Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
No texting or chat messages, please. Ordinary e-mails are welcome.
|
|
|
 |
 |
 |
 |
 This site complies with the HONcode standard for trustworthy health information: verify here. |
This website collects no information. If you e-mail me, neither your e-mail address nor any other information will ever be passed on to any third party, unless required by law.
This page was last modified July 5, 2010.
I have no sponsors and do not host paid advertisements. All external links are provided freely to sites that I believe my visitors will find helpful.
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. Ordinary e-mails are welcome.
DoctorGeorge.com is a larger, full-time service.
There is also a fee site at
at www.afraidtoask.com.
|
|
 If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office. |
|
 |
With one of four large boxes of "Pathguy" replies. |
I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
pathology.org -- my cyberfriends, great for current news and browsing for the general public
EnjoyPath -- a great resource for everyone, from beginning medical students to pathologists with years of experience
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.
Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.
Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.
Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.
If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.
I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!
Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.
This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.
During the fifteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at KCUMB
for making it possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!
LEARNING OBJECTIVES
Give short accounts of these non-neoplastic conditions:
Give accounts of these proliferative, benign, and "low-grade malignant" neoplastic
breast lesions, recognize obvious
examples microscopically, and tell the significance to the patient:
Recognize easy examples of ductal carcinoma in situ,
and distinguish the ones that are more likely to be aggressive.
Recognize non-infiltrating lobular carcinoma. Recognize Paget's
clinically and microscopically. Explain the significance of each.
Give an account of the risk factors, etiology, pathogenesis,
clinical findings, gross and microscopic pathology, metastatic patterns,
prognostic signs,
and lab workup (including markers) for each of the common types of
invasive breast cancer. Focus on the "why"'s when they are known.
Mention distinctive features of breast cancer in the male.
Read a breast biopsy with reasonable accuracy.
Accurately deal with patient questions about supposed health
hazards of breast implants.
Give a short account of how pop claims arise and how physicians should evaluate them.
We have often seen in the breast a tumor exactly resembling the animal the crab. Just as the crab
has legs on both sides of his body, so in this disease the veins extending out from the unnatural
growth take the shape of a crab's legs. We have often cured this disease in its early stages, but after
it has reached a large size no one has cured it without operation. In all operations we attempt to
excise a pathological tumor in a circle in the region where it borders the healthy tissue.
QUIZBANK Breast (all)
REVIEW OF ORIGIN, ANATOMY, PHYSIOLOGY
{47710} {47732} {47725}
The anatomy and the physiology of the breast should be familiar to you.
* One does not have to be a breast-feeding militant to
take issue with Rubin & Farber's past statement that "The breast has become
biologically superfluous in advanced societies."
The areolar tissue is pigmented, with smooth muscle and elastic
fibers. There are a few apocrine glands here. Montgomery's areolar
sebaceous glands (which prevent chapping) undergo hyperplasia during pregnancy; they
are the little bumps. No one knows what "Toker cells" (clear cells in the epidermis
of the nipple that can be mistaken for Paget's) really do.
The breast is composed of a system of branching ducts draining
into
6-12 lactiferous ducts. The systems are extensively intertwined,
and I would urge you to ignore talk about "separate lobes".
Elastic fibers surround the lactiferous ducts and their branches.
The lactiferous duct widens to become the lactiferous sinus underneath the nipple.
Little groups of terminal ducts / acini are surrounded by a solid fibrous
stroma. The stroma between these units is fibrofatty.
As a woman gets older, there is usually more fat relative to stroma
in the breast. This
shows cancers (which are non-fatty) to advantage on mammography.
The duct system branches several times and ends in the collecting ducts
(terminal ducts, interlobular ducts).
Terminal ductules (intralobular ductules) branch off the collecting duct. One collecting duct
and its terminal ductules and acini, plus the accompanying stroma,
is called a "lobule".
You can recognize lobules in normal breast because
the stroma is looser and contains less fat and no elastin,
and the little ductules and acini are clustered together.
During pregnancy, true secretory units sprout from each terminal duct,
coming to dominate the breast histology. After delivery, milk production
begins. You may see secretory units in a woman whose breasts
have become tender during the first few cycles on the oral contraceptive
pill, or "for no reason".
It's not clear to me that the male breast "is relatively
insensitive to hormonal
influences" (as Big Robbins once told us); men simply have little estrogen
and less progesterone on board. Hence the breast tissue does not
develop except under unusual circumstances.
Hormones to remember: During pregnancy, estrogen and progesterone prevent the milk from being
produced. When the pregnancy ends, lactation begins soon. Stimulation
of the nipple causes production of both prolactin (which keeps lactation going)
and oxytocin (which makes the milk come down).
At all levels of the duct-and-acinar system, there is a single
layer of myoepithelium. You can stain it for smooth-muscle-actin or S100 or high-MW keratin
or smooth-muscle myosin heavy-chain (probably best).
This contracts in response to oxytocin
to let the milk come down.
During the second half of the monthly cycle, progesterone causes some proliferation
of ducts and stroma in the lobules. When the cycle ends, these changes regress.
After menopause, the lobules may
vanish, leaving only the larger ducts.
Mother's hormones may produce some breast development in the
newborn baby girl, and there may even be a bit of secretion ("witch's milk").
You remember that some breast parenchyma extends toward the
axilla as the "tail of Spence". Generally, the upper outer quadrant of the breast is the most massive
anyway, which probably explains why most breast diseases are most common here.
{20793} normal breast
You should remember the duct cells, lobules, and myoepithelial cells.
You remember the anatomic "milk line" (check on most non-human female mammals).
Supernumerary nipples and supernumerary breasts (polythelia and polymastia) arise here, and are
very common. Accessory breasts may or may not have nipples, but undergo the same changes
during menstruation, pregnancy, lactation, and carcinogenesis as normal breast does.
DEVELOPMENTAL PROBLEMS
INVERTED NIPPLES are common, especially in larger breasts,
and may make nursing more difficult. If a previously-normal nipple
inverts, you have a problem, i.e., something has retracted underneath, and it's the stroma of a cancer
until proven otherwise.
JUVENILE HYPERTROPHY ("virginal hypertrophy"): very large breast(s) developing around puberty. Really hyperplasia, of
course. The etiology is unknown, and occurrence is usually sporadic,
though a familial syndrome is reported (J. Adol. Health 35: 151, 2004).
(Nowell's law at work, probably.)
{49360} giant fibroadenoma in a teen
HYPOMASTIA: almost complete failure of breast development. (* Around half of these women have
mitral-valve prolapse. See NEJM 309: 1230, 1984.)
By contrast, very large breasts are likely to cause serious low-back problems.
{49359} hypoplasia of breast
INFLAMMATIONS: Not common.
ACUTE MASTITIS and BREAST ABSCESS: Usually occurs during early lactation. (In a non-lactating
woman, the usual problem is a pre-existing dermatitis).
The bug is usually staph aureus FAT NECROSIS: A solid mass, often in a fat breast, caused by a blow or other injury. Necrotic fat cells
surrounded by a mixed inflammatory infiltrate, later with calcification, foreign body reaction,
scarring. Before there was much notice paid to domestic
violence, the etiology was "mysterious".
PERIDUCTAL MASTITIS ("recurrent subareolar abscess"): A hyperkeratinizing
squamous metaplasia going too far down a lactiferous duct. This gets inflamed
and needs to be cleaned up by a surgeon.
Almost all these people are smokers, and both men and women are affected.
DUCT ECTASIA: An uncommon cause of a breast mass, usually in older women, usually tender and
with nipple retraction. Chronic inflammation and fibrosis around ducts are typical. The ducts are
loaded with a lipid-and-macrophage rich material. The cause is unknown;
an old reported link to prolactinoma has not held up.
* "Plasma cell mastitis", an old diagnosis,
is probably just duct ectasia with a lot of plasma cells. * LYMPHOCYTIC MASTOPATHY is evidently an autoimmune disease.
It runs with Hashimoto's thyroiditis and type I diabetes. These lesions are patchy
but may produce masses.
* GESTATIONAL GIGANTOMASTIA is a thankfully rare, severely-crippling disease
in which a pregnant woman's breasts become enormous, become ulcerated, get infected,
etc., etc. It resolves after delivery and recurs with subsequent prenancies.
Review and algorithms: J. Plast. Recon. Surg. 118: 840, 2006.
* Probably the rarest breast disease with a name is
INFLAMMATORY GIGANTOMASTIA, featuring enormous overgrowth of the breast
stroma and atrophy of the lobules, with lymphocytes around the ducts
and anti-nuclear antibodies (J. Clin. Endo. Metab. 90: 5287, 2005; disturbing images).
* GRANULOMATOUS LOBULAR MASTITIS (Pathology 36: 254, 2004;
J. Am. Coll. Surg. 206: 269, 2008)
is confined to the breast lobules.
All these women have been pregnant. Probably there is some autoimmune
reaction against the secretory units. GALACTOCELE: One or more ducts became plugged during lactation.
MONDOR'S DISEASE is thrombophlebitis of one or more subcutaneous
veins of the breast, a minor mystery that is usually harmless (NEJM 352: 1024, 2004).
Check for an underlying cancer.
RUPTURE OF AN IMPLANT is commonplace, and in fact the fibrous capsules
that ordinarily form around implants helps contain this.
How radiologists tell whether the implant has ruptured: Plast. Rec. Surg. 120: 495, 2007.
{49350} lipogranuloma from ruptured polyethylene breast implant
"FIBROCYSTIC CHANGE OF THE BREAST" (don't call it mammary dysplasia, chronic cystic
mastitis, etc.)
This is the commonest "disease" of breast (exactly how common is debatable).
It presents as a lump or lumps. Actually, it is always multifocal.
The cause, of course, is obscure. Unopposed estrogen is a known factor, and
in the 1970's we noticed that women on the
estrogen-progesterone balanced pills get less fibrocystic disease.
Despite much "pop" / "medical" wisdom, there's not much to suggest
that modifying a lady's diet will help her fibrocystic disease:
J. Am. Diet. Assoc. 100: 1368, 2000.
* Toremifene (the estrogen receptor modulator that blocks estrogen effects) for premenstrual mastalgia: BJOG 113: 713, 2006.
Three patterns occur separately or together:
1. fibrosis
2. cyst formation (>3 mm)
3. adenosis
FIBROSIS: dense collagenization distorting and compressing the epithelial structures.
This is most common in upper outer quadrants, patients in 30's.
Your lecturer cannot agree with "Big Robbins's" old claim that the fibrosis
results from ruptured cysts. If the cysts were filled with water, there
would be no reaction. If the cysts were filled with something else,
there would be a macrophage reaction, which you don't see in "breast fibrosis".
CYSTS: dilated ducts containing cloudy serous fluid (sometimes bloody or infected)
All breasts during childbearing years contain microscopic cysts.
They are abnormal when they got
larger than 2 mm or so.
Grossly, the blue-dome cyst is very familiar. Epithelium may be flattened, cuboidal, columnar,
piled up, and/or show apocrine metaplasia. Surrounding stroma likely to be fibrous. Cysts likely
to be tender before menses and after drinking coffee.
ADENOSIS: {21062} fibrocystic changes, breast
PROLIFERATIVE BREAST DISEASE (review NEJM 353: 229, 2005)
2. Sclerosing adenosis
3. Small duct papillomas
EPITHELIAL HYPERPLASIA means more than the usual two layers of cells in
ducts and/or lobules. At
least one layer will be myoepithelial cells.
Cells are piled up and may even fill ducts and/or ductules.
Between the heaps of cells, you will see cracks and crevices, and at least
the bottom layer will be myoepithelium. Most often, there is a mixed population of cells.
If there is some anaplasia of architecture (i.e., swiss cheese)
or cells (ugly nuclei), but you can't quite diagnose ductal carcinoma in situ,
you may diagnose ATYPICAL DUCTAL HYPERPLASIA or ATYPICAL LOBULAR HYPERPLASIA / NEOPLASIA,
depending on location. The cells
do not fill the ducts or acini, as cells of an official "in-situ cancer" would.
Don't try to figure out exactly where
to draw the line between "atypical
hyperplasia" and "carcinoma-in-situ", because the line is obviously
a cultural
construct with little-or-no biological meaning. "Low-grade CIS" is only slightly
more likely to progress to invasive cancer and death than is "atypical
hyperplasia."
Since "atypical epithelial hyperplasia" gives a woman
at least five times her baseline chance of getting breast cancer,
and since one woman in nine will get breast cancer in her lifetime,
you'll want to follow these women closely.
FLAT EPITHELIAL ATYPIA, only recently characterized and about as
premalignant as atypical epithelial hyperplasia, consists of a stratified
epithelium with architectural atypia (scrambled cells) and some cellular atypia,
recalling dysplasia in the cervix (Hum. Path. 38: 35, 2007; Arch. Path. Lab. Med. 132: 615, 2008).
Often there's nearby atypical hyperplasia or worse, and if this is found, say,
on a needle biopsy, wider excision is in order.
Review of "flat ductal intraepithelial neoplasia" of the breast: Arch.
Path. Lab. Med. 133: 879, 2009.
* No one knows quite what to make of "columnar cell change",
in which the cells become tall and skinny, often in the setting
of some other hyperplasia. This has been reviewed and beyond it being
a sign of genetic instability, there's little else to conclude -- simply look
for the presence of atypical hyperplasia elsewhere in the same biopsy
(Am. J. Surg. Path. 29: 734, 2005; Cancer 113: 2415, 2008).
SCLEROSING ADENOSIS: proliferation of small ductules and sometimes even acini in a fibrous stroma.
This
mimics cancer both clinically and microscopically. Usually it's
a tender lump in the upper outer
quadrant. Patients are usually around age 30-40.
Tipoffs that you are looking at sclerosing adenosis rather than cancer:
(1) There'll always be myoepithelium, for which you can stain
(smooth-muscle actin, S100, high MW keratin).
(2) The normal
lobular architecture is preserved, though lobules may be expanded.
This is a low-magnification diagnosis.
(3) Sclerosing adenosis can be hard, but it
never cuts "gritty" like many breast cancers. {25570} sclerosing adenosis
* One particularly treacherous
sclerosing adenosis variant is "microglandular adenosis",
round uniform glands everywhere, even in the fat, no myoepithelium,
but with no anaplasia
and no desmoplasia. Thankfully, this hated lesion
stains positive with S100. It seems to be premalignant,
though most excisions are curative. (Arch. Path. Lab. Med. 131: 1397, 2007).
SMALL DUCT PAPILLOMAS seldom produce masses. These possess
fibrovascular cores, with epithelial hyperplasia-type lesions on the top.
Leave the diagnosis of actual malignancy in such lesions to us.
All of these have a multiplicative risk with familial history of breast
cancer, i.e., these benign lesions are probably are caused by mutations
of genes other than BRCA1, BRCA2, and p53.
RADIAL SCAR is a star-shaped fibrosing lesion that looks
like a typical crablike cancer on mammography but that proves utterly
benign on excisional biopsy and confers no increased
cancer risk. A larger version is called COMPLEX
SCLEROSING LESION. See Am. J. Surg. 180: 428, 2000.
FIBROADENOMA (pathology: Am. J. Clin. Path. 115: 736, 2001)
The most common benign breast tumor, occurs at any time during reproductive life, most often
under age 30.
It presents a small, sharply circumscribed, usually single, freely movable nodule within the breast substance.
A loose stroma surrounds ducts that are often crushed flat.
* Ignore the old distinction between pericanalicular and intracanalicular fibroadenomas.
{08461} fibroadenoma, gross
PHYLLODES TUMOR: a bad term for a "worrisome fibroadenoma" that exhibits two epithelial
cell layers along with a dense, metaplastic
and/or anaplastic stroma, a clefted (artichoke-like) gross appearance,
and supposedly rapid growth. The old name was
"cystosarcoma phyllodes" (especially
unfortunate since cysts are rare).
If it metastasizes, it will usually be as a sarcoma. But most patients do not develop metastases.
Pathologists are now reporting these as "benign" or "malignant" (the latter can metastasize as the
corresponding sarcoma). However, predicting behavior based on histopathology
isn't very reliable, and adding molecular markers (c-kit, p53, Ki-67) doesn't
really help either (nice review though, Arch. Path. Lab. Med. 130: 1516, 2006).
Update Arch. Path. Lab. Med. 131: 1568, 2007.
"Phyllodes" means "leaves", referring to the artichoke-like gross appearance of many
of these tumors.
It's interesting to speculate about how both epithelium and stroma overgrow in a fibroadenoma or a
phyllodes tumor. Since stromal mitoses are much more common adjacent to epithelium, the
epithelial cells are probably producing a factor that causes stromal overgrowth. In fully malignant
phyllodes tumor, the stroma becomes an autonomous sarcoma (Nowell's law again). See
Cancer 70: 2115, 1992; clinical review Cancer 77: 910, 1996.
LARGE DUCT PAPILLOMA This is a little (less than 1 cm) lesion in a major duct just below the nipple.
It produces bloody nipple discharge when bits twist and break off.
Occasionally it causes nipple retraction.
{20230} intraductal papilloma
One in 100 of these tumors is actually a papillary carcinoma. (This is a hard call. Do not expect your
pathologist to call these tumors benign or malignant on frozen section.)
All about papillary lesions of the breast: Arch. Path. Lab. Med. 133: 893, 2009.
Future radiologists: Visualize them using a galactogram, injecting dye into each of the
lactiferous sinuses (Am. J. Roent. 159: 487, 1992.)
INTRODUCING CARCINOMA OF THE BREAST ("breast cancer").
{00120} breast carcinoma, gross, skin dimpling
This is the commonest cancer in women (though no longer the #1 cancer killer), and still "the most
feared cancer" -- justifiably so!
There were around 180,000 new cases of breast cancer in 2007
in the U.S., and 41,000 deaths. (Of these, 2500 new cases will be in men, and 450 of these men will die of it.)
It is rare before age 25, and of course more common with increasing age.
Around 1 in 9 women will develop breast cancer during her life.
Breast cancer usually presents as a dominant, painless mass. Nowadays
it is often found on mammography long before symptoms appear. Remember
that 10% of breast cancers do not show up on mammography.
"Risk factors" (big review Lancet 346: 883, 1995):
Every ethnic group has a high incidence of breast cancer; American Indians have the least.
You'll go crazy trying to sort out all the studies, but the
key to protection is evidently the amount of time the woman has spent
lactating.
* A history of bilateral cancers and/or onset in a young women suggests a familial tendency.
Early-onset familial breast cancer is usually due
to germline mutations of BRCA1 or BRCA2, less often Cowden's, e-cadherin (see below),
Fanconi (FANC), CHEK2 (the supposed "Li-Fraumeni 2"), ataxia-telangiectasia (ATM),
Peutz-Jeghers, or Li-Fraumeni (TP53).
Of these, only BRCA1, BRCA2, and TP53 give a tremendous risk (10- to 20-fold.)
The rest are statistical associations ("less than twofold" to "two-to-fourfold").
Not surprisingly, BRCA1 tends to be lost in sporadic breast
cancers, though not by mutation (Nat. Genet. 21: 236, 1999); * "Big Robbins"
merely notes that BRCA1 mutations are uncommon in sporadic breast cancer.
You can't spot hereditary breast cancer syndromes by morphology.
It's generally known that BRCA1-deficient women tend to have
cancers with big cells, high mitotic rates, pushing borders, and lots of
lymphocytes; the morphology is often "medullary" by classic histopathology and the
immunophenotype is
"basal-like" (J. Clin. Path. 61: 1073, 2008; Arch. Path.
Lab. Med. 134: 130, 2010). Claims that
certain subtypes suggest BRCA2 deficiency haven't held up well.
* An attempt by insurers to deny benefits
to breast cancer victims with germline BRCA1 mutations "because it was a
pre-existing condition"
(Science 272: 1094, 1996) led to Uncle Sam making it
illegal for insurance companies to
consider genetic predisposition a "pre-existing condition" and denying coverage
(thanks Bill). The really good genetic non-discrimination bill
was passed only in 2008 (bipartisanship).
* Women are now coming in for prophylactic bilateral mastectomies
because they have the genes and/or a strong family history. This cuts the risk
by at least 90% -- but not entirely, since the breast is not a sharply-circumscribed
organ (NEJM 340: 77, 1999). These resected breasts are usually
normal on pathologic study: Arch. Path. Lab. Med. 124: 378, 2000.
A woman who chooses this option at age 30 adds 3-5 years
to her life expectancy (NEJM 336: 1465, 1997); what's more, patients seem to be
very happy about this (JAMA 284: 319, 2000).
* As noted, ataxia-telangiectasia carriers may be at extra risk; this continues to be discussed
(Mayo Clin. Proc. 72: 54, 1997).
A non-disease allele here is known to be more common in breast cancer patients
than in controls (Cancer 100: 1345, 2004).
The "balanced" estrogen-progesterone pill for post-menopausal women
seems to increase the risk even more: JAMA 283: 534, 2000.
Estrogen replacement as a risk factor for breast cancer after menopause
remains controversial. Most past studies have indicated no link
(Cancer 95: 960, 2002
found a link for Hispanic women).
Especially see JAMA 268:
1900, 1992. The latter authors decided that probably women who get estrogen replacement go to
the doctor more and get early detection of their breast cancers (sound familiar?)
Even the recent article that caused the hoopla over estrogen replacement
(JAMA 288: 872, 2002) didn't show a believable link.
* Watch for raloxifene ("Evista"), a medicine that was initially reported
as working as an estrogen
on bone, and an anti-estrogen on breast, as a handy drug for post-menopausal
women (JAMA 28: 2189, 1999). Since its introduction almost a decade ago,
it does seem to help slow osteoporosis and diminish the risk for
breast cancer, but at the price of increased risk of venous thromboembolism
and fatal stroke (NEJM 355: 125, 2006; J. Clin. Endo. Metab. 91:
3941, 2006).
* The conventional wisdom that estrogen replacement is absolutely
contra-indicated in women who have had breast cancer is now
being reconsidered: Geriatrics 57: 25, 2002; Am. J. Ob. Gyn. 187:
289, 2002.
* The "melatonin hypothesis", currently popular, links low melatonin levels
to breast cancer; the evidence includes claims that nurses who work night shifts
have greater risk, and that blind women have only half the rate of breast cancer.
Normal breast epithelial cells are loaded with melatonin receptors (Am. J. Clin. Path. 118: 451, 2002).
I predicted in 2002 that "the melatonin hypothesis" was based on recall bias
and would soon be discredited, and now one major
study found no relationship (JNCI 96: 475, 2004).
NOT risk factors... * The pop claim that antiperspirants
cause breast cancer is simply a lie.
The oral contraceptive pill is not a risk factor (at least I'm satisfied; NEJM 346: 2025, 2002
supports much previous work). Nor is intrauterine DES exposure (Cancer 107: 2212, 2006).
There is still talk of high-fat, low-fiber diet being a risk factor; I saw the earlier studies and was
totally unimpressed. In a study in which the researchers controlled for other risk factors, all
correlation between diet and breast cancer vanished (JAMA 268: 2037, 1992);
another big negative study: JAMA 281: 914, 1999, more recently
Am. J. Med. 113(S9B): 63S, 2002.
In a review of Adventist diet studies (they eat little or no meat),
the folks at Harvard, not noted for political incorrectness,
pointed out that Adventist women have at least as high a rate of
breast cancer (and men of prostate cancer) as meat-eaters.
The authors even cite (in my opinion weak) studies in which
vegetarianism seemed to be a risk
for breast cancer. The authors seemed to consider the
claimed link between fat consumption and breast cancer to be
fully discredited by the time the paper was written.
Am. J. Clin. Nutr. 78(S3):
539-S, 2003.
* Pregnancy after treatment for breast cancer does not increase the risk
of a bad outcome (Lancet 350: 319, 1997).
* Residental magnetic fields (Am. J. Epidem. 155: 446, 2002) -- let's get real.
* Some anti-abortion activists claim that having an abortion will increase the woman's later risk of
getting breast cancer. The Bush administration seems to have endorsed this claim
(Nat. Med. 10: 759, 2004),
but nevertheless it is probably not true.
Now is as good a time as any to bring up "statistical relationships" and the
problems they cause. For starters, there seems to be a massive reporting bias (i.e., women with
breast cancer confess to having had an abortion, healthy women deny it: Am. J. Epidem. 134: 1003,
1991). The Swedes keep records rather than relying on patient reports, and when these were
checked the effect disappeared (Br. Med. J. 299: 1430, 1989). A study from New York based only
on examination of reports of fetal deaths and breast cancer cases found a positive correlation; but
they did not take into account whether and when the women had term pregnancies. See also Int. J.
Cancer 48: 816, 1991. JAMA 275: 283, 1996 & 276: 31, 1996 indicated that there's small, if any,
increased risk from an elective abortion. NEJM 336: 81, 1997 found no overall risk.
Nor did Am. J. Pub. Health 89: 1244, 1999.
Neither did Br. J. Cancer 79: 1923, 1999.
Neither did Science 299: 1498, 2003.
Neither did Lancet 363: 1007, 2004 (I think this one should have closed the book).
Neither did the Scotch study (J. Epid. Comm. Health 59: 293, 2005).
A slight, probably bogus, protective effect from having had an abortion:
Int. J. Cancer 110: 443, 2004 (Boston).
No effect in African-Americans: Cancer Caus. Contr. 15: 104, 2004.
No effect from either spontaneous or induced abortion: Arch. Int. Med. 167: 814, 2007 (prospective cohort study).
You had still better mention
this "controversy" in "informed consent" if you are going to do abortions, though
by now the claim (which enjoyed a vogue with tort lawyers and state legislatures) has run
afoul of "Daubert", the anti-junk-science law.
* In the early 1990's, Greenpeace launched a massive campaign, directed
at the public, claiming that
organic chlorine compounds in industrial pollution
are the great cause of breast cancer today.
Supposedly these are estrogens and also cause
increased oxidative damage to DNA; however women
with breast cancer don't have any more of oxidative damage to DNA, or organochloride
compounds on board, than do controls
(Arch. Env. Contam. Tox. 41: 386, 2001; Env. Health Perspect. 109 (S1):
35, 2001).
Greenpeace's inflammatory rhetoric was typical of
junk-science-based disinformation campaigns
("Paradigm shift!" "Scientific-medical
establishment!").
The left breast is involved a few % more cases than the right. That's probably because the left
breast
is a few % bigger.
There are a host of tumor types that we'll cover now.
NONINVASIVE ("IN SITU") CARCINOMA
DUCTAL CARCINOMA IN SITU ("DCIS")
Of course, to confirm that the cancer is non-invasive, the savvy pathologist
can stain the myoepithelial cells.
Smooth-muscle myosin heavy chain is most popular today (SMMHC J. Clin. Path. 57: 625, 2004).
Please learn the Van Nuys grading-and-treatment scheme
for non-infiltrating ductal carcinoma: Lancet 345: 1154, 1995:
1: No necrosis (lumpectomy, skip the radiation)
2: Necrosis but no ugly nuclei (lumpectomy, maybe radiation)
3: Ugly nuclei (lumpectomy-radiation or mastectomy)
* Just to confuse you, here is the popular Scarff-Bloom-Richardson
for giving an architectural grade:
2: Can't decide
3: Comedocarcinoma
* And here's the latest synthesis:
Add 1 point if the tumor is 10 mm or more from the nearest margin,
add 2 if it is 1-9 mm, add 3 if it is <1 mm.
Add 1 if the tumor itself is <=15 mm across, add 2 if 16-40 mm,
add 3 if >41 mm.
Final scores of 3-4 have a 4% recurrence rate, 93% 8-year disease-free.
Final sores of 5-7 have 11% recurrence rate, 84% 8-year disease-free.
Final scores of 8-9 have 26% recurrence, 61% 8-year disease-free.
Low-grade ductal carcinoma, if left alone, turns invasive in maybe half
of patients, though often decades later. If an invasive cancer does
develop, usually it is at the site the the DCIS was (Cancer 103: 2481, 2005).
COMEDOCARCINOMA (solid intraductal proliferation, central necrosis)
is the most common. Unlike the other "DCIS" lesions, the cells of
comedocarcinoma are usually quite anaplastic and vary widely in size.
It resembles blackheads on gross exam, and the necrotic cores
can be squeezed out. Often the necrotic cores calcify, making them easy to spot
on mammography.
SOLID DCIS simply fills ducts. The cells are monomorphic
and monotonous; the nuclei may be big-ugly or small-tame.
CRIBRIFORM DCIS is swiss-cheese. As before, don't ask where "atypical intraductal
hyperplasia" ends and "cribriform DCIS" begins. Stupid lawsuits occur over this.
PAPILLARY DCIS looks like the papillary lesions of proliferative
breast disease, with fibrovascular cores, but has a monomorphic cell population.
MICROPAPILLARY DCIS is little mounds of cells along the wall without fibrovascular cores.
If it turns invasive, it is highly aggressive (Am. J. Clin. Path. 121: 857, 2004;
Arch. Path. Lab. Med. 129: 1277, 2005; Am. J. Clin. Path. 126: 740, 2006),
and just finding it on biopsy is ominous (which doesn't square with the older
idea that it's low-grade: Am. J. Clin. Path. 128: 86, 2007).
PAGET'S DISEASE OF THE NIPPLE: Intraepithelial growth of
large, pale, mostly-single cancer cells in the nipple. It looks inflamed. There is most often an
underlying duct carcinoma (with today's imaging studies, the vast majority have
a tumor that you can find: J. Am. Coll. Surg. 206: 316, 2008). Paget's with origin
in Toker cells: Virch. Arch. 441: 117, 2002. Do NOT treat "eczema of the nipple" with cortisone without further
studies!
* Any DCIS extending in the ducts may produce "cancerization of lobules" (i.e., filling
the terminal ductules in a lobular unit). This probably doesn't mean anything
prognostically (Am. J. Clin. Path. 834: 1999).
{10931} Paget's disease of breast, gross
* Radiation added to simple excision cuts the rates of recurrence
(more DCIS and invasive cancer), but even without radiation, fewer than 20%
of women recur after excision (Lancet 355: 528, 2000).
While we're talking about radiation... if the margin of excision is 10 mm or more,
radiation clearly gave no benefit, 1-9 mm was a weak effect,
1 mm or less, radiation clearly helped prevent recurrence (NEJM 340: 1455, 1999).
* DCIS WITH MICROINVASION usually is comedocarcinoma with invasive
cancer confined to 1 mm away from the ducts. The prognosis is better
than if it were deeply invasive (Am. J. Surg. Path. 24: 422, 2000).
{12527} intraductal breast carcinoma, comedocarcinoma pattern
NON-INFILTRATING (IN SITU) LOBULAR "CARCINOMA"
This is a distinctive proliferation of tame-looking cells,
slightly larger than normal, filling the ductules of one or more lobules.
The lobules are expanded but not distorted.
Often there are signet-ring cells.
It heralds (around 30% of the time)
infiltrating ductal or lobular carcinoma; however, the invasive
cancer is just as likely to be in the opposite breast.
"Lobular CIS" is usually
an incidental finding when tissue from the breast is excised and examined for some
other reason. As you'd guess, if you get a chance to examine both
breasts, it's usually bilateral.
ATYPICAL LOBULAR HYPERPLASIA / NEOPLASIA is on a continuum with this lesion, but the
cells are not so crowded. Both lesions, and the lobular carcinomas to
which they give rise, predictably stain negative for e-cadherin.
Ask a clinician whether to put a woman with either diagnosis on tamoxifen for five years
to prevent cancer.
{15525} lobular carcinoma in situ
INFILTRATING (INVASIVE) BREAST CARCINOMA
NO SPECIAL TYPE (NST) ("usual type", "undifferentiated", etc.)
About 75% of infiltrating ductal carcinomas are of this type.
Most of these are stellate or micronodular, and quite hard, and these are called "scirrhous". Such
tumors are chalky-white flecked with yellow (elastin bands) on cut section.
Cutting the tumor produces the gritty
sensation of cutting an unripe pear. Don't be surprised by the presence
of elastin in these tumors; you know that healthy breast ducts are suspended by elastin
fibers.
Microscopically, "scirrhous" carcinomas with cells often arranged in nests or cords or
streams in a very
desmoplastic stroma. Although the books tell you that single-file "Indian file"
arrangement of cells is more typical of invasive lobular carcinoma, you can see
it often enough in a scirrhous cancer arising from ducts.
The cells usually do not look very malignant. Elastic fibers may be
prominent.
MEDULLARY CARCINOMA
Big, bulky, and soft. Lymphocytes are plentiful among the tumor cells, perhaps
because the cells express HLA-DR strongly (nobody knows why). The prognosis is slightly
better than that of other types. (Do you think it's all those
lymphocytes fighting the cancer, or that this tumor is a distinct
disease? Maybe both.)
This type of cancer is much-overrepresented
among women with mutated BRCA1 syndrome (Lancet 349: 1505, 1997).
MUCINOUS CARCINOMA (colloid carcinoma, gelatinous carcinoma) (Am. J. Clin. Path. 127: 124, 2007; Am. J. Surg. 196: 549, 2008).
Clumps of cells in lakes of mucin. Grossly, the tumor is a gelatinous mass. Relatively favorable
prognosis.
* Pitfall: A "mucocele", looking perfectly benign, may be present next to an invasive
mucinous carcinoma (J. Clin. Path. 61: 11, 2008).
* ADENOID CYSTIC: Very low aggressiveness in the breast (Cancer 94:
219, 2002)
PAPILLARY CARCINOMA
This is the one breast cancer that we think really
arises from the large ducts. Leave the distinction between benign
and malignant papillary lesions
to the pathologists.
{15488} carcinoma of breast, colloid type
TUBULAR CARCINOMA
Well-formed glands usually one cell-layer thick. Best prognosis for any breast carcinoma, very little
mortality. If there are no metastases to the regional lymph nodes, a cure is near-certain.
You can tell this from microglandular adenosis because there'll be
impressive desmoplasia and the glands will be angulated. Usually the tumor
is star-shaped grossly.
METAPLASTIC CANCERS (several subtypes -- squamous, spindle-cell carcinoma,
mixture with a true sarcoma, mixture with benign- or malignant-looking
cartilage): Nobody really
knows how this happens. Perhaps the cell of origin is myoepithelium. All metaplastic
carcinomas tend to be aggressive: J. Clin. Path. 59: 1079, 2006; Am. J. Surg. 191: 657, 2006
INVASIVE LOBULAR CARCINOMA (10% of infiltrating breast cancer).
Infiltrating lobular carcinoma is famous for its cells arranged
in Indian files. The cells tend to be very small and to lack
much anaplasia; they look like the cells of lobular carcinoma in situ
and often include signet-ring cells.
If you see them making circles around the ducts, the diagnosis is
a cinch, but an experienced pathologist can recognize these cells anywhere.
Such tumors are often multifocal within a breast, and are often bilateral.
Lobular carcinoma is infamous for spreading to the arachnoid and to bone.
The molecular signature of lobular carcinoma (and its precursors,
atypical lobular hyperplasia / neoplasia and lobular carcinoma in situ) seems to be complete loss of e-cadherin expression; this
is now a robust finding, sensitive and specific (Am.
J. Clin. Path. 125: 377, 2006). Not surprisingly,
there is a germline mutation and cancer family syndrome JAMA 297:
2360, 2007. This also probably explains the
classic anatomic pathologist's observation that the cells
of lobular cancers and pre-cancers seem not to stick to one another.
There are subtypes that influence prognosis. You can read about them
in Cancer 113: 1511, 2008.
* When a morphologic ductal and a morphologic lobular carcinoma arise
in proximity in the same patient, they share mutations, i.e., both evolved
from the same pre-cancer. See Am. J. Clin. Path. 132: 871, 2009.
* All the lobular lesions of the breast: Arch. Path. Lab. Med. 133:
1116, 2009.
{15484} carcinoma of breast, infiltrating lobular type
When examining these patients, look for:
** bad prognosis, of course
A majority of breast cancers arise in the outer quadrants, particularly the upper outer quadrant, and
the left breast is slightly more often affected than the right one (because it's
slightly larger naturally).
We used to teach that the single most important prognostic indicator in a case of breast cancer is the
size of the tumor at presentation. Now it's clear that the presence or absence of metastatic tumor in
the axillary lymph nodes is even more important (Cancer 70(6S): 1755, 1992).
Today, histology competes with rapid reverse-transcription-PCR technology
for mammaglobin and cytokeratin 19 mRNA on sentinel nodes:
Ann. Surg. 247: 136, 2008.
Even micrometastatic disease in the sentinel node is ominous.
When the cancer has spread, axillary dissection seems to help survival
(J. Am. Coll. Surg. 206: 261, 2008).
Other favorable prognostic factors, in addition to those already cited, include:
The age-adjusted incidence of breast cancer among US women rose by 30%
during the 1980's. This is an artifact of finding them much, much earlier
(Soc. Sci. Med. 46: 907, 1998).
The newer studies mostly (not all) support breast cancer screening by mammogram
as a way of cutting mortality (though the impact is not huge): Lancet 353:
1903, 1999. The benefits drop to near-zero in the elderly (JAMA 282: 2156, 1999).
Prognosticating breast cancer by a 186-gene "invasiveness" profile: NEJM 356: 217, 2007. Works well
for the common histopathologies. Patients with good scores had almost no deaths,
and were much less likely to have metastasatic disease;
and it was as powerful a predictor as initial tumor size and grade.
As with profiling as a guide to typing and management, this sort of thing will probably have a major impact by the time you are in practice (the
term may be "IGS" or Invasive Gene Signature).
Fine-needle aspiration is becoming very popular, and panels of
molecular tests help with the prognostication (Am. J. Clin. Path. 113(5S1):
S49 & S84, 2001). These include DNA ploidy, proliferation rate,
HER-2/neu status
(FISH, immunohistochemistry; JAMA 291: 1972, 2004; Am. J. Clin. Path. 122: 110, 2004),
and p53 status.
Future pathologists: The p63 stain stains the nuclei of myoepithelium,
which is very helpful (i.e.,fibroadenomas will have abundant staining,
most noninvasive lesions will have myoepitelium throughout, ductal carcinoma in situ will have a few
myoepithelial cells but just on the edges, cancers lack myoepithelium,
and only very obvious breast
cancers are likely to stain with p63). Update: Am. J. Clin. Path. 128:
80, 2007.
Future clinicians: Here's a breakdown on these little lesions, which you'll localize by needle or wire
and excise (from Am. J. Surg. 164: 427, 1992, from Wash. U.; see also Br. J. Surg. 79: 1038, 1992)
80%...
benign
16 mm average size
NOTE: A great many genetic abnormalities have been found in breast cancer, but unlike many
cancers, there is no known invariable change. No claim relating prognosis to a particular genetic
lesion has stood up strikingly well, though checking for amplified c-erb-B2/HER-2/neu
is
now commonplace. Pathologists stain for the oncoprotein
(Am. J. Clin. Path. 113:251 & 669 & 675, 2000; assays
Arch. Path. Lab. Med. 126: 803, 2002); those with the amplification
may be treated with trastuzumab ("Herceptin"), a monoclonal antibody targeting
the protein. This is now mainstream and getting the protocols down
now occupies the research oncologists: Lancet 375: 377, 2010.
Here's the Nottingham-Bloom-Richardson system that's becoming popular:
+1 if the nuclei are small, regular, and uniform
+1 if there are 0-7 mitotic figures per 10 high power field
Scoring:
Unfavorable prognostic factors, in addition to those already cited, include:
One success story of the women's movement is the more rational, more thoughtful approach to the
therapy of breast cancer. Today's woman will be given an account of the risks of various
interventions, and be allowed to make her best choice. This is good. Rational management begins
with rational diagnosis.
{04607} metastatic breast carcinoma in brain, scan
You learn staging (which is not a "pathology" subject -- though watch for flow cytometry
of the blood to alter the current system Cancer 113: 2422, 2008) and
therapies on rotations. Therapies include:
NOTE: If a woman "wants to save her breast", and chooses radiation over surgery, she's risking
brachial plexus injury, with chronic severe pain and loss of the use of the arm. This was recently
brought to the public's attention by a women's pressure group, and rightly so. See Br. Med. J. 308:
188, 1994.
A variety of hormonal manipulations are available.
Tamoxifen, the anti-estrogen, is now standard for adjuvant therapy of
hormone-sensitive post-menopausal
breast cancer (Lancet 359: 2126, 2002). The use of tamoxifen
prophylaxis for women at high risk (i.e., lobular CIS, atypical hyperplasia,
strong family history)
is still under study, with both risks and benefits
rather small (Ann. Int. Med. 137: 59, 2002). The known hazards
include endometrial cancer, thromboemboli, exacerbation of endometriosis,
fatty liver, and
deceptive small blue "tamoxifen cells" on pap smear (Arch. Path. Lab. Med. 125:
1047, 2001).
The anti-progesterone agent RU486 / mifepristone (once "the
controversial abortion pill") has been tried and is now occasionally
used in advanced breast cancer (Fert. Ster. 68: 967, 1997).
Its use is still mostly in the lab.
The story of the politics: JNCI 92: 1970, 2000.
The late-1990's experiments with high-dose chemotherapy plus autologous
bone marrow transplantation for disseminated disease ("My HMO won't pay!")
ended up showing no advantage over conventional chemotherapy (NEJM 342: 1069, 2000).
Since protocols often depend on whether there are cancer cells in the lymph
nodes, pathologists now use keratin stains to show these up easily:
Am. J. Surg. Path. 23: 263, 1999; Lancet 354: 896, 1999.
{24707} post-mastectomy, post-radiation with lymphedema
Clinical course: The disease is likely to metastasize, but is often indolent, and late recurrences are
common.
If the metastases appear in bone, survival for many years is common.
Visceral metastases (lungs, liver, brain) are more ominous.
The key to surviving breast cancer is early diagnosis.
* Future pathologists: We have several stains that may be of help
in distinguishing identifying a metastasis as being of breast origin, a relatively
common situation.
Updates Am. J. Clin. Path. 127:
103, 2007;Arch. Path. Lab. Med. 132: 239, 2008.
DISEASES OF THE MALE BREAST
GYNECOMASTIA
Proliferation of a man's ducts and stroma, unilateral or bilateral
It can be idiopathic (adolescents or older men), due to hypoandrogenism (remember XXY), or due to hyperestrinism (tumors,
iatrogenic, female impersonators, testicular tumors (don't miss this one),
guys using anabolic steroids to look more masculine, heh heh).
For decades I've been mystified by bath oils and soaps
containing weird herbal concoctions, and the men who use them. Lavender and tea-tree oils
have estrogen-like activity and seem to cause gynecomastia (NEJM 356:
479, 2007). Stay tuned for more unpleasant surprises.
Other drugs to remember are digitalis and spironolactone; soy products contain
natural estrogens. Idiopathic gynecomastia puts a plain-vanilla
man at no greater
risk for cancer, but note that XXY's and female impersonators on estrogens
are at increased risk. The severity is widely variable. A man can be
cured by office surgery, if he wishes.
"Pseudogynecomastia" is seen on obese men; unlike in true
gynecomastia, there is no hard nubbin under the nipple.
{49363} gynecomastia
CARCINOMA OF THE MALE BREAST
Uncommon (100x less common than in women, 20x more common in XXY's than among other
men, and much more common in breast cancer families), but with only about 50% cure rate.
It is almost always an infiltrating ductal carcinoma, usually without much desmoplasia
{24603} carcinoma of breast, man
OTHER CANCERS
These can look totally benign clinically and microscopically, and
then metastasize. Many pathologists will tell you that all
hemangiomas of the breast should be considered malignant unless they are obviously
very sharply circumscribed, thoroughly benign-looking, and completely away from the lobules.
THE BREAST IMPLANT FIASCO: The U.S. public pays for willful ignorance of the fundamental
methods of science and rational decision-making, with women, as usual, the big losers (NEJM 326:
1696, 1992; NEJM 342: 781, 2000).
In April 1992, the FDA banned the use of silicone breast implants except in studies, even for women
with mastectomies (NEJM 326: 1713, 1992). In previous years, about 120,000 women per year got
breast implants for breast augmentation (i.e., "to look better"), and 30,000 got the implants for
reconstruction after mastectomy.
The "scientific rationale" was slim but not altogether lacking. We do know that silicone slowly
leaks out through the capsule of the implant. There was a series of four women with implants who
then got scleroderma (Ann. Int. Med. 111: 377, 1989). One other patient with a ruptured implant
got "scleroderma" and it resolved (!) when the implant was removed (Arch. Derm. 126: 1198, 1990).
Somebody was impressed enough to coin the term "human adjuvant disease", conjecturing that the gel was causing
people to get sensitized to their own proteins, and the rest is history.
Shortly after the ban, a California study found anti-nuclear antibodies in 11 women with implants plus
scleroderma (most common), lupus, or some overlap syndrome; there was no typical serologic
picture, but the study related disease onset to traumatic rupture of the implants (Lancet 340: 1304,
1992). The most interesting work I've seen so far was 3 cases from South Carolina, in which silicone
was demonstrated at sites of connective tissue disease, and the illness remitted after removal of the
implants (Arch. Derm. 129: 63, 1993). A Danish mega-review found only 32 cases of all
connective tissue disease, mostly scleroderma (Kjoller et. al., 93134723, abstract), "much less than
you'd expect by chance" (gee whiz), but was impressed by anecdotes of disease clearing on removal of the
implants. A big review found no increase in connective tissue disease in implant recipients: NEJM
332: 1666, 1995; the only recent "study" that found a link took women's self-reports and made no
attempt to confirm them (i.e., if an implant recipient said she had lupus, then she had lupus).
Updates: NEJM 334: 1505 & 1513, 1996; Neurology 46: 308, 1996 ("neuromythology
of silicone breast implants"); Plast. Recon. Surg.
99: 1362, 1997; Br. Med. J. 316: 147, 1998 seems to have finished
the "connective tissue disease" claim off. Most recently, there was an essentially
negative study in Am. J. Epidem. 160: 691, 2004.
"Antipolymer antibody"'s existence remains
unsubstantiated by the general scientific community.
The link with fibromyalgia (which is a real disease / syndrome but one that a pathologist cannot
exhibit) remains a public concern and I think with some reason.
The FDA did a survey of recipients' health
and x-rayed to see if the silicone had leaked. When the obvious confounders
were controlled for, everything pretty much disappeared except for a link
between implant rupture and "fibromyalgia".
Nobody's reproduced this surprising finding yet,
previous studies were negative (J. Rheum. 27: 2237, 2000)
or extremely weak (the Wichita group suggested that psychological
factors contribute both to fibromyalgia and to getting implants),
and the folks in Denmark found that
whether or not the implants have ruptured seems to have no effect
on how Danish women say they feel (Plast. Rec. Surg. 111: 723, 2003).
A huge meta-analysis found nothing except people misinterpreting
foreign-body reactions as evidence of systemic disease, and examining flaws in the
previous work: Plast. Rec. Surg. 120:
625, 2007. Flow cytometry and sub-subclassification of circulating lymphocytes
shows no differences ("no pro-inflammatory effect") in implant patients
(Plast. Rec. Surg. 121: 25, 2008).
Under a 1976 law, manufacturers had to prove their devices were "safe and effective". Of course,
that doesn't mean risk-free. The FDA merely had to decide that the benefits outweighed any
demonstrated risks. Unfortunately, because the benefits of breast augmentation are subjective, the
FDA acted as if there were no benefits (NEJM 326: 1695, 1992). Internal memos from
manufacturers of the implants painted a less-than-edifying portrait of corporate America.
"Consumer advocates" who have always tolerated alcohol and tobacco (including all those tobacco
advertisements directed at young girls) and who raised no fuss over tainted "health-food" tryptophan
presented anecdotes and scare-stories designed to terrify the two-million-plus women with implants.
Militant feminists were divided between "a woman's right to make decisions about her own body"
and the need to oppose the "sexist" pressures that makes some women feel they needed breast
augmentation in the first place. (It seems to your lecturer that a reasonable person can say
"no" to the
latter while still supporting the former.) The result was a media circus that led to the ban, as well
as around $4 billion dollars in liability payments; the whole thing may end up costing $40-$60
billion (Science 276: 1564, 1997). See also Cleveland Clinic J. Med. 59: 539, 1992; Plast. Rec.
Surg. 90: 1102, 1992; CMAJ 147: 772, 1127 & 1141, 1992; Arthr. Rheum. 39: 1615, 1996. It
was ironic, in mid-1994 in the wake of the (expected) studies showing no serious risk (NEJM
330: 1697, 1994 was best-known), to hear the same investigative
journalists turn wildly indignant against the
FDA's ban ("Government interference in our private lives!")
A psychologist explains how this sort of thing contributes to public
ill-health by making people somatize: Ann. Rheum. Dis. 60: 653, 2001.
We need a word to go with "iatrogenic disease" to describe people
who develop real (though subjective) symptoms because of pop claims
about things that are probably harmless
(other people's perfume, other people eating
peanuts on the airplane, etc.) The FDA decided in late 2003
not to allow the devices to be reintroduced, then reversed itself
in late 2006, and fourteen years after their withdrawal, they
are available again (Br. Med. J. 333: 1139, 2006). I've given up trying to make sense of this.
In late 2008, a Dutch group reported a tiny-sample association between
the very-rate ALK-negative anaplastic large T-cell lymphoma and implants
(JAMA 300: 2030, 2008. Your instructor believes this will
not be replicated.
By the way: "Women who undergo breast augmentation with silicone implants have a lower risk of
breast cancer than the general population. This finding suggests that these women are drawn from a
population already at low risk and that the implants do not substantially increase the risk (NEJM
326: 1649, 1992)". Well, looking at the statistics again, there probably isn't any real effect one way
or the other (NEJM 332: 1535, 1995; Plast. Rec. Surg. 120(S1): 70-S, 2008). For some reason that I cannot explain, nobody seems to have
looked at bust size as a natural risk factor for breast cancer.
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about
breast pathology
to consult these standard textbooks.
In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!
*SLICE OF LIFE REVIEW
{11770} breast, normal
Ed says, "This world would be a sorry place if
people like me who call ourselves Christians
didn't try to act as good as
other
good people
."
Prayer Request
Teaching Pathology
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
MedEdPORTAL -- American Association of Medical Colleges. Primarily for medical school faculty.
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta Tumor Photos -- and lots more. Highly recommended.
Bristol Biomedical
Image Archive
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
U. of Virginia Case Studies
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Upstate NY Cases -- works only on some browsers
Society for ultrastructural pathology -- electron microscope cases
PathologyPics -- where pathologists share favorite images. Thanks!
WebPath:
Internet Pathology
Laboratory -- great site
My team:Ed Lulo's Pathology Gallery
Also:
Bryan Lee's Pathology Museum
Dino Laporte: Pathology Museum
Tom Demark: Pathology Museum
Path Consult -- great photos and text for more advanced learners
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
Review the normal anatomy and hormone effects.
Inverted nipples
Tell what we know, and don't know, about the causes of "fibrocystic change".
Describe the range of anatomic pathology, and distinguish it yourself from cancer
under the microscope.
"Virginal hypertrophy
Acute mastitis
Periductal mastitis
Duct ectasia
Galactocele
Fat necrosis
Gynecomastia
Benign hyperplasia
Atypical ductal hyperplasia
Atypical lobular hyperplasia / neoplasia
Sclerosing adenosis
Small duct papillomas
Fibroadenoma
Phyllodes tumor
Large duct papilloma
-- Cornelius
Celsus, ancient Roman physician.
Breast / Heme (?!)
Taiwanese pathology site
Good place to go to practice
Archive of Histologic Images
of Gynecologic & Breast Path
Greek, minimal commentary
Breast Images
University of Washington
Pictures and comments
Gynecologic and Breast Pathology
Photomicrograph collection
In Portuguese
Breast Exhibit
Virtual Pathology Museum
University of Connecticut
Digital Atlas of Breast Pathology
Meenakshi Singh, MD
Outstanding resource
Estrogen: Develops the big ducts
Progesterone: Develops the lobules and ductules ("acini")
Prolactin: Develops the secretory units and causes milk production
Oxytocin: Makes the myoepithelial cells contract and express milk
{11769} normal breast, histology
{11770} normal breast, histology
{10748} pregnant lady's breast
Pregnant lady's breast
WebPath Photo -- comments are down right now
{49361} supernumerary nipple
{12439} supernumerary nipple
(abscess-maker). More than half of the staph cultured from breast
abscesses are now methicillin-resistant staph
(Arch. Surg. 142: 881, 2007). Less often it's a
streptococcus
(spreading cellulitis). The surgeon may need to drain it; it is almost never a sign of cancer (Am. J. Surg. 192: 869, 2006).
Obviously you'll want to rule out TB
, sarcoidosis, and reaction to a ruptured
implant.
Benign Breast Lesions
www.breastdiseases.com
Physician guidelines area
This extremely common change means extra, crowded acini in some of the lobules. Often the lumens
are a bit distended ("blunt duct adenosis"), but they are not deformed, compressed
or distorted. Calcification is common.
{25567} fibrosis of breast
{25568} fibrosis of breast
{25569} cystic disease of breast
Fibrocystic disease
WebPath Photo -- comments are down right now
Fibrocystic disease
Microcalcification
WebPath Photo -- comments are down right now
Fibrocystic disease
WebPath Photo -- comments are down right now
Sclerosing adenosis
WebPath Photo -- comments are down right now
Atypical hyperplasia
WebPath Photo -- comments are down right now
"Fibrocystic disease" probably doesn't put a woman at any extra risk
for anything. It's biopsied to rule out cancer.
Three entities have been removed from the "fibrocystic disease"
category
because they confer a significant cancer risk (i.e., mutations have begun
accumulating). They are:
1. Epithelial hyperplasia
Totally benign-looking hyperplasias
Atypical ductal hyperplasias
Atypical lobular hyperplasia / neoplasia
Epithelial hyperplasia of any sort is usually an incidental finding, and does not produce a mass.
Here are some helpful indicators that you're looking
at "benign change" rather than "cancer":
Regrettably, you need to excise these for diagnosis, even if the
imaging studies look perfect for "classic radial scar."
Needle biopsy misses too many cancers: J. Clin. Path. 60: 295, 2007.
Radial scar of breast
AFIP. Quite benign.
Wikimedia Commons
{08942} fibroadenoma, histology
{08943} fibroadenoma, histology
{08944} fibroadenoma, histology
Fibroadenoma of breast
Great labels
Romanian Pathology Atlas
Fibroadenoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Phyllodes tumor
WebPath Photo -- comments are down right now
Papilloma
WebPath Photo -- comments are down right now
Breast Cancer
Australian Pathology Museum
High-tech gross photos
Breast cancer
Ed Uthman
Wikimedia Commons
{00126} breast carcinoma, gross, recurrent at mastectomy site
{07561} breast carcinoma, gross
{10924} breast carcinoma, gross
{10928} breast carcinoma, gross
{12441} breast carcinoma, gross
{12533} breast carcinoma, infiltrating, gross
{49362} breast carcinoma
{49352} breast carcinoma
{24600} breast carcinoma
{10749} breast carcinoma
{00123} breast carcinoma, cytology
See also Lancet 360: 187, 2002. These analysis
conclude that the risk of breast cancer would be cut by 2/3 in the developed
world if women would just have as many babies and breastfeed for as long
as do the women in the poor nations.
Actually, "prevention of breast cancer", especially in patients at high
risk, is now fraught with medicolegal
issues (Postgrad. Med. 111:
83, Feb. 2002).
Much more dubious...
Cigaret smoking is not a risk factor for breast cancer, nor does it protect against it; a challenge to
this well-known observation bombed in 1996 (bad study JAMA 276: 1494, 1996,
trashed in Br.
Med. J. 313: 1226, 1996).
Despite a total lack of empirical
evidence or a scientific basis to believe one might get a positive
result, a massive controlled study
of a diet very high
in fruits and vegetables and fiber and low in fat was undertaken in women
with newly-diagnosed breast cancer ("the Women's Healthy Eating and Living
randomized trial.") It was a stunning failure -- no impact on
cancer outcome, new cancers, or overall health or mortality (JAMA 298: 289, 2007).
Obviously the study was driven by pop claims; sadly, the failure has
received no media attention.
Uh, sorry....!
* Urban folklore has noticed
this and attributes the increase to more fondling by right-handed
partners.
If you're asked about this, it might be easiest to explain
that the left breast is normally bigger, and that there
is a much higher
incidence of breast cancer in nuns than
in past or present CSW's.
Ductal Carcinoma in Situ
www.breastdiseases.com
Physician guidelines area
Now that women go for mammography, we are finding a lot of these.
These lesions are non-invasive (yet), but can form masses by
filling ducts and/or lobules.
This is the most commonly-identified lesion on mammography.
These lesions are usually unilateral, they
often around for decades, and probably only a minority
ever invade.
Criteria for "ugly nuclei" are more than twice as wide
as a red cell, marked variation in size and shape,
coarse uneven chromatin, large nucleoli, more than two
nucleoli per nucleus, lots of mitotic figures.
1: Solid, cribriform, or micropapillary
Start with the Van Nuys number.
Along with multifocality and micropapillary growth, comedocarcinoma
is one of the findings that indicate that a ductal carcinoma in situ is likely
to turn invasive; however, the vast majority of these invasive cancers prove
non-fatal, since the women are under close follow-up (Am. J. Clin. Path. 128:
86, 2007).
.jpg){kind=small}
Cancerization of lobules
Breast
Wikimedia Commons
{24449} Paget's disease of breast
Paget's
WebPath Photo -- comments are down right now
Paget's
WebPath Photo -- comments are down right now
Paget's
PAS stain
WebPath Photo -- comments are down right now
Just what to do after an excisional biopsy reveals "ductal carcinoma in situ"
is still under study. On the one hand, it's more likely than not that the
woman will have no further problems following simple excision. On the other
hand, if cancer recurs and becomes invasive, it can kill her.
{12530} intraductal breast carcinoma, comedocarcinoma of breast pattern
{15498} intraductal breast carcinoma
Nowadays, women with breast cancer may be offered a contralateral prophylactic
mastectomy. This works to prevent breast cancer, and true to classic
teaching, invasive lobular carcinoma in the original breast is a strong
predictor of disease in the other (Cancer 101: 1977, 2004).
{15526} lobular carcinoma in situ
Lobular carcinoma
WebPath Photo -- comments are down right now
Cribriform cancer
WebPath Photo -- comments are down right now
Comedocarcinoma
WebPath Photo -- comments are down right now
Comedocarcinoma
Dystrophic calcification
WebPath Photo -- comments are down right now
Breast cancer
Inked margins
WebPath Photo -- comments are down right now
Fine needle aspiration
WebPath Photo -- comments are down right now
Scirrhous cancer
WebPath Photo -- comments are down right now
Breast cancer
Microcalcifications
WebPath Photo -- comments are down right now
infiltrating breast cancer
Microcalcification
WebPath Photo -- comments are down right now
Breast cancer
Both phases
WebPath Photo -- comments are down right now
Scirrhous cancer
WebPath Photo -- comments are down right now
Scirrhous cancer
WebPath Photo -- comments are down right now
Scirrhous cancer
WebPath Photo -- comments are down right now
Breast cancer
Both phases
WebPath Photo -- comments are down right now
Scirrhous cancer
WebPath Photo -- comments are down right now
Cribriform breast adenocarcinoma
Classic drawing
Adami & McCrae, 1914
Breast Adenocarcinoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
.jpg){kind=small}
Breast
Ductal CIS
Wikimedia Commons
Invasive Breast Carcinoma
www.breastdiseases.com
Physician guidelines area
Invasive ductal carcinoma of the breast
Great labels
Romanian Pathology Atlas
INVASIVE DUCTAL CARCINOMA:
The large majority of breast cancers are called "ductal",
(even though current thinking is that the "cell of origin", if there's
really any such thing, is usually in the lobules.)
* The "encapsulated" variant has finally
been established to be non-invasive, with excellent prognosis
(Am. J. Clin. Path. 131: 228, 2009).
Mucinous / colloid cancer
WebPath Photo -- comments are down right now
Metaplastic breast cancer
Great photos
Pittsburgh Pathology Cases
{15485} carcinoma of breast, infiltrating lobular type
Infiltrating lobular carcinoma
WebPath Photo -- comments are down right now
Lobular carcinoma
Indian files
WebPath Photo -- comments are down right now
No one really knows what to make of a new trend to reclassify
breast cancers based on their genetic profiles (in 2008 we were up to 496 genes;
microarray updates Ann. Int. Med. 148: 358, 2008; CA 59: 303, 2009;
NEJM 360: 790, 2009; commercial kits are available)
instead of their histopathology.
Here is the current "Sorlie" research system (ER=estrogen receptor, PR=progesterone receptor. It is starting
to become part of clinical practice. See, for example, J. Clin. Path. 62: 6, 2009
AFTER THE DIAGNOSIS OF BREAST CANCER IS MADE...
See Nature 406: 707, 2000; JAMA 295 2492, 2006; Cancer Res. 66: 4636, 2006.
You will learn a great deal about the management of these patients
while you are on rotations. The protocols will probably be different
by then.
Inflammatory carcinoma
Trust me
WebPath Photo -- comments are down right now
Today, the pathologist will examine the "sentinel lymph node", and probably
stain with cytokeratin 19 and/or mammaglobin to spot cancer cells not easy to see on H&E: Am. J.
Clin. Path. 117: 729, 2002.
Rapid techniques for immediate results during
surgery: Cancer 104: 14, 2005. The touch-prep / frozen section are fine,
even after neoadjuvant chemotherapy: Ann. Surg. 251: 319, 2010.
(
cyclin E, Ki67,
MIB-1 identify tumors that
are faster-growing and more likely to respond to chemotherapy;
"MIB-1 below 10% exclude from
chemotherapy"; methods
and cutoffs Cancer 94: 2151, 2002)
Not surprisingly, it's very hard to call ductal carcinoma in situ
on a needle aspirate without some
special studies.
15%...
small invasive cancers
5%...
carcinoma in situ
_HER2_expression.JPG){kind=small}
Breast cancer
HER2 expression
Wikimedia Commons
+1 if 75+% of the tumor has cells making tubules
+2 if 10%-75% of the tumor has cells making tubules
+3 if less than 10% of the tumor has cells making tubules
+2 if the nuclei are big and/or vary some in size
+3 if the nuclei vary a lot in size
+2 if there are 8-14 mitotic figures per 10 high power field
+3 if there are 15 or more mitotic figures per 10 high power field3-5: Grade I
6-7: Grade II
8-9: Grade III
The popularity of breast conservation surgery has given support
to our ideas about clonal selection. When there is a local recurrence
despite "the margins being free of cancer", there was often a "monomorphic
epithelial proliferation" near the edge, which though not malignant by
light microscopy must be the breeding-ground for the real cancer.
Eradicating this stuff is probably why radiation after this kind of surgery
reduces the risk: Am. J. Clin. Path. 128: 1023, 2007.
* Adjuvant chemotherapy following mastectomy for younger women in certain risk
categories seems to produce about 10% better survival at 10 years, but there are
quality-of-life issues as well: Lancet 352: 930, 1998.
* Most alarming, the guy who reported the big studies showing
an advantage refused to turn all of his materials over to an investigating
team, and the team concluded he had presented falsified data at two
international meetings (Lancet 355: 999, 2000).
{12442} reconstruction after mastectomy
* Comorbidity and compliance issues affect outcome. The British found
that their wealthier patients did better than their poorer patients despite
"getting equal care" (Br. Med. J. 320: 1442, 2000).
I'm not sure I believe this, since retrospectively the British
health care system has been notoriously bad about getting women
with breast lumps seen in a timely manner -- this became a
scandal and it's ongoing (BMJ 355: 288, 2007).
* Today, the greatest barrier to early diagnosis and treatment is
not poverty, but a level of ignorance that should not exist today.
Plenty of people believe that biopsying cancer makes it spread,
that the devil decides who gets cancer, and/or that chiropractors can
treat breast cancer effectively. These beliefs are most widespread
in a particular "culture" that has
a dramatically higher average stage at presentation
(JAMA 279: 1801, 1998.)
Adenoid cystic carcinoma
of the breast
Pittsburgh Illustrated Case
* On rotations and afterwards, you'll learn a great deal more about
mammography and the follow-up of worrisome lesions.
No one really knows what to do about very small lesions,
5 mm or less; some say they can safely be watched (Am. J. Surg. 190:
633, 2005).
For example,
mammaglobin is positive in about half of breast cancers, but rarely in cancers
of other derivation, and is useful in identifying tumors
of unknown primary as of breast origin.
Another protein is GCDFP-15, apparently even more specific; the acronym
is for "gross cystic disease fluid protein 15".
{12512} gynecomastia, histology
{49434} gynecomastia, 5 year old male, some kind of hormonal problem
Gynecomastia
WebPath Photo -- comments are down right now
The one entity that needs to be mentioned here is the ANGIOSARCOMA,
cancer of the blood vessels. These occur in young women and/or after radiation, and
a majority are fatal (Cancer 104: 2682, 2005).
Silicone implant
WebPath Photo -- comments are down right now
Silicone implant
In place
WebPath Photo -- comments are down right now
Silicone leak
Granulomas
WebPath Photo -- comments are down right now
* In Isaac Bashevis Singer's famous short story Gimpel the Fool,
one of the characters dies of cancer of the breast. The story deals with
a simple baker's struggle to be a good person in a world full of deceit.
Highly recommended.
Carter's Interpretation of Breast Biopsies
Harris's Diseases of the Breast
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silverberg's Surgical Pathology
Sternberg's Diagnostic Surgical Pathology
{14992} mammary gland (prepubertal), normal
{14992} mammary gland (prepubertal), normal
{14993} mammary gland (prepubertal), normal
{14993} mammary gland (prepubertal), normal
{14994} mammary gland (secreting), normal
{14994} mammary gland (secreting), normal
{14995} mammary gland (secreting), normal
{14995} mammary gland (secreting), normal
{14996} mammary gland (ct stain), normal
{14996} mammary gland (ct stain), normal
{14997} mammary alveolus (active), normal
{14997} mammary alveolus (active), normal
{14998} mammary ducts (mature), normal
{14998} mammary ducts (mature), normal
{14999} mammary ducts (mature), normal
{14999} mammary ducts (mature), normal
{17489} breast, normal
{20293} breast, normal
{20690} mammary gland, normal
{20690} mammary gland, normal
{20691} mammary gland, gland epithelium
{20693} mammary gland, gland epithelium
{20694} mammary gland, gland epithelium
{20793} mammary gland
{20794} mammary gland
{20968} mammary gland
{20969} mammary gland, alveolus
{50571} breast, normal duct
{50572} breast, normal duct
Visitors to www.pathguy.com
reset Jan. 30, 2005:
If you have a
Second Life
account, please visit my teammates and me at the
Medical Examiner's office.
PathMax -- Shawn E. Cowper MD's
pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic
Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification
Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science
Trivia Quiz -- have a chuckle!
Rudolf
Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Pathological Chess
Taser Video
83.4 MB
7:26 min
Breast
Normal breast
Normal breast
Fibrocystic disease of breast
Breast cyst
Hyperplasia
Hyperplasia
Fibroadenoma
Fibroadenoma
Fibroadenoma
Breast Cancer
Indian Files
Breast cancer