporosis, and
this has now been demonstrated (J. Clin.
Endo. Metab. 91: 995, 2006). In the severe, autosomal-recessive variant, the skull becomes so deformed from the disease itself and
the extramedullary hematopoiesis that the foramina for the optic and other cranial nerves are
compromised. Radiologists note a striking resemblance between skull x-rays of these kids and the
"Alien" from the Sigourney Weaver space thrillers (Radiology 183: 129, 1992).
There are several autosomal dominant osteopetrosis genes; as you'd expect,
most feature excessive numbers of non-functioning osteoclasts, while a deficiency in
functioning RANKL produces osteopetrosis without osteoclasts (Nat. Gen. 39: 960, 2007).
As you would expect, the problem seems to be with the osteoclasts. If you get a chance to examine
these, they are likely to look bizarre.
Marrow transplantation cures the underlying lesion: Blood 97: 1947, 2001.
"Osteopetrosis tarda" is a forme fruste, usually a subclinical x-ray finding
in older folks (Am. Fam. Phys. 57: 1293, 1998).
An infectious cause has been hypothesized but not found.
ACHONDROPLASIA (Lancet 370: 162, 2007)
An autosomal dominant condition (often a new mutation) in which there is impaired formation of the
long bones by the familiar endochondral process. The limb bones are short, with abnormally wide
ends. The patient has a head and trunk of normal size, and disproportionately short but well-muscled arms and legs. The face
usually has a large forehead, prominent supraorbital ridges, and deepset root of the nose
(looks like a very mild Apert's).
Sexuality is generally normal, and intelligence is distributed as for the general population, with
many well above-average (Am. J. Med. Genet. 41: 208, 1991).
The achondroplasia locus is the receptor for fibroblast growth factor 3.
* The mutation is usually the same, a substitution: Nat. Gen. 13: 233, 1996. Other, worse alleles here give
thanatophoric dwarfism, with excessively short ribs and suffocation shortly after birth (update Am. J. Path. 161: 1325, 2002).
Rat model
Nature Genetics 12: 390, 1996. Some short people have a forme fruste ("hypochondroplasia")
with mutated FGF3 (J. Ped. 133: 5, 1998). Sun Hudson,
the baby in the 2005 Texas
"life support" case, suffered from thanatophoric dwarfism.
Advanced paternal age is one of the known risk factors for new mutations.
Apparently this mutation, and maybe the similar Apert's mutation (see below)
give a growth advantage to the sperm clone (Science 301: 606 & 643, 2003).
{25610} achondroplasia
* Several of history's best-loved entertainers were achondroplastic dwarves (legendary gladiators, the
Egyptian good-luck spirit Bes, Pharaoh Pepi's Nubian dancer, Tom Thumb and his wife, the great
Renaissance fiction-writer Morgante. The "Munchkins" from the movie
version of "The Wizard of Oz" were apparently
a mix of pituitary and achondroplastic
dwarves. Some people
say that Aesop was a black
achondroplastic dwarf).
The traditional teaching is that
dachshund dogs are achondroplastics; we now know that the FGF3 genes seem
to be normal, and the gene(s) for the short legs of dachshunds, basset
hounds, and bulldogs remains unknown (Can. J. Vet. Res. 64: 243, 2000).
* In fact, achondroplasia has a mystique, and has even been considered a desirable trait. See Clin.
Genet. 37: 279, 1990. Everyone's heard of the "Little People"'s organizations, and there is much
friendly rivalry between achondroplastic and pituitary dwarves as to "which is better", etc.,
etc.
There are several other dwarfism syndromes that result from defective bone growth. Those that
compromise the lengthening of the ribs are fatal shortly after birth (why?)
* Apert's (deformed face, syndactyly; the official name is
"acrocephalosyndactyly") is mutated fibroblast growth factor receptor 2 (Nat. Genet. 13:
48, 1996); documentary "Mary Ann" about an Apert's baby who was so ugly that everybody
assumed she was retarded, too, and they put her in a home for retarded kids; she wasn't retarded.
Apert's is usually a new mutation, and almost always on Dad's chromosome (Nat. Genet. 13: 9,
1996); this is another of the few genetic diseases that gets more common with advanced paternal age.
A milder allele causes Crouzon syndrome; the same advanced paternal age effect
has been noted (Am. J. Hum. Genet. 66: 768, 2000).
One of the "pseudoachondroplasia" diseases
results from a mutated cartilage matrix protein,
which is improperly processed and causes apoptosis of the growth cartilage
(Am. J. Path. 163:
101, 2003).
A "midget" is a normally-proportioned miniature adult; a
"dwarf" is short because of disproportion.
{53757} Apert's
Here is the evidence: All this fits with pycnodysostosis and probably nothing else.
Making the call: JAMA 191: 111, 1965; more recently Nat. Genet. 10: 128, 1995.
This is an autosomal recessive illness caused (at least sometimes)
by defective cathepsin K, found only in osteoclasts (J. Clin. Endo. Metab. 85:
425, 2000). Pathology J. Clin. Endo. Metab. 89: 1538, 2004.
* OTHER GENETIC SYNDROMES
Camurati-Engelmann disease, or "progressive diaphyseal dysplasia",
features bone laid down under the periosteum; the gene is TGF-β1
(Nat. Genet. 26: 273, 2000;
J. Biol. Chem. 278: 7718, 2003).
BONE INFARCTS
Infarction and necrosis in the shaft is more difficult because of collateral
circulation, and usually results from trauma. Eventually, a bone infarct becomes radiodense. This is probably
because of dystrophic calcification of the dead marrow-fat.
Remember osteonecrosis (formerly "avascular necrosis") of the femoral head
(J. Bone Joint Surg. 88A: 1117, 2006). It's a dread complication
of sickle cell disease, decompression sickness, and of course femoral neck fracture. There is a mysterious link
to alcohol abuse and glucocorticoid use. If there is a link to anabolic steroids (as was reported in the 1990's),
no one has demonstrated it convincingly.
PYOGENIC OSTEOMYELITIS (Lancet 364: 369, 2004)
Common bacteria can reach the bone via the blood, during surgical or other trauma, or from
surrounding tissues (don't forget infected teeth, or the gangrenous feet of diabetics).
Osteomyelitis is especially serious, since the rise in pressure caused by the suppuration (like in a ripe
pimple, of course) is often enough to cause infarction of spongy bone and marrow, sequestering
the infection and turning it into a chronic infection refractory to all but the most aggressive
treatment.
The most common bug is staph The anatomic pathology of pyogenic osteomyelitis has many variants. Rupture through the cortex
via Haversian and Volkmann canals, will
produce PERIOSTITIS or (in a growing child) a SUBPERIOSTEAL ABSCESS surrounding the entire shaft.
Dead cortical bone becomes a SEQUESTRUM (and acts like any other foreign body; consider surgical
debridement), while new living
bone that grows around the dead bone
is called the INVOLUCRUM. Rupture through the skin produces refractory
pus-draining SINUSES, where
squamous skin cancer is likely to arise because of the ongoing destruction-and-regeneration
of the squamous epithelium. A walled-off area full of bacteria is a BRODIE'S ABSCESS,
which can keep the infection going, and perhaps spreading via the bloodstream, for many years.
In the chronic infection, the infiltrate is a mix of neutrohpils,
lymphocytes, plasma cells, and lipid-laden macrophages; sometimes the plasma cells or
macrophages are by far the most abundant.
Look for numerous resorption pits in the dead bone or injured, signs of osteoclastic activity
at the end.
Healed osteomyelitis is often very radio-dense.
Remember that osteomyelitis is likely to complicate bedsores and foot gangrene.
Osteomyelitis often becomes a clinician and patient's nightmare. You're already familiar with
amyloidosis A, one of the many feared outcomes.
* When there is an open wound that is being managed, pathologists are now being
asked to examine a bone biopsy to see whether osteomyelitis is present. This guides
antibiotic therapy (Am. J. Med. Sci. 321: 367, 2001).
Autopsy series of osteomyelitis in sacral decubiti: Arch. Path. Lab. Med. 127: 1599, 2003.
{05293} osteomyelitis, x-ray (see it? areas of dead bone often end up mottled-radiodense)
* SAPHO SYNDROME (now, "acquired hyperostosis syndrome")
is a rare (and/or underdiagnosed?) illness in which
abscesses appear unpredictably in the skeleton. Anti-TNF-alpha infliximab makes the synovial lesions much better and the
skin lesions worse: Rheumatology 45: 730, 2006.
SYPHILIS was famous for producing gummas and periostitis, and Shakespeare even calls it "the Neapolitan bone-ache."
TUBERCULOUS This used to be common everywhere and is still common in the poor nations. While the onset is
more insidious than pyogenic osteomyelitis, the infection is extremely destructive and hard to treat.
POTT'S DISEASE is the dread tuberculosis of the spine, and TB is the common cause of the infamous
PSOAS ABSCESS.
OSTEOPOROSIS (Ann. Int. Med. 126: 458, 1997; Med. Clin. N.A 87: 1039, 2003;
J. Clin. Inv. 115: 3318, 2005)
This is a very important process results from a slight excess of bone resorption over bone deposition,
continuing over many years. As we get older, we all get some osteoporosis.
The histology is banal (thin cortex, thin trabeculae), and the radiology equally so (there are
parameters on hand x-ray, and so forth). These belie the devastating consequences, which include
pathologic fractures (hip, compression fractures of vertebrae causing "dowager's hump" kyphosis),
and chronic pain. Osteoporosis causes 1.2 million fractures per year in the U.S. alone.
In a man, or a pre-menopausal woman, look for one of the known "causes" of "secondary
osteoporosis" (Arch. Int. Med. 149: 1069, 1989). These include, but are not limited to:
The first discovered gene was
the vitamin D3 receptor (* VDR gene product).
Original work: Nature 367: 576, 1994; Lancet 345: 423, 1995.
Update Ann. Int. Med. 145: 255, 2006 (some alleles probably do, others probably don't).
Also well-established is the presence of certain alleles at locus
for the estrogen receptor alpha. This interacts with VDR type (J. Clin. Endo.
Metab. 88: 3777, 2003).
Another gene turns out to be the one for type I collagen, where
certain alleles cause less bone mass and increase the risk for
osteoporosis (NEJM 338: 1016, 1998); collagen mutations can also promote
fractures independent of bone mass (i.e., the bone is poorly-made).
Several other less-well-known genes also seem important
(for example, a couple of lipoprotein-receptor-related genes Endocrinology 148: 2622, 2007;
JAMA 299: 1277, 2008).
Genetics updates:
J. Clin. Endo. Metab. 87: 2460, 2002; Lancet 371: 1505, 2008;
NEJM 358: 2355, 2008 -- includes osteoprotegrin, RANKL, RANK (?), and the
estrogen receptor alpha -- not really surprising).
Although in "pure" osteoporosis, labs will be normal, it's probably worth
spending $75 to get each of these people a serum TSH (if on thyroid replacement), serum calcium,
serum PTH, serum 25(0H)vitamin D, CBC, chem profile,
and 24 hour urine calcium (J. Clin. Endo. Metab. 87: J. Clin. Endo. Metab. 87:
4431, 2002.
X-rays will be normal until about half of the bone is gone.
Today, "proven" ways of slowing osteoporosis include estrogen replacement (after menopause,
whether natural or artificial, see Am. Fam. Phys. 40: 205, 1989) and calcitonin (J. Ped. 118: 703,
1991). Nowadays, androgens and diphosphonate are also pretty much standard (South. Med. J. 87:
S-23, 1994).
However, the idea that taking extra calcium even when you're a kid
is important because
it keeps you from getting osteoporosis years later is still dogma
(despite the meta-analysis Br. Med. J. 333: 775, 2006, which
reached the same conclusion based on clinical studies as I did by reasoning
from the basic pathology).
Your lecturer believes that this is driven by the fact that most Americans
simply and understandably won't comply with the "recommendations". ("Recent research has raised
doubts about the efficacy of calcium supplementation in preventing fractures;
however, adequate calcium intake remains important." -- Am. J. Clin. Nutr. 85:
1361, 2007). Tell your patients "Uncle Sam still stays you need a lot
of calcium", just to cover yourself when they break a bone.
* Paradoxically, the amino-terminal end of parathyroid hormone
increases the formation and total mass of bone, and this is now
finding clinical use: NEJM 344: 434, 2001.
{46507} osteoporosis, gross
Egyptian mummy ladies had much less osteoporosis for their ages than our ladies do; perhaps they were
more active physically than American folks today (Lancet 341: 673, 1993, no television).
OSTEOMALACIA
Failure of the bone to mineralize properly in an adult.
Think first of inadequate intake of vitamin D and/or calcium.
This is a topic under "nutritional disease" and of course in childhood
it produces rickets.
Adults with dietary calcium deficiency (poverty, elderly "tea and toast" eaters,
people subsisting mostly
on vegetables) or malabsorption are prone to osteomalacia, which in turn results in bone pain and
even fractures.
And the truth is that adult vitamin D deficiency is rampant in our "civilized" society,
and accounts for many of your patients with persistent, nonspecific musculoskeletal pain
(Mayo Clin. Proc. 78: 1463, 2003). Even people "who are not at risk"
turn up with it, and curiously, the "complementary medicine community" vitamin buffs
are paying this very little attention. Before your write your "total body pain"
patient off as "having fibromyalgia" or "being mental", check vitamin D levels.
* A study out of New Zealand (J. Am. Diet. Assoc. 104: 250, 2004)
followed 50 children who had avoided drinking cow's milk for a long time
and did not use calcium-rich supplements (i.e., the vegan or faddist
parents didn't know what they were doing).
They had almost three times as many fractures as other kids, most often
following trivial injury. This does not surprise me at all.
* Osteomalacia can also be caused by
paraneoplastic renal phosphate wasting:
NEJM 348: 1656 & 1705, 2003; JAMA 294: 1260, 2005;
"oncogenic osteomalacia", from tumor-produced
FGF23 (fibroblast growth factor 23)
which you'll recognize
by the bone pain and the remarkably low serum phosphate levels; patients have sarcomas that
may be small, low-grade lesions
most notably the infamous "phosphaturic mesenchymal tumor": Arch. Path. Lab. Med. 126:
1245, 2002; JAMA 294: 1260, 2005; Am. J. Med. Sci. 332:142, 2006.
If you are looking at a section of bone that was made without the bone
being decalcified (which is hard to do), you'll see that the osteoid seams aren't well-mineralized.
More likely, you'll be looking at decalcified bone, and recognize
osteomalacia as very wide osteoid seams (the osteoblasts don't stop laying down
the collagen until they sense they've mineralized it).
It's a component of renal osteodystrophy; sorting this out is a mess we'll discuss under "kidney".
* HYPOPHOSPHATASIA, an inborn error that causes osteomalacia of
variable severity, is caused by mutations (recessive or a dominant poison-protein)
of alkaline phosphatase (J. Clin. Endo. Metab. 85: 743, 2000).
Of course, a mutated FGF23 causing overproduction of
its protein
causes osteomalacia ("autosomal dominant hypophosphatemic rickets").
Another osteomalacia gene that's probably fairly common is mutant
NHERF1, which governs resorption of phosphate by the kidney ("renal phosphate leak"; NEJM 359: 1128, 2008).
OSTEITIS FIBROSA CYSTICA and RENAL OSTEODYSTROPHY
Review these in "Big Robbins" if you need to do so. Remember that osteoclasts in
normal adult bone
are rare -- if you see even one osteoclast
in a random slide of adult bone, think of hyperparathyroidism from some cause.
Look for the cutting cones going through the centers of the trabeculae of spongy bone.
Renal osteodystrophy includes lesions of hypovitaminosis D, osteomalacia,
and hyperparathyroidism.
* FLUOROSIS
Nerve compression and increased radio-opacity are typical. You may see the
disease if you visit certain parts of Ethiopia or India (J. Bone. Joint Surg. 86: 594, 2004). Everybody in a particular
town will have it.
PAGET'S OSTEITIS DEFORMANS (Am. Fam. Phys. 65: 2069, 2002; J. Clin.
Inv. 115: 200, 2005; Lancet 372: 155, 2008)
A common, usually-subclinical process seen in maybe 3% of older people, in which portions of one
or more bones become involved in abnormally rapid production and destruction of osteoid, leading
to curious, abnormally-vascular, abnormally-brittle bone that tends to deform along lines of stress.
Most often involved are the pelvis (usually quiet), femurs (bowing of the legs), humerus (usually
quiet), spine (be careful) and/or skull. The forehead can grow larger ("leontiasis ossea").
The bone thickens and will feel warm because of
hyperperfusion. Patients may experience bowing of the legs, bone pain (usually mild) and increased
hat size. Deafness can result from impingement on the VIII nerve's foramina and/or disease of the
ossicles. Even more ominous are the (uncommon) development of high-output heart failure
(pagetic bone is very vascular and arteries communicate directly with veins)
and/or a
vicious osteosarcoma (or other bone cancer; fortunately only about 1% of patients develop
this; Cancer 70: 2802, 1992; Clin. Orth. 438: 97, 2005) and/or compression of the brain at the foramen magnum.
The microscopic picture is distinctive. Osteoblasts and osteoclasts
are both increased in number. Osteoclasts may be gigantic, with
100 or more nuclei.
The trabeculae are thick, made of woven bone, and shaped
weirdly, with a mosaic pattern of seams / cement lines ("geographic bone"; "crazy quilt")
where osteoblasts have filled irregularly-shaped, giant resorption pits. The marrow space
along the trabecula is
replaced by highly vascular fibrous tissue. (In very severe cases, this contains
enough arteriovenous shunts to produce high-output heart failure).
A ghoulish but helpful
autopsy-table observation: Everybody seems to know that the
calvarium of a Paget's skull doesn't hold water.
The idea that Paget's is a slow-virus infection -- once very popular --
seens to be discredited.
* The most impressive positive studies
(for example, a supposed trademark strain of measles --
J. Bone Min. Res. 17: 145, 2002) remain unconfirmed,
most genetic studies have turned up negative, and a
review team found contamination in one major lab reporting
positive results (J. Bone Min. Res. 22(S1: S-281, 2007).
Putting together what we know about the etiology of Paget's: J. Clin. Inv. 115:
200, 2005. The fundamental lesion is that osteoclast precursors are too sensitive
to factors that transform them into osteoclasts. At the beginning, the process
is entirely lytic, but soon the osteoblasts, which remain coupled, catch up.
Nobody knows why Paget's tends to be focal.
It is likely that Beethoven's deafness was due to Paget's. (Why do we think so? Hint: Note the
shape of his head, and read up on his later-life health problems.)
* Egil the Viking, who acquired a hideously deformed, massive face and head, and whose skull
survived a blow from an axe from another Viking (who knew how to use axes),
probably had Paget's, which was common (Sci.
Am. 272(1): 82, 1995). Great pictures.
There are several familial syndromes.
The two genes worth knowing (SQSTM1 and TNFRSF11B/osteoprotegrin)
both interact with RANK and NFkappaB. Egil's severe familial
disease was probably SQSTM1. See NEJM 347:
175 & 210, 2002; Arth. Rheum. 50: 1650, 2004; many more.
The treatment of Paget's has been revolutionized by the introduction of the bisphosphonates,
osteoclast inhibitors (Br. Med. J. 312: 454, 1996; Hosp. Pract. 32(3): 63, March 15, 1997).
Don't confuse "Paget's disease of bone" with "Paget's disease of the nipple" or "Paget's disease of the
skin". Both result from growth of underlying adenocarcinomas into the epidermis.
{13384} Paget's disease, skull, gross
HYPERTROPHIC OSTEOARTHROPATHY
Mysterious periosteal new bone formation at the distal ends of tubular bones
throughout the body, with arthritis.
* Usually these patients also have clubbing, which
probably reflects megakaryocyte embolization in most cases. However,
something else is perhaps going on in hypertrophic osteoarthropathy.
Most of these patients have an underlying
non-oat-cell
bronchogenic carcinoma or cystic fibrosis. (Other notable causes of
clubbing, most especially right-to-left cardiac shunts, SBE, and Crohn's disease,
usually don't
cause the hypertrophic osteoarthropathy). Some cases are "primary", idiopathic,
progressing over decades.
This can be very painful and crippling, and require special treatment
(drugs, radiation). * Pamidronate in cystic fibrosis: Chest 121: 1363, 2002.
Historically, it was seen in radium painters and workers with white phosphorus ("phossy jaw").
It has always been known as a complication of osteopetrosis/
It has returned as a known risk to patients treated with high doses of bisphosphonates (Clin. Tox. 45: 753, 2007).
No one understands why the upper and lower jaws are selectively involved.
I suspect that the team that identified bacterial biofilms is on the right track,
and that the cause will be found to be biofilm formation around dead bone that is not
removed on time by osteoclasts.
(J. Oral Max. Surg. 66: 767, 2008).
* Bones are a perennial symbol of human mortality, and in a larger sense, of all of human biology.
"A soft tongue can break hard bones": Proverbs 28:19.
"Bone of my bone..." -- Adam. "Cursed be he who moves my bones" -- Shakespeare's epitaph.
"Them bones, them bones gonna rise..." -- Afro-American Spiritual. As a kid, I was much affected
by Yeats's cryptic ghost tale The
Dreaming of the Bones. As an Irishman, Yeats couldn't actually say, "Isn't
it time we forgave the English?", but the very-short piece
is recommended reading in any era of political hatred.
INTRODUCTION TO BONE AND SOFT TISSUE TUMORS
Primary tumors of bone by definition arise from the mesenchymal cells (as opposed to the marrow
elements, plasma cells, and so forth). Soft tissue tumor by definition arise from
mesenchyme not part of bone. If malignant, primary bone and soft tissue tumors
are called sarcomas. Benign or malignant, they are especially troublesome.
The common primary bone cancers (as opposed to metastatic and hematopoietic cancers including myeloma) are osteosarcoma
(most common), Ewing's sarcoma, chondrosarcoma, and malignant giant cell tumor.
Among all cancers, only 0.2% or so arise in bone, with an incidence of 1/100,000.
The World Health Organization's nomenclature is standard.
If you are asked, "What is the most common primary bone cancer producing a mass?", you must ask,
"Do we include plasma cell myeloma?" This often produces one or more masses, and is
more common than any sarcoma arising in bone.
When we are discussing bone tumors and mention "osteoid", we are referring
to a lace-like pattern of collagen deposited in the tumor, like spongy bone.
Where do bone tumors arise?
Diaphysis: enchondromas; some chondroSARComas; Ewing's, and eosinophilic granulomas
Epiphysis: chondroBLASTomas; most giant cell tumors (supposedly)
Metaphysis: all other primary bone tumors (why? because this is where a tumor
arising from the growth plate will appear)
(Osteomas arise from the cortical bone of the face. Plasma cell myeloma produces its "punched-out"
lesions throughout bone.)
Most patients with primary bone cancer are young. While any primary bone tumor can occur in a
child or adolescent, remember these general ranges:
Metastatic neuroblastoma: infants and toddlers
Ewing's sarcoma: older children and adolescents
Osteosarcoma: adolescents and young adults
Giant cell tumors: young adults and middle age
Chondrosarcoma: middle age
Metastatic cancer: middle and old age
Cancers present with pain/tenderness, swelling, and/or a fracture. Benign tumors, if symptomatic at all, usually
present as a painless mass. (Osteoid osteomas are painful, enchondromas may cause a stress
fracture, and other benign tumors can sometimes do these things.)
The more aggressive cancers look like other cancers, and there is usually destruction of surrounding
bone.
Radiologists suspect cancer whenever a tumor lifts up the periosteum. You can tell because this
results in new bone formation (Codman's triangle; "sunburst" deeper in the bone).
Risk factors for bone sarcoma include some familial syndromes, radiation and chemotherapy
Cancer 67: 193, 1991). However, most cases occur without any of these.
Unlike carcinomas, there's more known about chromosomal breaks than point mutations in these tumors.
(I suspect this is because the mutagens are more likely to reach epithelial cell nuclei.)
In the previously irradiated patient, the commonest primary bone cancers:
Tall kids get more Ewing's sarcomas and osteosarcomas.
Most bone tumors are slightly more common in males than in females. Chondrosarcomas in
particular are a man's disease (3:1).
Making the diagnosis of a primary bone tumor poses special problems.
The pathologist will always want to see the x-rays before making the diagnosis. (Lytic or blastic?
What sort of edge? Reaction in surrounding bone?)
Most cases will go for consultation. Few community pathologists have much experience with these
things. The tumors mostly look very similar anyway. It is easy to miss the tumor on biopsy. The
patients are kids. The treatment is horrible. What if she is pregnant?
* Biopsying these tumors: Clin. Orthp. Rel. Res. 368:
212, 1999. Open biopsy is the gold standard;
Tru-Cut core needle biopsy is now most common.
Fine needle aspiration of bone: Clin. Orthop. Rel. Res. 373:
80, 2000; Cancer 90: 47, 2000, Am. J. Clin. Path.
111: 632, 1999; Am. J. Clin. Path. 115: 59, 2001;
Arch. Path. Lab. Med. 128: 759, 2004.
White knuckles.
Treatment for bone tumors is much better than in the old days.
Benign tumors may be treated by curettage and packing with bone chips from elsewhere.
Malignant tumors require resection, radiation, and/or chemotherapy.
FIBROUS DYSPLASIA
Since mutations are involved, this is best considered among the bone tumors.
In this condition, a portion of bone when the spongy trabeculae should be is replaced by fibrous
tissue in which poorly-formed spicules of woven bone are abundant. Simple fibrous dysplasia can
be MONOSTOTIC or POLYOSTOTIC.
Monostotic fibrous dysplasia is usually asymptomatic, a radiologist's curiosity.
Often one side of the jaw is involved, producing a distinctive asymmetry of the lower face.
Involvement of the shoulders and hips can produce disability. (* Ask a radiologist to show you the
"shepherd's crook" deformity of the proximal femur.)
* Leave the variant "osteofibrous dysplasia" of the lower leg bones to us; it can be more debilitating (i.e., bow legs) but often self-cures.
MCCUNE-ALBRIGHT POLYOSTOTIC FIBROUS DYSPLASIA is a curious disease also featuring café-au-lait spots
(irregular borders, in contrast to those of neurofibromatosis), precocious puberty, and often other
endocrine dysfunctions (notably hyperthyroidism, cushingism, acromegaly, and/or vitamin D
resistance). It looks like a genetic disease, but isn't inherited in any familiar fashion.
The defect is in the gene that codes for the 5α-subunit (GNAS-1) of the G-protein (i.e., the one
that operates from the cyclic-GMP/ras system) that is in charge of stimulating adenyl cyclase. This
means that when a cell is given a signal via cyclic-GMP, it responds as if it had been stimulated by
cyclic-AMP. This probably accounts for the endocrinopathies, but what about the spots?
It turns out these patients are all mosaics for affected and normal cells, and that only the places
where the cells bear the mutation are affected. (Even one dose of the McCune-Albright must be
lethal to the fertilized egg; the mutation is post-zygotic and clones of cells bearing the mutation are
distributed segmentally throughout the body and must go back to the not-very-many-cells stage.
Ask an embryologist.)
* How it was worked out: NEJM 325: 1688, 1991. There's also a
number of alleles at the same locus ("Albright's hereditary osteodystrophy") that can be inherited;
this should be familiar from "pseudohypoparathyroidism" and "pseudo-pseudohypoparathyroidism": J.
Clin. End. Metab. 76: 1560, 1993.
Regardless of etiology, the common problem in fibrous dysplasia seems to be activation of adenylate
cyclase, leading to c-fos overexpression, etc., etc. NEJM 332: 1546, 1995.
Transformation of fibrous dysplasia to cancer is rare.
While we're on the subject of scrambled bone growth: An
ANEURYSMAL BONE CYST is a
rapidly-expanding lesion with wide blood vessels. There may or may not be bone and/or giant cells
forming in the septa between the blood vesels.
These seem to expand a bone just like an aneurysm expands a blood vessel ("blowout expansion");
curiously, these can also "spread" across a joint. These can grow rapidly and
be very destructive.
Sometimes an "aneurysmal bone cyst" can be the first sign of some other
underlying tumor.
BONE-FORMING TUMORS
OSTEOMA: a lump of ordinary, dense/compact bone jutting off a head bone
(especially jaw or paranasal sinuses). A non-tumor; if multiple,
think of Gardner's.
Although they have no malignant potential,
they may impinge on the brain, obstruct sinus drainage, or just look ugly.
If multiple, suspect Gardner's disease (intestinal polyps, soft tissue sarcomas,
desmoids, epidermoid cysts).
OSTEOID OSTEOMA: a common benign tumor of osteoblasts.
A nidus of miniature bony trabeculae and fibrous tissue,
surrounded by very dense bone.
Occurs in the vertebrae or long bones of young adults, where it causes well-localized pain and
tenderness. The pain responds dramatically to aspirin (i.e., it must be
mediated by the very large amounts of prostaglandin E2 in these
lesions; Clin. Ortho. Rel. Res. 393: 258, 2001),
and the rim is also very heavily innervated
(Mod. Path. 11: 175, 1998).
Enucleation is curative, though of course difficult for physcian
and patient alike. The patient will tell you
in the recovery room whether you got it all out.
The modern initial treatment is computer-guided thermocoagulation, with or without
a prior tissue diagnosis, by the radiologists (Radiology 224: 92, 2002). {10830} osteoid osteoma, histology
OSTEOBLASTOMA ("giant osteoid osteoma"): a rare non-metastasizing but
locally destructive tumor of osteoblasts.
This usually arises in the vertebral bodies of young adults.
The tumor cells make new osteoid. All osteoblastomas are by definition larger
than 1.5 cm.
Cells in the center can look nasty, but they appear to "mature" at periphery.
This lets you know it's not an osteosarcoma, and likely to be better-behaved.
We won't ask you to make the distinction.
OSTEOSARCOMA: the commonest primary cancer of bone (not counting
plasma cell myeloma of course). There are about 6000 new cases in the US each year.
Cancer of the osteoblasts.
Pathology update: Am. J. Clin. Path. 125: 555, 2006 (great photos).
By definition, any and all tumors in which malignant cells
themselves directly
make osteoid are osteosarcomas.
Warniing: Benign endochondral bone formation can take place in any cartilaginous tumor.
You must see the malignant cells themselves making the bone.
Warning: When the malignant cells are absorbed into the new bone
and become "osteocytes", they may look very benign.
Warning:
Remember also that normal bone surrounding any diseased area may show proliferative changes.
* The old term "osteogenic sarcoma" is ambiguous
and should be discarded.
* There are elaborate subclassifications. The old one was based on how much cartilage,
fibrous matrix, and recognizable osteoid the tumor was producing, and turned out to
have no bearing whatever on prognosis or treatment.
Don't worry about these.
Most osteosarcomas arise in the medullary
areas of the metaphysis of long bones (especially the knee; occasionally in the jaw or elsewhere; sometimes on
bone surface, sometimes
not even in bone: "extra-osseous osteosarcoma" Cancer 65: 2762, 1990). As noted, most patients are adolescents or young adults, and there is a slight male preponderance.
(Of course, many teenaged males have a painful knee, hence the delays in making the diagnosis.)
People in retinoblastoma families are at much greater risk, and deletions of the Rb anti-oncogene on
long arm of chromosome 13 are the rule in osteosarcomas. Li-Fraumeni (p53) families are also at
great risk.
"Secondary" osteosarcomas occur in old people with Paget's disease (especially in the pelvis), or
patients of any age with familial conditions with many osteochondromas and/or enchondromas. Paget's
of bone is very common in the elderly, and accounts for famous
"second peak" in osteosarcoma frequency during later life. Other "secondary" osteosarcomas follow radiation, chemotherapy, chronic osteomyelitis, bone
infarcts (caisson workers).
Osteosarcomas present variable histopathology.
Tumors are usually predominantly made of new bone, cartilage and fibrous tissue.
Less often, there may be a preponderance of vessels
("telangiectatic osteosarcoma", a variant easily mistaken
on conventional x-ray for aneurysmal bone cyst: Cancer 109: 1627, 2007). * When there is
a preponderance of small cells in an apparent "osteosarcoma",
gene studies will usually be more typical of a Ewing's sarcoma.
Leave the diagnosis of "epithelioid osteosarcoma", "osteoblastoma-like
osteosarcoma", and "low grade central osteosarcoma" to us.
Grading of osteosarcomas has not proved very helpful for prognosticating
outcome, since almost all the "classic" ones
that arise in the medulla are anaplastic "high grade" tumors.
There are two important subtypes with a generally good prognosis and low grade that arise on
the bone surface.
JUXTACORTICAL ("parosteal") OSTEOSARCOMA: dense bone with a dense,
fibrous, only mildly-anaplastic stroma, usually at the distal femur.
Often it's hard to tell
you're even looking at tumor microscopically. There may be cartilage,
and the most treacherous
even carry a cartilage cap (i.e., pretending to be osteochondromas).
Juxtacortical osteosarcomas carry a good prognosis, unless there is de-differentiation (at presentation
or later) into a more aggressive sarcoma (Cancer 103: 2373, 2005).
PERIOSTEAL OSTEOSARCOMA, a rarity, is a ring of
clearly-malignant, calcifying cartilage-and-new-bone around a bone in a young
person. It may occur remote from bone: Arch. Path. Lab. Med. 115: 906,
1991. The prognosis is generally good and chemotherapy does not seem to be indicated (Eur. J. Cancer 41: 2806, 2005; update
Clin. Orth. 453: 314, 2007).
It's uncommon, but not unheard-of, for an aggressive osteosarcoma
to arise on the bone surface; these behave as do the common sort that
begin inside the bone (Cancer 85: 1044, 1999; update on "high-grade
surface osteosarcoma Cancer 112: 1592, 2008).
* Future pathologists: Immunostaining for osteoblast markers
(i.e., osteopontin, osteonectin, osteocalcin) isn't sufficient
to establish that a tumor is an osteosarcoma; for example, giant cell
tumor stroma often stains for these as well (Clin. Orth. 459: 8, 2007).
Once almost always fatal, the five-year
survival in osteosarcomas presenting
without metastatic disease and
receiving modern therapy is running
around 70%.
It is quite acceptable to remove lung metastases surgically,
even several times (Cancer 104: 1721, 2005). These patients can still often
be cured this way.
{05755} osteosarcoma, x-ray
CHONDROMATOUS TUMORS (remember cartilage often undergoes dystrophic calcification)
OSTEOCHONDROMA ("exostosis", "ecchondroma"): "the commonest bone tumor", actually a hamartoma
A cap of normal cartilage on a bony stalk, usually near the growth plates. These grow up over time but usually stop when growth stops.
An incidental finding, with a slight potential for transformation into chondrosarcoma,
especially if multiple (Gardner's, or the familial exostosis syndromes).
However, any osteochondroma that continues to grow is suspicions for
transformation to chondrosarcoma (Clin. Orth. 411: 193, 2003).
* The gene EXT1 is known, and governs surface expression of heparan sulfate.
(Nat. Genet. 19:
158, 1998).
EXT2 has also been discovered
(Am. J. Hum. Genet. 62: 346, 1998). Both are probably
tumor suppressor genes. One sees these in the familial forms; usually they are NOT mutated in lone osteochondromas.
This is the bone tumor that is best-linked to previous trauma (i.e., a bit of a normal growth surface
got pushed over to the site where the tumor developed).
{05842} exostosis ("osteochondroma")
ENCHONDROMA (or just plain "chondroma"): a common oddity; a popcorn-shaped lump of cartilage inside the shaft of a bone
Most often involves the proximal phalanges. It is an incidental finding on bone scan or x-ray, or is
discovered when a child or athlete presents with a stress fracture.
Usually enchondromas are harmless.
If multiple (syndromes include
Ollier's generally with unilateral involvement, Maffucci's with
hemangiomas) or in large bones, there is about a 25% chance that
at least one will
transform into
chondrosarcoma -- and since these enchondromas may have a bit of atypica
even then they are benign, you'll want consultation.
Ollier's and Maffucci's must be anti-oncogene deletion syndromes but the
genes have
evaded discovery (Hum. Mut. 24: 466, 2004).
Ollier's is usually unilateral (i.e., post-zygotic mutation);
there is a distinct bilateral hands-and-feet-only variant (J. Ped. Ortho. 6: 15, 1997).
Malignant transformation: Hum. Path. 31: 1299, 2000.
* CHONDROMYXOID FIBROMA ("fibromyxoid chondroma"): a rare, benign spindle-cell tumor that
differentiates as cartilage, with different regions
showing differing amounts of hyaline cartilage matrix.
Occurs in the legs and feet of young adults.
This is a famous tricky-call
for the pathologist.
Future pathologists: Look for lobularity, with more cellularity at the edges than at the centers
Review,
emphsizing what's still not known: Clin. Orth. 439: 171, 2005.
* CHONDROBLASTOMA: a rare, benign tumor of primitive cells that stain as cartilage
Occurs in the legs of young people.
Most are very cellular and tend to focal calcifications, and there may be a few mitoses.
The "chicken wire" pattern of calcification is famous.
You probably won't recognize cartilage, at least easily, but the tumor cells stain for S-100, the cartilage marker.
CHONDROSARCOMA: the second commonest bone tumor (again not counting
metastases or plasma cell myeloma); sarcoma of cartilage, with a true hyaline-cartilage matrix
Primary chondrosarcoma arises most often in the pelvis in middle-aged men.
Prognosis depends on the grade:
* Grade I: mild cellular atypia (slightly anaplastic
nuclei, binucleate cells, two cells in a lacune,
mitoses; especially, encasing a bone spicule on all sides helps distinguish it from a
frisky enchondroma, which is the tough call)
* Grade II: crowded cells, perhaps a few bizarre cells
* Grade III: nasty-looking (includes "mesenchymal chondrosarcoma"; the only way
you may be able to make this hard call is by finding that it stains for type II collagen: Mod. Path. 18: 1088, 2005)
* Warning: Agreement among pathologists (even "bone tumor experts")
on the grade of a particular chondrosarcoma is notoriously bad: J. Bone Joint Surg. 89-A: 2113, 2007.
The Grade III lesions are by far the most likely to metastasize,
but when the lower-grade lesions recur locally,
the grade may be higher.
* For some reason, chondrosarcomas of the cricoid cartilage are fairly common.
Managing them is tricky.
Chondrosarcomas are notoriously unresponsive to chemotherapy and even radiation. And the basic
molecular biology remains almost completely unknown. Update Orthop. Clin. N.A.
37: 9, 2006.
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
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
Dan Hammoudi's Site
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
We comply with the
HONcode standard for trustworthy health
information:
verify
here. 
QUIZBANK
Muscle & soft tissue #'s 55-61
Musculoskeletal
Utah cases for path students
Juliana Szakacs MD
Fetal growth plate
WebPath Tutorial -- comments are down right now
Cancellous (lamellar) bone
Polarized light
WebPath Tutorial -- comments are down right now
Tulane Pathology Course
Great for this unit
Exact links are always changing
Bone and Soft Tissue
Great pathology images
Indiana Med School
Musculoskeletal Pathology
Virginia Commonwealth U.
Great pictures
Clinical Musculoskeletal Pathology
Go through IMC
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Bone Exhibit
Virtual Pathology Museum
University of Connecticut
{46508} osteoclasts, normal
{14647} osteoclasts, normal
INTRODUCING BONE
Don't worry about Haversian longitudinal systems or Volkmann's transverse / oblique
canals just now. I have no plans to review
bone physiology here. The plural of trabecula is trabeculae.
Parts of the long bone (i.e., a bone that formed from a cartilage model):
People's "bone structure" is widely variable,
and contributes (with muscle mass and body fat) to "build". (Long clavicles and narrow iliac
wings
contribute to "well-built" in a man, but muscle development
overrides these.)
Epidermoid inclusion cyst
"Solitary bone cyst"
NJ Med Pathology -- Case study
Open fracture
Not wearing a seat belt
WebPath Case of the Week
Clavicular pseudarthrosis (trust me)
Prize photograph
Institute of Medical Illustrators
{08994} healing fracture, histology
Healing fracture
WebPath Tutorial -- comments are down right now
Healing fracture
WebPath Tutorial -- comments are down right now
* Future pathologists: Here's a rough guide to the
x-ray dating of children's fractures.
Two days: Soft tissue edema is usually gone
Although the vast majority of osteogenesis imperfecta mutations
result from mutations in the type I collagen gene, there's a
recessive form resulting from a mutated protein (CRTAP)
required for the post-translational hydroxylation of proline (NEJM 355: 2757, 2006).
Watch this mutation site as a risk, in single dose, for osteoporosis.
{12402} osteogenesis imperfecta
{15795} osteogenesis imperfecta, blue sclera
{18255} osteogenesis imperfecta type II
{15801} osteogenesis imperfecta type II
{18256} osteogenesis imperfecta, x-ray
{15813} osteogenesis imperfecta, sutures not present
"Unbreakable" increased
public
awareness of
osteogenesis imperfecta.
Mr. Jackson is rather tall for...
Osteogenesis imperfecta
X-rays from Harvard
* Other alleles at collagen loci:
Stickler's syndrome: Gawky people with some degree of nerve deafness; COL2A1 (the
major type II collagen gene) or another
collagen locus: J. Med. Genet. 36: 353, 1999
The most common recessive gene is a defect in an ATPase that is
only expressed in osteoclasts (Am. J. Path. 162: 57, 2003).
{25688} achondroplasia
{49474} "achondroplasia" (looks like a thanatophoric dwarf to me, failure of rib development)
{53760} Apert's* PYCNODYSOSTOSIS
There seems to be a consensus today that artist Henri de Toulouse-Lautrec's
dwarfism and deformities were caused by PYCNODYSOSTOSIS.
Henri de Toulouse-Lautrec
There are a host of genetic syndromes involving bone, from
families where several members share a minor skeletal anomaly
to the horrible FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (formerly "bad myositis
ossificans"),
a dominant-but-variably-expressed
mutation (stay tuned; the locus remains elusive)
that causes overproduction of bone morphogenetic protein 4 in which wound
healing is accompanied by exuberant endochondral bone production.
Fibrodysplasia ossificans progressiva
25 year old man
From NEJM
Fibrodysplasia ossificans progressiva
Six year old girl
From Kaplan JBJSA 75A
Spongy bone can be infarcted easily wherever it has an end-artery pattern of vascularization
and the artery is compromised. This is most likely near the convex surfaces of joints.
The feared result is detachment of the articular cartilage (the dread "crescent sign" on x-ray).
The overlying cartilage and synovium / joint space will be spared.
,
though most of the common bacteria can produce osteomyelitis. In sicklers,
salmonella is the usual culprit, and drug abusers who mix their works with tap water are prone to
pseudomonas. In 50% or so of cases, you'll grow nothing, probably because
somebody gave an antibiotic already.
{39505} osteomyelitis, x-ray
{40090} osteomyelitis, draining sinus
Healing osteomyelitis
WebPath Tutorial -- comments are down right now
* CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS is a pediatric
disease. It is as bad as it sounds,
and as mysterious. It may run with Crohn's regional enteritis,
and has responded to TNF-alpha blockers (Pediatrics 116: 1231, 2005).
The acronym stands for synovitis,
acne, pustulosis, hyperostosis (bone bumps especially on the joints,
especially those of the chest), and osteitis. The cause is completely
obscure, but it's being recognized
more nowadays, and being treated effectively with anti-inflammatories, bisphosphonates,
and retinoic acid derivatives. See J. Neurosurg. 93: 693, 2000.
Syphilis
Skull showing old gummas
AFIP
Syphilitic periostitis, skull
Classic photo
Adami & McCrae, 1914
OSTEOMYELITIS
* Literature buffs: Elizabeth Barrett Browning ("Sonnets from the Portuguese", etc.) was completely
disabled by severe chronic pain from (probably)
Pott's disease for over a decade. When she was given free
access to morphine, she became a productive writer and much happier person. Despite ideology,
there may be a lesson here.
Elizabeth Barrett Browning
Pathology of Osteoporosis
WebPath Tutorial
The genes that predispose to osteoporosis are being discovered.
Heavy calcium intake (popular with the Tums manufacturers, of course) remains
"unproven" as a means of preventing the dread late effects of
osteoporosis. Children and teens are exhorted to take lots of calcium
to prevent osteoporosis in old age.
Not only are good current epidemiologic studies not there (meta-analysis BMJ 333: 775, 2006),
the idea also doesn't make sense -- osteoporosis reflects a lack of matrix protein,
not a lack of calcium.
Your lecturer believes that old work on plentiful calcium
preventing "bone loss" on x-ray resulted from its preventing osteomalacia (which
of course it often does), not osteoporosis. The two look the same on imaging studies. Go figure.
{13844} osteoporosis, histology (thin trabeculae)
Osteoporosis
WebPath Tutorial -- comments are down right now
Osteoporotic compression fracture
WebPath Tutorial -- comments are down right now
{46509} osteomalacia, thick unmineralized osteoid seams
{46510} osteomalacia, von Kossa stain for calcium (calcified is black, non-calcified is orange)
{12027} renal rickets
{12734} osteitis fibrosa cystica (osteoclast city!)
Certain locales have very high concentrations of fluoride ion in the
water. This is good for preventing dental caries (the teeth are very dark-mottled), but ultimately
causes hyperostosis of the skeleton.
The famous "paramyxovirus-like particles" seen in the osteoclast
nuclei have been spotted in a variety of other diseaes with abnormal
osteoclasts.
The same group that reviewed the viruses with negative results
also did not find somatic mutations in Pagetic bone, which is
good to know.
{18781} Paget's disease, skull
{09376} Paget's disease, bowed lower extremities
{09377} Paget's disease, bowed upper extremities
{38210} Paget's disease, histology
{18810} Paget's disease, histology
{13847} Paget's disease, histology
{13850} Paget's disease, polarized light; woven bone
Paget's osteitis deformans
WebPath Tutorial -- comments are down right now
Paget's osteitis deformans
WebPath Tutorial -- comments are down right now
* Worth mentioning here is another disease in which bone
mysteriously transforms, thankfully ultra-rare. GORHAM'S
ESSENTIAL OSTEOLYSIS features replacement of bone (usually a single one,
or part of one) by cavernous hemangioma (or maybe just nothing: Virch. Arch. 442: 400, 2003). For some reason, these patients
also tend to get a chylothorax if the spine is involved.
OSTEONECROSIS OF THE JAW (Clin. Tox. 45: 753, 2007; Am. J. Med. 121: 475.e3, 2008; South. Med. J. 101: 160, 2008):
This is a once-and-future major disease.
The bone and/or marrow becomes necrotic.
The disease is focal, most often just behind the lingual side of the canine teeth.
Sarcoma Images
University of Washington
Pictures and comments
* Here are two infamous trick pathology questions for rotations.
If you are asked, "What is the most common bone cancer?", you must ask,
"Do we include metastatic carcinoma?" This is the most common cancer in bone.
* One infamous fooler in radiology is the "sports tumor" of young
people, elevated periosteum and tremendous osteoblastic activity on scan where the adductor muscles attach to the femur:
Am. J. Roent. 176: 1227, 2001.
Osteosarcomas and Ewing's sarcomas are typically
treated with chemotherapy before resection, and the more necrosis seen
in the resected specimen, the better the prognosis.
Fibrous dysplasia
NJ Med Pathology
Case study
Aneurysmal bone cyst
WebPath Tutorial -- comments are down right now
Aneurysmal bone cyst
WebPath Tutorial -- comments are down right now
Aneurysmal bone cyst
WebPath Tutorial -- comments are down right now
* Results are widely variable. Some of the
failures probably were because the lesions weren't really
osteoid osteomas.
Osteoid osteoma
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Osteoid osteoma
WebPath Tutorial -- comments are down right now
* ADAMANTINOMA of bone appears benign
clinically, radiographically, and histologically (it recalls tooth enamel cells),
but is locally aggressive and occasionally metastasizes. In the jaw, we call
these ameloblastomas. Otherwise, it'll be in the shaft of the tibia.
Osteoid osteoma
NJ Med Pathology
Case study
Osteoblastoma
NJ Med Pathology
Case study
The tumor typically passes through the cortex, eventually eroding it, and
elevating the periosteum. "Codman's triangle" of new bone under elevated
periosteum is common.
* Rothmund-Thomson fragile-chromosome syndrome (RECQL4)
features an increased cancer risk, notably osteosarcomas (JNCI 95: 669, 2003).
Paget sarcomas are almost always high-grade and aggressive.
Around 90% are osteosarcomas, and 10% of them are non-osteosarcomas
(Arch. Path. Lab. Med. 131: 942, 2007).
{05906} osteosarcoma, gross
{05909} osteosarcoma, gross
{05927} osteosarcoma, gross
{05930} osteosarcoma, gross
{24747} osteosarcoma, gross
{21118} osteosarcoma, with pathologic fracture
{10322} parosteal osteosarcoma, gross
{05838} parosteal osteosarcoma, x-ray
{05864} osteosarcoma, histology
{25613} osteosarcoma, histology
{32123} osteosarcoma, histology
Parosteal osteosarcoma
WebPath Tutorial -- comments are down right now
Clickable osteosarcoma
WebPath Tutorial -- comments are down right now
Osteosarcoma
WebPath Tutorial -- comments are down right now
Osteosarcoma
WebPath Tutorial -- comments are down right now
Osteosarcoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Cartilage Exhibit
Virtual Pathology Museum
University of Connecticut
Osteochondroma
WebPath Tutorial -- comments are down right now
Osteochondroma
WebPath Tutorial -- comments are down right now
Osteochondroma
WebPath Tutorial -- comments are down right now
Osteochondroma
WebPath Tutorial -- comments are down right now
Chondromyxoid fibroma
NJ Med Pathology
Case study
Low-grade chondrosarcoma
Soap bubble x-ray
NJ Med Pathology -- Case study
Osteoblasts
Woven bone
Hyperparathyroid bone disease
Brown tumor
Brown tumor
Osteopetrosis
Achondroplastic dwarf
Adamantinoma
Enchondromatosis, 1870's