MEN'S DISEASES
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
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.
DoctorGeorge.com is a larger, full-time service.
There is also a fee site at
www.afraidtoask.com.
 |
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
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from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent
Slice
of Life videodisk. No medical student should
be without access to this wonderful resource.
Someday you may be able to access these
pictures directly from this page.
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
handling about 200 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:
I've spent time there and they are good. Write "Thanks
Ed" on your check.
My home page
More of my notes
My medical students
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 linked below. 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 February 9, 2008.
During the thirteen 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!
More of Ed's Notes:
LEARNING OBJECTIVES
Describe the following anatomic defects, how they arise, and what may
happen as a result:Distinguish priapism from a normal erection, explain why it can be serious,
and mention some illnesses and how they cause priapism.
Describe how infectious urethritis occurs, and briefly describe Reiter's
disease.
Describe the range of HPV-induced and syphilis-induced
pathology in the male. Give an account of squamous cell carcinoma
of the penis, and its various precursor lesions.
Tell what a general physician needs to know about cryptorchidism, epididymitis,
orchitis, and torsion.
Recognize each of the common germ cell tumors microscopically, and
describe their gross appearances, frequencies, known risk factors, markers, and
behavior. Recognize and describe Leydig cell adenomas and testicular
lymphomas.
Tell what can cause pain in the prostate. Give accounts of bacterial
and nonbacterial prostatitis.
Tell what we know about the etiology, pathogenesis, pathophysiology,
anatomic pathology, and consequences of prostatic hyperplasia.
Describe adenocarcinoma of the prostate in terms of its etiology, pathogenesis,
markers, anatomic pathology, patterns of growth and spread,
and clinical diagnosis, including the use of the lab.
Read a prostate needle biopsy, distinguishing cancer from the other
common lesions, and do simple grading of adenocarcinoma.
Use your pathology knowledge, along with your knowledge from other
lectures in this unit, to help answer common individual
patient questions in the primary
care setting.
QUIZBANK
I used to pray, "Lord, give me chastity, but not yet!"
-- St. Augustine, Confessions
A man should definitely get married. If it's a good
marriage, he will be happy. If it's a bad marriage,
he will become philosophical.
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Iron John. Iron John. What MY wife wants
is iron-ING John!.
|
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{47692} index identifies this as "human male"
{10268} prostate, normal gross section
{11762} prostate, normal histology
{11763} prostate, normal histology
{17008} prostate, normal histology
{15027} prostate, normal histology, with concretion
{00083} testis, normal histology
{20941} testis, normal histology, good Leydig cell
{15016} epididymis, normal histology, with sperms
{15026} seminal vesicles, normal histology
{25832} sperms, Pap stain; note two-headed sperm in center (not too unusual)
Testis, epididymis, penis
"Pathology Outlines"
Nat Pernick MD
Even where there is no mensch, strive to be a mensch.
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While you are away, movie stars are taking your women. Robert Redford is dating your girlfriend.
Tom Selleck is kissing your lady. Bart Simpson is making love to your wife.
|
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Love, who is fairest among the immortal gods,
loosener of limbs, by whom all gods and all men
find their thoughts and wise counsels overcome in their hearts.
HYPOSPADIAS: Abnormal opening of the urethra onto the ventral surface of the penis or scrotum.
This results from failure of fusion of the urethral folds, i.e., it is a form of feminization.
To date, no gene has been identified that causes what must be a multifactorial-etiology
problem. Not surprisingly, the first statistical link is to the 5-alpha-reductase
gene (J. Clin. Endo. Metab. 90: 6695, 2005), which activates testosterone
on the skin and is inhibited by today's baldness-cures.
* And of course there are a host of statistical differences in other hormonal
levels between these youngsters and their normal counterparts, including
high-levels of mullerian inhibiting substance (J. Urol. 168: 1784, 2002).
Wherever the opening occurs, a fibrous band (chordee) distal to it will cause ventral curvature of the
erect penis.
There is often associated cryptorchidism, ureterovesical reflux, inguinal hernia, and/or other
developmental problems (J. Postgrad. Med. 37: 140, 1991).
A massive review of the anatomy: J. Urol. 160: 1108, 1998.
In the late 1990's, a "green" claim was presented to the public to
the effect that
hypospadias has doubled in frequency in the past twenty years,
and the cause is chemical pollutants acting as "endocrine disruptors", after
an initial CDC report seemd to spot a trend (Pediatrics 100: 831, 1997).
There was a huge hoopla and a bunch of studies.
All confirmed there's no increase in either incidence or repair rates
(Urology 57: 151, 2001; Env. Health Perspect. 108: 463, 2000; Pediatrics
115: e495, 2005; Arch. Dis. Child. Fetal-Neo. 89: F149, 2004).
In the old days, many children with the birth defect were simply not placed
in registries as they are today. The "green" claim that DDT is the
cause also fails under examination: Env. Health. Perspect. 113: 220, 2005.
Even Greenpeace has dropped these claims from their website (2008).
EPISPADIAS: Abnormal opening of the urethra on the dorsal surface of the penis.
Epispadias is actually a form of exstrophy of the urinary bladder. There is usually an associated
separation of the pubic bones and inadequacy of the urinary sphincters. Incontinence and bladder
infections are usual. There are many variants (J. Urol. 141: 903, 1989).
Epispadias is less common than hypospadias and more difficult to correct surgically.
PHIMOSIS: Present when the prepuce cannot be retracted over the corona.
Phimosis may be congenital, the orifice of the prepuce being too small.
More often, phimosis is due to poor hygiene, resulting in chronic inflammation and scarring, which
sets up a vicious cycle requiring circumcision.
Such an ongoing infection of the glans and prepuce is called BALANOPOSTHITIS. Many organisms may
participate. All about it: Urol. Clin. N.A. 19: 143, 1992.
* Jogger's phimosis: Br. J. Ur. 63: 549,
1989.
The word "phimosis" can also be used when scar contraction causes narrowing
following circumcision in the newborn (J. Urol. 169: 2332, 2003)
or balanitis xerotica in a kid (J. Urol. 165: 219, 2001 -- this is a lichen
sclerosus variant, usually seen in uncircumcised males and which is
helped by circumcision: South. Med. J. 96: 7, 2003).
Balanoposthitis
Little boy
EMBBS
{24987} balanitis
PARAPHIMOSIS results when a tight foreskin is forcibly retracted, and edema of the glans prevents its
replacement. This can quickly lead to acute urinary retention and even gangrene of the glans.
PRIAPISM: A persistent, non-pleasurable erection (Mayo Clin. Proc. 72: 350, 1997;
Urol. Clin. N.A. 28: 391, 2001).
* "Priapus" was the classical-era Greek god of erections, but priapism is no joke.
Most cases of priapism are probably due to obstruction of the deep dorsal vein of the penis.
Typically the corpus spongiosum is uninvolved (i.e., the urethra and glans stay limp).
Causes include sickle cell disease (J. Urol. 145: 65, 1991), black widow
spider bite (famous; Pediatrics 114: e128, 2004), leukemia, metastatic cancer, papaverine
treatment of impotence (rare), and trauma (J. Urol. 148: 380, 1992); many cases are "idiopathic"
(i.e., something is causing abnormal thrombosis).
URETHRITIS
GONORRHEA and "NON-GONOCOCCAL URETHRITIS" ("urethral syndrome", due to
chlamydia
,
mycoplasma, others), are important sexually-transmitted diseases.
Gonorrhea tends to come on fast after the contact, while
chlamydia
comes
on insidiously. Gonorrhea tends to have a more purulent
discharge.
Nowadays, it's a simply matter to check first-stream urine for DNA from
researchers to check for known pathogens.
One group checked for gonorrhea, Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma parvum and
urealyticum, herpes 1 and 2, adenovirus, and Gardnerella -- but for some reason
not for trichomonas (known to be an important cause -- J. Inf. Dis. 188:
465, 2003).
There's plenty of urethritis due to each bug in the study. Men tend to get herpes&1 and
adenovirus from oral sex (especially from other men), and most of the others from
unprotected vaginal sex with women. and there's at least one
unknown entity transmitted by oral sex.
Update on all this in J. Inf. Dis. 193: 336, 2006.
REITER'S DISEASE (formerly "Reiter's syndrome"): the enigmatic triad of (1) arthritis involving many joints, (2) conjunctivitis, and
(3) urethritis (for this handout, anyway). It's a man's disease and lasts for several months.
Update Am. Fam. Phys. 60: 499, 1999.
The urethritis is usually (if not always)
chlamydia,
and one old study found chlamydial RNA in the
synovium (Arth. Rheum. 35: 521, 1992); if the initial episode of urethritis is treated appropriately,
Reiter's is much less likely to ensue (Arth. Rheum. 35: 190, 1992).
As with other "reactive arthropathies" (you may hear enteropathic
arthritis called "Reiter's"), there's an impressive proliferation of T-cells specific for
chlamydia within the affected joints (Arth. Rheum. 34: 588, 1991).
Most patients are positive for HLA-B27.
* Patients with Reiter's syndrome are likely to have circinate balanitis, keratoderma blennorrhagica
of soles, ulcers of the mouth, iritis, or even ankylosing spondylitis ("poker-back").
Before assuring a guy his urethritis "must be due to chlamydia" (because his gonococcal culture
came back negative), ask whether he eats lots of those little Mexican peppers. The hot chemical in
these can and does cause a urethritis.
PEYRONIE'S DISEASE: Proliferation of dense fibrous tissue involving a portion of the fascia.
This leads to curvature of erection. * Other names: "painful erection in the wrong direction", "squint
of the cock" (Osler).
This is one of several abnormal hyperplasias of fibrous tissue that
are sometimes called
"fibromatoses": another common one is palmar fibromatosis (Dupuytren's contracture of the hand)
which often occurs with Peyronie's disease. Photomicrographs: J. Urol. 157: 282, 1997.
* Metaplastic ossification and calcification are common.
The etiology is completely obscure. Trauma as a possible
cause: Yes (J. Urol. 158: 1388, 1997); no (J. Urol. 172: 186, 2004).
Treatment for Peyronie's disease is not very satisfactory, and many patients eventually require a
penile prosthesis.
New procedures: J. Urol. 167: 2066, 2002.
Natural history of Peyronie's: J. Urol. 144: 1376, 1990.
{25287} Peyronie's, histology
WARTS: There are two common "warts" involving the penis:
CONDYLOMA ACUMINATUM ("pointed knob"): a papillary, keratinizing lesion caused by the
sexually-transmitted "human papilloma virus" (usually strain 6). In males, it commonly occurs in
the urethral meatus, which is perhaps the worst possible location (why?)
To spot HPV involvement, wet the man's external genitalia with acetic acid ("* sheep dip") and
involved areas show white ("acetowhite", as on the uterine cervix). It's now called "androscopy"
(J.F.P. 29(3): 286, 1989). See J. Urol. 143: 920, 1990 for a discussion on criteria for diagnosing
HPV histologically on biopsies of acetowhite areas. All about the histopathology of HPV, warts and
men: Arch. Derm. 128: 495, 1992.
We have lots of ways of dealing with these warts, ranging from electrocautery and lasers to
interferon and fluorouracil (Postgrad. Med. 86: 197, 1989, by my friend Dr. Ila Peterson). It's
important to treat both partners, since this reduces reinfection.
{24460} condyloma, gross
{25098} condyloma, histology; note HPV-effect (shrunken, wrinkled nuclei, perinuclear halo)
Warts
Male patient photos
Health Awareness Connection
CONDYLOMA LATUM ("flat knob"): groups of flat-topped lesions that
may ooze serous fluid; caused
by secondary syphilis. Typically occur in skin folds.
GENITAL HERPES
is familiar to you.
PEARLY PENILE PAPULES ("PPP on the pp") aren't warts at all, but little bumps, sometimes hairy, which pop up in young
adults, especially on the corona.
Each is a single big dermal papilla. No need to treat.
About one man in 100 has them, and I get a very large number of questions
from visitors to my site. I point out they can be considered a "plus".
CANCER OF THE PENIS: Almost all are variations on squamous cell carcinoma (histopathology:
Urol. Clin. N.A. 19: 227, 1992; review South. Med. J. 87: 848, 1994).
This is a disease of older men, and it originates on glans and prepuce.
Only 1% of cancers among American men begin on the penis; the figure is as high as 18% in the
Orient.
Risk factors include phimosis, smegma, and balanoposthitis. However, by far the strongest risk is
infection with HPV, notably HPV-16. The other risk factors seem to create the fertile soil where
Nowell's Law can operate.
Good reading: Cancer of the penis is the second most-common male cancer, and cancer of the cervix
the most common female cancer, on the island of Bali, where the men are uncircumcised and
unhygienic, and both cancers are strongly HPV-linked (Cancer 64: 559, 1989).
Males circumcised as infants almost never get cancer of the penis. The incidence is much lower in
those circumcised at a later age than among the uncircumcised.
The basaloid variant, which usually arises on the glans, is quite anaplastic
and very aggressive; by contrast, the verrucous variant
has very little propensity to metastasize (J. Urol. 176: 1431, 2006.)
Today's patient is likely to be offered laser therapy instead of surgery
(J. Urol. 169: 2118, 2003). Mohs' microsurgery seems effective: J. Urol. 178:
1980, 2007.
Carcinoma of the penis spreads to the inguinal lymph nodes. Five year survival is around 50%
overall.
{46450} squamous cancer of the penis, metastatic to the head
{46451} squamous cancer of the penis, with inguinal node metastasis
Cancer of the Penis
Dino Laporte's PathosWeb
PREMALIGNANT LESIONS OF THE PENIS
Three diseases, all usually occurring in uncircumcised men.
ERYTHROPLASIA OF QUEYRAT: A raised, velvety plaque on the uncircumcised glans or prepuce.
Histologic study shows dysplasia of the squamous epithelium.
* Treatment has historically been with topical 5-fluorouracil,
whether patients are HPV-positive or negative. Imiquimod (the immune-modulator
widely used nowadays in dermatology) also seems to work (J. Am. Acad. Derm. 55:
901, 2006).
A minority of cases (5-30%, estimates vary) develop into squamous cell carcinoma if not removed.
{25095} erythroplasia of Queyrat, gross
{25096} erythroplasia of Queyrat, histology
BOWEN'S DISEASE: Carcinoma in situ of the skin, most often on the penis or scrotum in men.
Look for individual very weird cells with lots of mitoses.
Some cases (maybe 10%) develop into invasive squamous cell carcinoma.
* There is a popular claim that
the appearance of Bowen's disease on the skin heralds the growth of another
malignancy internally. I am not aware of any reason to believe this is true.
BOWENOID PAPULOSIS: Multifocal intraepithelial neoplasia, caused by HPV-16. The atypia
is mild.
* Future pathologists: Bowenoid papulosis tends to spare the hairs
and involve the sweat glands. Bowen's disease tends to spare the sweat
glands and involve the hairs.
Giant condyloma of Buscké-Lowenstein, or VERRUCOUS CARCINOMA: Another HPV-related, very ugly
cauliflower-like lesion. (See Arch. Derm. 126: 1208, 1990; J. Urol. 141: 950, 1989). Invasive
cancer can breed here.
{25101} verrucous carcinoma, gross
{25102} verrucous carcinoma, histology
I never trust a man unless I've got his pecker in my pocket.
When we've got them by the balls, their hearts and minds will follow.
-- Charles Colson (pre-conversion), about the Vietnamese
MALE INFERTILITY
Leave the pathology of these problems to specialists. Male infertility (i.e., she's fertile, and they've
been trying without success for a year) has a variety of causes, known (Down's, Klinefelter's, old
torsion, old mumps,
cryptorchidism, some cases of old age, after radiation, after some kinds of
chemotherapy -- all will give a "Sertoli-only" histology) and unknown.
Spermatogenesis can be temporarily diminished or even stopped by a host of factors ranging from
heavy drinking to anabolic steroid abuse to bicycling.
Obstruction of the sperm passages (can you think of etiologies?) may be more amenable than the
above to surgical help.
The pesticides DBCP (dibromodichloropropane) and chlordecone
do cause infertility in men, by preventing the sperms
from differentiating. This has been known since the 1950's, and the
fact that companies still used them overseas after they were rightly
banned in the US is all-too-typical. The rat model, and an easy way to restore
their fertility: Tox. Sci. 76: 418, 2003.
{00086} testicular atrophy, no sperms
{25154} testicular feminization (no sperms, hyperplasia of useless Leydig cells, why?)
* Some guys ("fertile eunuchs", a misnomer) just don't make LH, and may or may not make FSH.
They become fertile if you replace the gonadotropins.
* Evaluation of the azoospermic patient, by Jon Jarow MD,
a lifetime friend of your lecturer: J. Urol. 142: 62, 1989. He's
also reviewed anabolic-steroid induced hypogonadotropic hypogonadism: Am. J. Sports Med. 18:
429, 1990.
Slow-learner guy with large testes: Fragile X!
CRYPTORCHIDISM (cryptorchism): Incomplete descent of the testis into the scrotal sac.
Review Am. Fam. Phys. 62: 2037, 2000.
Unilateral or bilateral cryptorchidism occurs in around 4% of prepubertal boys. (Maybe 1 boy in 10 is
born with at least one not fully descended, but the majority do descend in the first year.)
Cryptorchid testes
may be found anywhere along the normal route of descent (abdomen, inguinal canal, prepubic).
Occasionally a testis that is present in the scrotum at birth may retract
back into the abdomen (or have the cord fail to grow as the boy
does: J. Urol. 157: 1892, 1997);
this is also cryptorchidism and has the same associated risks and basically
the same histology: J. Urol. 162: 878, 1999.
The epididymis is likely to be malformed or at least elongated. See J. Urol. 143: 340, 1990.
Some centers biopsy each testis at the time of surgery, and
administer gonadotropin releasing hormone if the histology shows very few
germ cells per tubule (read about it J. Urol. 169: 659, 2003).
ECTOPIC TESTIS is less common; it may stray into the superficial inguinal region, penis, or femoral
sheath.
Failure of the testes to descend into the scrotum causes problems:
- The tubules will undergo atrophy and fibrosis, beginning in infancy and hopelessly
advanced around puberty. There will be few or no germ cells, and the rete is also
likely to fail to develop (Arch. Path. Lab. Med. 121: 1259, 1997).
- There is an increased risk of torsion of the spermatic cord and gangrene of the testis.
- The risk of germ cell cancer (usually seminoma)
in undescended testes is around 30x greater than normal.
Review Mayo Clin. Proc. 66: 372, 1991.
The risk is also higher in previously-undescended testes.
Even if the guy is an adult with no hope of having it rendered
fertile, the testis needs to come
down so he can check for tumors.
In 1989, 300 brave Danish men who had been treated for cryptorchidism consented to needle
biopsy; 5 had carcinoma in situ and 2 other had already been treated for testicular cancer (J. Urol.
142: 998, 1989).
Most cryptorchidism is idiopathic. It may be accompanied by other developmental abnormalities,
diethyl-stilbestrol exposure, and poorly-understood anatomic and hormonal problems.
EPIDIDYMITIS AND ORCHITIS: Ouch!
NONSPECIFIC INFECTIONS of the contents of the scrotum are usually complications of urinary tract
infection, instrumentation (for example, clean-intermittent catheterization: Eur. Ur. 22: 53, 1992),
or prostate surgery.
GONORRHEA: the infection often spreads to the epididymis, less often the testis.
{40116} abscess of the epididymis, gonococcal I'd bet; the tan structure with the white rim is a
cross-section of testis
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Chlamydia of the epididymis
Yutaka Tsutsumi MD
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MUMPS:
orchitis is common in adolescents and adults. It usually follows the onset of parotitis by a
week or so, and may cause atrophy of the germinal epithelium and infertility. The Leydig cells are
spared.
* Thanks to anti-immunization activism, there has been a tremendous
resurgence in Europe. See J. Roy. Soc. Med. 99: 573, 2006.
{25221} tuberculosis of epididymis
TORSION OF SPERMATIC CORD ("torsion of the testis"): Am. Fam. Phys. 74: 1739, 2006
Twisting of the spermatic cord is likely to result in venous infarction and gangrene in a few hours.
This is quite common, especially in children and adolescents.
Spasm of the cremaster muscle keeps the process going (pain spasm pain cycle). The involved testis
is painful and elevated; the cord is typically twisted 540 degrees.
There may or may not be a history of trauma (often minor, as in baseball or break dancing; see
JAMA 256: 3366, 1984).
The underlying problem may be abnormal fixation of the testis or cryptorchidism. Ask a urologist
about the "bell clapper" deformity, with the tunica vaginalis running too high up the
spermatic cord. This supposedly results in torsion after intermittent episodes of
testicular pain (J. Urol. 148: 134, 1992). Of course, once the process
starts, spasm of the cremaster
muscle still plays a role.
You, the physician, may be able to untwist the cord manually. If not,
emergency surgical intervention is indicated. You'll learn about the diagnostic pitfalls
(imaging studies can be unreliable, etc.) on rotations.
An old infarcted (hyalinized) testis is a common surprise finding in autopsy series -- suggesting that
the diagnosis of torsion is often missed.
More seriously, unilateral spermatic cord torsion can somehow damage the opposite testis. Nobody
knows how this happens (J. Urol. 144: 366, 1990); reflex vasoconstriction? autoimmunity?
Torsion of the appendices of the testis and epididymis are painful but not so serious.
A person can also suffer loss of one testis by catching it in a hernia. (There's no room here to talk
about hernias!)
* As noted above, after unilateral torsion of a testis, there is some increase in risk
of infertility even though there was never damage to the other testis.
No one understands the reason; a group
of men who had survived torsion underwent contralateral
biopsy and all had some increase in apoptosis of the germinal
cells (J. Urol. 160: 1158, 1998).
{10892} torsion, gross
{25208} torsion, gross
{10898} testes: normal vs. "atrophic" (could have been old torsion, old mumps, or whatever)
Torsion
WebPath Photo
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GERM CELL TUMORS (cancer of the testis): Cancer of the germinal epithelium. These tumors
are the commonest solid cancers of men in their 20's and 30's.
In 2006, there were around 8250 cses and 370 deaths in the US.
Pathologists see Arch. Path. Lab. Med. 131: 1267, 2007.
Clinicians see Lancet 367: 754, 2006.
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About 95% of tumors of the testis are malignant germ cell tumors.
Remarkably little is known of the molecular biology,
despite their importance. The best-known finding is that the tumors
of young adults (but not the pediatric tumors or spermatocytic
seminoma) usually feature amplification with an isochromosome of the
short arm of 12.
It is now clear that the cells of origin of the "germ cell tumors"
really are the germ cells.
In adults (but not in children, and not in spermatocytic
seminoma), the in situ lesion
INTRATUBULAR GERM CELL NEOPLASIA, UNCLASSIFIED
(IGCNU) can usually be identified in nearby seminiferous tubules (Arch. Pathol. Lab.
Med. 109: 555, 1985 for the original pictures).
The in-situ precursor is now easy to spot.
The tubules are full of cells with big dark nuclei, big nuelcoli,
and abundant, usually glycgen-rich / PAS-positive cytoplasm (normaltubular epithelium
is PAS-negative).
IGCNU cells usually stain with placental alkaline phosphatase (PLAP),
cKit/CD117, p53, and OCT3/4 (the latter a seminoma / embryonal
cell carcinoma nuclear marker.)
Embryonal carcinoma in situ:
Arch. Path. Lab. Med. 126: 48, 2002. Microinvasive carcinoma: Cancer 70: 659, 1992.
We believe that most or all IGCNU will turn invasive if left alone, half within five years.
A German group examined sections from all males coming to autopsy, and
found that the prevalence of carcinoma in situ of the testis (6 out of 1388)
was good match for lifetime risk, i.e., it usually starts in situ, and the in situ lesion
usually turns invasive.
(J. Urol. 173: 1577, 2005)
See below.
Almost all germ cell tumors of the testis
present as painless, non-tender masses in the testis.
The primary may be occult, especially if it's a pure choriocarcinoma.
Many cause gynecomastia (after puberty) or precocious puberty (children.)
Risk factors for this disease are poorly understood. They include cryptorchidism and some intersex
malformations (Arch. Path. Lab. Med. 114: 679, 1990).
There are some familial cases (Mayo Clin. Proc. 65: 804,
1990) but if there is an anti-oncogene syndrome, it remains elusive.
Other risk factors are earlier puberty, and supposedly
lack of exercise as a kid.
Today's boys have both,
compared to us men who are now middle-aged, and this is probably why cancer of the testis is
becoming significantly more common around the world: Br. Med. J. 308: 1393, 1994;
J. Urol. 170: 5, 2003; mostly seminomas in the US: Cancer 97: 63, 2003.
* A study that "showed" that heavy exercise increases a young
man's risk for testicular cancer by 2.5x
(Am. J. Epid. 151: 78, 2000) suffered from a major flaw.
Despite the authors' confidence that everybody was telling the truth in
a retrospective survey,
it seems to me that men who's just lost a testis will want to play
up what macho-athletes they've been. Thankfully (especially with Lance Armstrong)
this obviously bogus "risk factor" never
made it into the news.
Cancer in a testis confers approximately 50x increased risk of there
being at least carcinoma in situ in the opposite
testis. No one really knows what to do about this fact: J. Urol. 160: 1353, 1998.
* Anti-Ma2 is an autoantibody most often seen in testicular cancer
patients that causes a brainstem and limbic encephalitis (can't move eyes, Parkinsonism,
stop talking;
Brain 127: 1831, 2004).
SEMINOMA (Cancer 64: 1608, 1989): cancer that closely resembles young spermatocytes.
Grossly these tumors are homogeneously soft and yellowish.
Tumor cells have "fried egg" appearance (* glycogen-rich cytoplasm);
arranged in masses separated by fibrous septa with a
lymphocytic infiltrate, may have syncytiotrophoblast and/or granuloma formation.
The diagnosis on microscopy is easy.
If help is needed, seminomas are positive for PLAP, c-Kit/CD117,
OKT3/4, and podoplanin/D2-40 (reported as "specific for seminomas"),
but negative for epithelial membrane antigen and (usually, mostly) negative
for cytokeratins.
* Tumors with more than 30 mitotic figures per 10 hpf
have historically been considered more aggressive
(the old "anaplastic seminoma") but since cure rates are so high
nowadays, this is moot.
Chorionic gonadotropin (hCG) is a tumor marker for the 20% or so of seminomas that contain
syncytiotrophoblast (i.e., the man has a positive pregnancy test). * You may be told this is a bad
prognostic indicator but this is probably not important (J. Urol. 151: 67, 1994).
Seminomas typically metastasize to the retroperitoneal lymph nodes and then to the lungs.
Seminomas are remarkable for their good response to radiation or chemotherapy as appropriate, and
even widespread disease can usually be treated with five-year survivals of 95% or better.
* The traditional wisdom is that two years following complete remission, the patient can probably consider himself cured.
Later recurrence of seminoma is uncommon but does occur: Cancer 95: 520, 2002 (many of these
are the people who have apparently benign teratomas left behind.)
Tumors with histology and response to therapy like testicular seminomas (or other germ cell tumors)
also arise in other midline structures including the retroperitoneum, thymus, and pineal
("germinomas"), as well as in the ovary ("dysgerminoma").
{25352} seminoma, gross
{25353} seminoma, histology
{08863} seminoma, histology
{40217} seminoma, histology (PAS stain for glycogen)
{08862} seminoma in situ in the tubular epithelium
{25355} spermatocytic seminoma, gross
{25173} spermatocytic seminoma, histology
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Testicular Seminoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
* If you don't let me play, I'm going to take my ball and go home.
-- Johnny Kruk, Philadelphia Phillies
On being asked not to return to baseball until
he was fully recovered from seminoma surgery
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SPERMATOCYTIC SEMINOMA
It is now clear that this is a rare indolent tumor of older men,
distinct from true seminoma.
The cells
bear a typical nuclear chromatin pattern looking
like the stuck-for-days-unwinding pattern
of normal spermatocytes.
* Unlike true seminomas, staining for OCT3/4 and PLAP are negative.
It almost never metastasizes "as itself", but about 5%
transform into some sort of sarcoma (Cancer 61: 409, 1988) and can metastasize
as such.
EMBRYONAL CELL CARCINOMA: a very primitive cancer that arises in the testis.
Grossly these are grayish-white masses with hemorrhage and necrosis. Microscopically, the tumor
cells grow in sheets, knobs, etc.
Future pathologists: distinguish from a seminoma by absent glycogen
and positive staining for cytokeratin (seminomas are usually weak or negative).
OCT3/4 is usually positive, D2-40 is negative,
and Ki-1/CD30 is usually positive in embryonal carcinomas
but negative in other germ cell tumors.
If the tumor seems to be stage I, metastases are much
more likely if there is vascular invasion seen in the primary; the pathologist
will note this on report.
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{23954} embryonal cell carcinoma, lumen of some kind and some wilder stuff
{23956} embryonal cell carcinoma; cartilage and erectile tissue (subtle)
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Embryonal cell carcinoma
WebPath Photo
{25401} teratocarcinoma
{25402} teratocarcinoma
Tumor markers for common mixtures that include embryonal cell carcinoma include hCG (from
trophoblast areas), α-fetoprotein (AFP, from yolk-sac areas), and * lactate dehydrogenase (LD,
LDH, which is nonspecific and probably of no value).
Tumors with an embryonal cell carcinoma component metastasize to the retroperitoneum and
everywhere else.
Metastases very often mature into benign teratomas during treatment.
It is now clear
that these are usually (but not always) benign, and that persistently elevated tumor markers
can be due to slow leakage from cyst fluid (J. Urol. 171: 168, 2004).
Do not overtreat.
Or the cured metastases may turn into scar tissue, or just plain necrotic debris (J. Urol. 142: 1239,
1989).
The response to newer chemotherapy protocols is very good, with around 85% apparent cures even
when metastatic disease is widespread (Cancer 56: 2411, 1985).
* Most protocols are now based on ifosfamide and platinum. They are highly successful,
and the old retroperitoneal lymph node dissection procedure is now reserved
for hard cases. The pathology specimens are often curious,
with the tumors much altered by chemotherapy (Cancer 109: 528, 2007); any viable
tumor in the specimen is ominous (Cancer 107: 1483 & 1503, 2006).
The most infamous after-effect of the traditional
retroperitoneal lymph node dissection was the loss of the ability to ejaculate
(why?); see J. Urol. 142: 1487, 1989 and Cancer 64: 2399, 1989 for psychological well-being after
testicular cancer.
There's also a nerve-sparing retroperitoneal
lymph node dissection technique that supposedly leave the
ability to ejaculate intact (update J. Urol. 169: 1710, 2003). Some centers now use nerve-sparing surgery-only,
no chemotherapy (Urol. Clin. NA 25: 461, 1998).
Again, a two-year disease-free survival generally indicates cure.
CHORIOCARCINOMA:
The bloodiest solid tumor in pathology; solid areas may be hard to find.
The malignant cells resemble placenta, and the pathologist must identify cytotrophoblast and
syncytiotrophoblast. There are no villi.
HCG levels are always very elevated (serum, urine.)
Choriocarcinoma most often is a component in a teratocarcinoma, but may be pure or mixed with
any other germ cell tumor components.
Until recently, choriocarcinoma arising in the testis was always lethal.
Today the prognosis is not much worse than for embryonal cell carcinoma, even if the tumor is
"pure choriocarcinoma".
YOLK SAC TUMOR ("endodermal sinus tumor", "orchioblastoma", "infantile embryonal cell
carcinoma"):
The commonest testicular tumor of children (but still quite rare), usually occurs "pure" rather than
mixed with other germ cell tumor types.
In adults, it tends to be a component of an embryonal cell carcinoma.
It is composed of papillary structures (Schiller-Duval bodies) with extracellular globs of
α-fetoprotein and α-1-protease inhibitor.
This carcinoma is also unusual because it metastasizes hematogenously.
Response to chemotherapy is very good in kids, and pretty good in adults.
* Two rarities that remind us that the testis is about reproduction:
POLYEMBRYOMA features a mix of embryonal cell carcinoma
and yolk sac tumor with a cavity resembling the amnion,
studded with embryoid bodies (i.e., structures like the early
embryo, with the three germ layers. DIFFUSE EMBRYOMA
has a layer of yolk sac tumor surrounding an embryonal cell
carcinoma, as if it were itself the amnion.
{25175} yolk sac cancer, gross
{11551} yolk sac cancer, histology
Yolk sac carcinoma
Liver
Pittsburgh Pathology Cases
Yolk sac tumor
WebPath Photo
TERATOMAS:
Cystic teratoma of testis is rare (but common in ovary) and
seldom contains hair. (Teratomas are the only testicular tumors
that are often cystic.)
Solid teratomas are of two types:
Mature solid teratoma is benign, usually occurs in children.
Immature solid teratoma is malignant, usually contains embryonal cell carcinoma
(TERATOCARCINOMA)
or sometimes squamous cell carcinoma.
* Even if an adult's teratoma appears altogether benign, there is likely to be nearby intratubular
carcinoma in situ (Cancer 64: 715, 1989).
A common misunderstanding is that "most teratomas of the adult testis
are malignant", because most of them contain embryonal cell carcinoma.
Technically, it's correct to say this.
WARNING: Any tumor of germ cell origin may be mixed with any other tumor of germ cell origin.
Mixed germ cell tumor of testis
Great photos
Pittsburgh Pathology Cases
Further, any tumor of germ cell origin may metastasize as another histologic type of germ cell
tumor. For example, a seminoma turning into a yolk-sac tumor generated much surprise: Am. J. Clin.
Path. 97: 468, 1992.
We now know both in-situ and microinvasive testicular cancer. See Cancer 70: 659, 1992; Urol.
Clin. N.A. 20: 127, 1993; Cancer 64: 715, 1989. A monoclonal antibody that stains carcinoma in
situ: Cancer 65: 1135, 1990.
MALIGNANT LYMPHOMA arises in the testes of older men with some frequency.
Update Arch. Path. Lab. Med. 131: 1040, 2007.
ADENOMATOID TUMOR is a benign, hard spherical
nubbin, usually in the head of the epididymis,
derived from mesothelium (* positive for EMA, cytokeratin).
Germ-cell tumors (seminomas, embryonal cell tumors, teratocarcinomas, choriocarcinomas, and the
usual mixtures) can and do arise in the retroperitoneum, mediastinum, and pineal "because they are
midline structures" (?!). Their behavior is similar to testicular tumors. Review Chest 103-S4: 331-S, 1993.
* Famous testicular cancer victims include funmaker Tom Green
(non-seminoma), Olympic gold-medal swimmer
Alex Baumann, Russian writer Alexander Solzhenitsyn ("Cancer Ward", had seminoma),
cyclist Lance Armstrong (nonseminoma), figure skater Scott Hamilton
(non-seminoma), Chinese dissident Chen Ziming, football player Brian Piccolo ("Brian's song"),
runner Steve Scott, and more.
STROMAL TUMORS
LEYDIG CELL TUMORS: occur at any age, are usually benign, can produce precocious puberty or
gynecomastia. Update Arch. Path. Lab. Med. 131: 311, 2007.
The gross and microscopic appearances are typical for endocrine tumors. Sometimes, the
pathologist can make the diagnosis easy by identifying a Reinke crystalloid!
* Future pathologists: The tumor marker for Sertoli-Leydig differentiation
is inhibin (Am. J. Surg. Path. 22: 615, 1998.)
* Criteria for malignancy are necrosis, mitotic figures, local invasion,
and nuclear pleomorphism, just like you'd expect. MIB-1, the proliferation
marker, seems to be a powerful predictor (Am. J. Surg. Path. 22: 1361,
1998).
The tendency today seems to take the tumor and leave the testis behind,
as long as there's no suspicion of malignanc (J. Urol. 178:
507, 2007).
Sertoli cell tumors ("androblastomas"; Urology 25: 1985; Am. J. Clin. Path. 96: 717, 1991),
are uncommon.
Animal model Am. J. Path. 144: 454, 1994; Urol. Clin. N.A. 27: 529, 2000. Calcified sertolioma:
think Peutz-Jegher's.
Leydig cell tumor
Pittsburgh Pathology Cases
HYDROCELE: Fluid in the tunica vaginalis. Usually idiopathic, a hydrocele may contain 100 cc
or more of serous fluid.
If ascites is present and the patient has a patent processus vaginalis, a hydrocele will appear and
disappear as the patient changes position.
You can distinguish a hydrocele from a tumor mass by trans-illuminating it with a bright flashlight
in a dark room.
* Today's man can choose between traditional surgery and sclerosing therapy.
{24589} hydrocele, gross
Hydrocele
WebPath Photo
HEMATOCELE: Blood in the tunica vaginalis. May follow trauma (J. Urol. 127: 1195, 1982), or warn
of an underlying testicular cancer.
{25191} hematocele (guy got kicked probably)
VARICOCELE: Varicosities of the pampiniform plexus, usually on the left side (why?)
This is common in young men, may cause fertility problems by warming the testes.
A new varicocele in an old man often indicates occlusion of the vein by renal cell carcinoma,
especially if the veins do not collapse when the patient lies down.
SPERMATOCELE: a cystic lesion up to 1 cm or so in the area of the rete testis, filled with fluid and dead
sperms.
PROSTATITIS
You remember the normal gross and microscopic anatomy of the prostate gland.
The lobes actually are only distinct in embryos.
Pathologists distinguish three types of acini. The mucosal and submucosal
are in the periurethral ("inner") zone, separated by smooth muscle from the external acini
("cortical" / "outer").
Acute and chronic prostatitis are uncomfortable problems, and are common in men who catch
sexually-transmitted urethritis or lower urinary tract infections.
The diagnosis depends on physical and lab exams.
In acute prostatitis the gland is exquisitely tender. You should probably not attempt to express fluid!
Gonorrhea is an important cause of acute prostatitis (secondary to urethritis; remember it can also
cause epididymitis).
{25212} acute prostatitis, gross
{25213} acute prostatitis, histology
{25214} chronic prostatitis, histology
{25215} chronic prostatitis, histology
In "non-bacterial prostatitis", the findings are as in chronic prostatitis (expect
white cells in the semen), but no organisms grow.
(Probably chlamydia
cause some of these infections. See J. Urol. 141: 328 & 332, 1989.)
Trichomonas is another candidate (Am. Fam. Phys. 39: 177, Feb. 1989). Autoimmunity is yet
another: J. Urol. 152: 247, 1994). No longer a taboo subject:
heroic abstinence (no partner, no self-entertainment) makes this problem MUCH
worse (Int. J. Urol. 6: 130, 1999).
"Prostatodynia" is a stress-related pain syndrome in which there are no WBC's in the prostatic fluid.
Other exacerbating factors include constipation, smoking, coffee, and spices (all of which make an
infected prostate hurt more, too. See Urology 26: 320, 1985.)
* "Prostatosis" is an old term for both non-bacterial prostatitis and prostatodynia.
Granulomatous prostatitis may be due to TB (hematogenous spread from the lungs), "idiopathic"
(no TB, no caseation, no clues as to the etiology) or * exotic (J. Urol. 143: 365, 1990). * The
histiocytes may resemble cancer cells.
Prostate infarcts, which produce hematuria and a painful lump,
usually result from instrumentation that causes arterial thrombosis.
* Squamous metaplasia in prostate epithelium occurs at the edges of infarcts, or in men treated with
estrogens or finasteride.
{23968} granulomatous prostatitis
PROSTATIC HYPERPLASIA ("benign prostatic hypertrophy or hyperplasia", "BPH"). Review:
Disease-a-Month 41: 437, 1995; Urol. Clin. N.A. May 1995.
This is something that happens to most intact men over about age 50; 10% of men living to age 80
will need prostate surgery.
Surprisingly, there is remarkably little work on its basic biology.
The normal prostate weighs around 20 gm. Old men's prostates enlarge to 60-200+ gm.
The increased tissue is nodular overgrowth of periurethral glands and stroma. The hyperplasia most
often involves the lateral and median lobes.
Future pathologists: Look for expanded glands, often with papillary infoldings, and dense, stroma.
The low-power view proves that the overall architecture of the gland is preserved. All about the
histopathology: Urol. Clin. N.A. 17: 477, 1990.
* "Sclerosing adenosis", a fooler for cancer, has true myoepithlium
(S100 +, muscle-actin +), unlike cancer or common hyperplasia.
The site where the hyperplasia arises ("the transition zone") is well-characterized (Urol. Clin. N.A.
17: 477, 1990).
By contrast, "the posterior lobe is the most common site for the development of prostatic
adenocarcinoma". (* Do you think that this might simply reflect the fact that cancers here are easier
to detect early?)
Median lobe hyperplasia by itself produces a "median bar" (today, a "midline dorsal nodule"), obstruction without an enlarged gland.
Don't be fooled.
The etiology of prostatic hyperplasia is obscure. It probably has something to do with sex hormones
and their receptors. Heroic abstinence is also rumored to be a risk factor,
although probably for everybody else there's little
protection from more-frequent ejaculation (Urology 61: 348, 2003).
The most interesting work
focuses on various proteins produced by the
stroma that cause hyperlasia of glands, and proteins produced
by glands that cause hyperplasia of the stroma.
Long-studied, there are updates in
J. Urol. 172: 1784, 2004 and Endocrinology 146: 13, 2005.
There's a mouse model -- a transgenic mouse with its int-2 proto-oncogene (fibroblast growth
factor #3) revved up. It shows the same androgen dependency as do old men's prostates (J. Urol.
149: 633, 1993).
* Cell culture researchers talk about mysterious interactions
between epithelium and stroma (J. Clin. End. Metab. 83:
206, 1998.
Prostatic hyperplasia causes many problems (collectively called "prostatism"), though most patients
are asymptomatic.
- Frequency (i.e., only small amounts are voided at a time), nocturia (urinating at night, same reason),
difficulty starting and stopping urination, incontinence (dribbling), dysuria (painful urination),
hernias (from straining), acute urinary retention (emergency).
- Hematuria (due to stretching of veins), bladder hypertrophy and trabeculation (accentuation of the
normal muscles), bladder diverticula, bladder stones, hydronephrosis, renal failure
- Residual urine accumulates in an enlarged bladder behind the prostate gland. This gets infected,
etc., etc.
The treatment is surgical -- one favorite procedure is trans-urethral resection (TURP), or try the
laser approach (J. Urol. 154: 174, 1995) or the newer cryosurgery
or microwave
techniques (pathology of cooked prostate: J. Urol. 171: 672, 2004;
also J. Urol. 170: 12, 2003).
Hyperthermia:
J. Urol. 144: 1390, 1990. How and when to intervene: Urol. Clin. N.A. 17: 509, 1990. Treatment
guidelines from the Feds: Geriatrics 49: 25, 1994.
I still think I'd opt for surgery rather than some of the
new hormonal manipulations.
Patients treated with 5-alpha reductase inhibitors (i.e., finesteride)
tend to get atrophy of the glands and some squamous metaplasia, but it is not spectacular.
The much-promoted saw palmetto fails a controlled study miserably: J. Urol. 171: 284, 2004;
another failure NEJM 354: 557, 2006.
{10743} prostate hyperplasia, gross. Don't try this paper clip trick at home.
{17007} prostate hyperplasia, gross cut surface
{15382} prostate hyperplasia, gross; both gland and bladder have been opened anteriorly
{18766} prostate hyperplasia, gross
{24445} prostate hyperplasia, gross
{17458} prostate hyperplasia, good median bar
{08856} prostate hyperplasia, histology
{17457} prostate hyperplasia, histology
{17197} prostate hyperplasia, histology
{08857} prostate hyperplasia, histology
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PROSTATE CANCER: Adenocarcinoma of the subcapsular glands. All about the pathology:
Cancer 70(S1): 235, 1992; Cancer 71(S3): 906, 1993 (deja vu);
changes after therapy Arch. Path. Lab. Med. 131:
360, 2007; review of the disease Br. Med. J. 308: 780, 1994;
Sci. Am. 279(6): 74, Dec. 1998.
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Prostate cancer is the commonest cancer in men, and the second leading cancer killer of men. There are around
198,000 new cases in the US yearly, and 31,000 deaths (i.e., it's now our most common men's
cancer, but most of these men die of something else; see Lancet 1: 799, 1989).
This doesn't include LATENT PROSTATE CANCER (i.e., you found it only at autopsy, and it caused no
problems), and probably not all cases of INCIDENTAL
PROSTATE CANCER (i.e., you found it on the turp
chips). OCCULT PROSTATE CANCER might pop up in bone marrow or lymph node prior to becoming
symptomatic.
The tremendous increase in the incidence of prostate cancer during the 1990's
(about 30%) reflects the improved screening.
A man's lifetime risk of dyingof the disease is
actually decreasing.
The in-situ lesion (formerly "prostatic dysplasia", now "prostatic intra-epithelial neoplasia") is now
well-characterized (J. Urol. 149: 170, 1993; Am. J. Cln. Path. 96: 628, 1991). There's
always nuclear enlargement and crowding, there are usually nucleoli and some piling-up, and the
nuclei are more hyperchromatic as the grade increases. But there is no invasion or architectural
distortion. Low-grade "PIN" is common in young men (J. Clin. Path. 42: 383, 1989; J. Urol. 150:
379, 1993), and it probably takes decades to transform; some pathologists simply
don't report it even if they see it, and today's wisdom is that this is the correct
thing to do (J. Urol. 166: 402, 2001). The high-grade kind, distinguished by prominent nucleoli, is much
wickeder: J. Urol. 158: 12, 1997. Atypical prostate biopsies:
J. Urol. 159: 2018, 1998.
* Much of the work on this lesion was done by former
Mayo pathologist Dave Bostwick MD; I was his "path
resident" when he was a med student in 1978. I'm
proud of you, Dave!
Nobody knows yet exactly what to do when you
discover PROSTATIC INTRAEPITHELIAL NEOPLASIA
("carcinoma in situ" or whatever; update Arch. Path. Lab. Med. 131:
1257, 2007). Usually these lesions will involve
part of a single gland. Nowadays, the feeling is that PIN3 requires
re-biopsy. Of course, we are going to assume that we are
not simply looking at an aggressive cancer spreading down the ducts,
which can look identical. Here's
how to make the call:
Low grade
PIN1: loss of secretion, piling up of cells ("tufting"),
blue cytoplasm, looks lush
High grade (HGPIN)
PIN2: As PIN1, but with high N/C ratio
PIN3: As PIN2, but with prominent nucleoli and a papillary or cribriform pattern
Any: The basal layer is at least somewhat intact. (It is NEVER
intact in true adenocarcinoma). Racemase / AMACR / P504S
is very often (some say almost always) positive in PIN.
Future pathologists beware: Some cribriform growth in the center
of the prostate is normal, there's a benign "adenoid-cystic-like adenoid basal
cell tumor", and there's a benign clear-cell cribriform
hyperplasia.
Future pathologists beware: "Adenomatous hyperplasia" is an
mass of crowded glands, but without any nuclear abnormalities.
Best call it benign.
Prostate cancer is mostly a disease of men over age 50.
Prostate cancer is rare in Oriental folks in Asia, more common in Asian-Americans, common in U.S.
whites, and most common in U.S. Blacks.
The majority, but not all, prostate cancers supposedly
arise in the posterior lobe. Again, I wonder whether this merely reflects how much
easier these are to detect.
In classic studies, serial sections of prostates at autopsy show little adenocarcinomas in 10% or so of
US 50-year-old men and nearly 100% of 100-year-old men.
The most recent stuff is about the same (1 in 3 of men in their sixties,
about of half of men in their seventies: J. Urol. 179: 892, 2008).
Most are "occult", however. Today, some urologists will
advise patients to leave these alone if discovered (i.e., prostate-specific
antigen levels less than 15 ng/mL, Gleason 3+4 or less,
and a majority of cores negative on repeat biopsy after 18-24 months.
Update J. Urol. 178: 833, 2007).
Grade and volume determine metastatic
potential. Surprised? Of course not. And if the gland is clinically benign, the rate of metastasis
seems to be extremely low (or maybe even zero, Arch. Path. Lab. Med. 119: 731, 1995).
* How many turp chips should the pathologist check?
Most pathologists probably submit all the chips if they weigh
in aggregate 30 gm or less; at least one cassette for every 5 grams if more.
The etiology of prostate cancer is essentially unknown.
Androgens play some role; early castration prevents the development of adenocarcinoma (* not
worth it, though....)
There is probably no link to infection or prostatic hyperplasia, or to lack of sexual activity.
For some reason this was re-examined recently and the conventional
wisdom stands. Frequency of ejaculation does not seem to have any impact (good or bad)
on risk for
prostate cancer (JAMA 291: 1578, 2004).
Industrial exposure to cadmium (i.e., battery factories) is supposedly linked to increased prostate
cancer. (Everything bad about cadmium: Nature 361: 369, 1993.) The link
strongly disputed: J. Tox. 6: 227, 2003; J. Occ. Env. Med. 43: 593, 2001;
the animal model isn't striking Prostate 46: 11, 2001);
today most regulatory agencies don't classify it as a carcinogen.
* Your lecturer suspects the old alleged "link" between vasectomy and prostate cancer simply reflects the
fact that men who get vasectomies go to the doctor more often, and get their prostates checked more
often. (See JAMA 269: 913, 1993).
There is a longstanding hoopla over high-fat / meat diet as a very important risk factor for cancer of the
prostate (Ann. Int. Med. 118: 793, 1993; update J. Urol. 171: S-19, 2004).
You remember the same claim about breast cancer in the
1980's; it didn't hold up.
A huge study about carotenes, lycopenoids, etc., etc. and prostate cancer
turned up no correlation with overall risk
with some possible weak favorable correlations suggesting
protection against advance disease
(lots of warnings against inferring cause and effect: Am. J. Clin. Nutr. 86: 672, 2007).
* Not so long ago there was a flap about milk consumption as being a risk factor.
The results are amazingly inconsistent (skim milk appears more
dangerous than whole milk: Int. J. Cancer 73: 634. 1997;
no no, it's the animal fat that's dangerous Br. J. Cancer 80: 107, 1999;
no it's the calcium and the effect is very small: Am. J. Clin. Nutr. 74:
549, 2001;
very weak link Int. J. Cancer 80: 704, 1999).
I can't really take this seriously when there so many confounding variables,
known and unknown.
I was more impressed with J. Urol. 154: 153, 1995; smokers don't have a higher rate of prostate
cancer, but the cancers are higher-grade and meaner.
* Molecular signatures that actually matter
to the prognosis or easy diagnosis remain elusive (J. Clin. Path. 58:
67, 2005). The only one so far that is typcially overexpressed in prostate
cancer regardless of grade, and not in benign prostate lesions, is PAX2
(J. Urol. 165: 2115, 2001). Expression of
survivin, an apoptosis inhibitor, seems to predict poor
prognosis: J. Urol. 171: 18855, 2004.
The tumor loses its androgen sensitivity when
(Nowell's law!)
the androgen receptor gene mutates
(no surprise, NEJM 332: 1440, 1995).
The best-studied prostate cancer gene is HPC1 / RNASEL, where a single
nucleotide substitution increases risk but apparently not aggressiveness (J. Urol. 179:
1344, 2008).
There is another prostate-cancer-family gene: HPC2 / ELAC2; curiously, it gives only about double the normal risk.
The same's true of each of five newly-identified loci
(NEJM 358: 910, 2008.
Not surprisingly, the high-grade cancers tend to stain for telomerase
and the low-grade ones don't (why?; Cancer 95: 2487, 2002).
Cancer of the prostate presents as a painless lump in the gland.
These tumors are easier to feel than to see; they are firmer than hyperplastic nodules, poorly
circumscribed, and yellowish.
Diagnosis is by biopsy or fine-needle aspiration. Or it may turn up in a routine prostatectomy
specimen. (If you're going to operate for obstruction anyway, there's no reason to biopsy first.)
* Future pathologists: With all these guys getting needle biopsies nowadays, you need to try to find
tiny cancers. You must section several levels of the core biopsy (Am. J. Clin. Path. 107: 26, 1997;
Arch. Path. Lab. Med. 122: 833, 1998).
Prostate biopsies are tiny. In around 5% of them, the pathologist
is likely to ask for re-biopsy. Arch. Path. Lab. Med. 123: 687, 1995.
Help with your tough calls: Arch. Path. Lab. Med. 124: 98, 2000.
Recently, the trend has been to get lots of cores; ten is now commonplace
and twenty may become standard (J. Urol. 179: 504, 2008).
When given a metastasis from a suspected primary, the pathologist stains for prostatic acid
phosphatase and/or prostate-specific antigen -- both are highly sensitive and specific for prostatic
origin.
Almost all are "prostate type" adenocarcinomas. (I find the traditional distinction
between "large duct" and "small acinar" to be less-than-helpful.)
To diagnose prostate cancer, you want to see one or more
of the following:
- prominent nucleoli in nuclei with marginated chromatin (best; see Cancer 65:
1017, 1990)
- invasion (especially perineural invasion; at least loss of the normal gland-stroma
interaction); sometimes prostate cancer shows first as indian-files between the
normal glands
- obvious distortion of the architecture
- loss of the outer layer ("basal layer") of the glands
* Future pathologists: you
can use keratin 34βE12 ("keratin 903" or "K903"; most popular) or some
other special keratin
stain to see the cytoplasm basal layer; if absent or very discontinuous, think cancer.
* Nuclei with sharp angles, and cytoplasm with vacuoles, suggests
that your "single-layered" acinus is basal cells, with the secretory
cells gone from atrophy.
- 34βE12 staining of the cytoplasm (i.e., it's basal cells) or p63 staining of the nucleus suggests the lesion is benign
- P504S (AMACR / racemase) granular staining of the cytoplasm suggests malignancy
Some cases in which you see an isolated small acinus
cannot be resolved and should probably be called "atypical small acinar proliferation
suspicious for malignancy"; in any case this lesion is followed, more often
than not, by frank cancer (Arch. Path. Lab. Med. 130: 952, 2006;
also Am. J. Clin. Path. 128: 648, 2007). Update on "current prostate biopsy interpretation": Arch. Path. Lab. Med.
130: 835, 2006; the immunostains Am. J. Clin. Path. 123: 231, 2005;
combining three Am. J. Clin. Path. 127: 248, 2007.
Beware: As in breast, several benign lesions exist that are easily mistaken for cancer. Let us
pathologists worry about these. Good reading: Am. J. Clin. Path. 101: 48, 1994.
* On fine needle aspiration biopsy, pathologists pay special attention
to the presence or absence of the basal layer, which conveniently will
lie in its own plane of focus.
Grading of prostate cancer is now performed on the Gleason I-V system, based on low-power H&E
pattern of tumor. Oversimplified Gleason's:
|
I: Glands with some stroma between, sharp edge to the lesion (rare, you'll probably not diagnose it except as an incidental finding on prostatectomy)
II: Glands that are very crowded, less sharp edge to the lesion
III: Nests / cribriform pattern / tiny glands
IV: You can still tell it's of glandular origin, but the acini are very abnormal or fused
V: You can't really tell it's of glandular origin OR you see masses of necrosis
|
 Gleason grading
Online quiz
Hopkins
|
Grade correlates with stage and prognosis. Most prostate cancers, even the ones that have
metastasized, are fairly well-differentiated adenocarcinomas.
* Genetic
prognostication (cyclin D1 and other cell-cycle kinases seem to be the
key genes: Cancer 80: 753, 1997.)
Biomarkers (microarray technology -- i.e., which genes are activated?):
Nature 412: 822, 2001; Cancer 104: 209, 2005.
* Gleason grading is not precise and there is considerable
inter-pathologist variability: Arch. Path. Lab. Med. 129:
1004, 2005.
* Staging of course also affects prognosis.
For the TNM system --
Tx: occult tumor
T1: not palpable, within prostate
T2: palpable, within prostate
T3: through the capsule
T4: fixed or invades something other than the seminal vesicles
Nx: nodes not assessed
N0: no nodes
N1: one positive node, 2 cm or less
N2: no node 5 cm or larger
N3: some node 5 cm or larger
Mx: metastases not assessed
M0: no distant metastases
M1: distant metastases
More familiar:
A1: well-differentiated carcinoma on 5 or fewer turp chips / fewer than 3 foci / fewer than 5% of the
chip mass (rules vary).
A2: still occult, but on more than 5 chips or high-grade
B: palpable nodule
C: through the "capsule" or in the seminal vesicles
D: metastases
Before you decide you can tell benign from malignant
reliably on physical exam, note that even a pathologist
with the sectioned gland in his/her hand prior to microscopy is only 2/3 sensitive
and 5/6 specific (Am. J. Clin. Path. 110: 38, 1998).
Uncommon prostate cancers include squamous and endometrioid (J. Roy. Soc. Med. 85: 394, 1992;
Acta Cytol. 35: 45, 1991), plus adenoidcystic, colloid, carcinosarcoma, signet-ring,
oat-cell, carcinoid, and lymphoepithelioma.
Cancer of the prostate seldom causes problems (or is diagnosed) unless it spreads.
Rectal exam is still the most effective method of diagnosis (cost per life saved a mere $6300; see
JAMA 252: 3261, 1984).
For more on "prostate specific antigen", see the upcoming lecture on cancer screening and
monitoring. Nowadays, urologists are likely to do sextant biopsies on prostates of
men with elevated PSA's and no palpable lump.
Prostate cancer is often indolent even when it has metastasized, but some prostate cancers are very
aggressive.
* Mucin-producing prostate cancer is an aggressive lesion with its own
molecular signature; it is probably a different disease (J. Urol. 54:
141, 1999).
* Finasteride has been offered for prostate cancer prophylaxis (NEJM 349:
205, 2003). On the plus
side, there was a few percent fewer cases of low-grade prostate cancer.
On the minus side, there was no change in the rate of high-grade prostate
cancers or cancer deaths. You'll have to decide for yourself whether the effects
of taking finasteride at these doses (fewer and softer erections, diminished
seminal fluid volume, loss of chest hair, preservation of scalp hair) are good or bad.
You will care for many patients with metastatic prostate cancer.
Prostate cancer typically metastasizes to the axial skeleton (there's a direct connection
between the prostate and the valveless venous plexus that surrounds the inside of the spinal column), eventually causing miserable bone pain.
(Future radiologists: prostatic metastases are often osteoblastic.)
Prostate cancer seldom producers actual brain metastases, but is also infamous
for metastasizing to the leptomeninges.
{17012} prostate cancer in bone, x-ray
Serum acid phosphatase (* tartrate inhibited) is a classic tumor marker for prostate cancer (see
JAMA 253: 665, 1985). The best new tests measure only the prostatic component.
Patterns of metastatic spread: Cancer 54: 3078, 1984.
Treating prostate cancer:
Surgery and/or radiation are useful for localized disease. Conventional chemotherapy is of limited
usefulness in prostate cancer, but protocols do exist.
Prostate cancer is usually quite responsive to endocrine manipulations.
Castration (orchiectomy -- oh no!) and/or estrogen therapy (causes cardiovascular problems) were
for many years the standard treatments for patients with symptomatic bony metastases. Now they
are being replaced with newer agents.
One important new agent is leuprolide, a GnRH (gonadotropin releasing hormone) agonist.
* When large amounts of leuprolide are present for a while, the pituitary stops making GnRH
receptors and thus stops making gonadotropins. (Seems paradoxical, doesn't it?) The patient soon
has stopped making androgens, and the prostate cancer cells undergo apoptosis.
* The histopathology of leuprolide response is sufficiently distinctive to be recognizable by a good
pathologist: Cancer 73: 1472, 1994.
Another approach is the non-steroidal anti-androgen Flutamide, which shrinks prostate cancer
supposedly "without causing impotence".
The anti-fungal agent ketoconazole blocks synthesis of androgens and has also proved useful as an
anti-prostatic cancer drug.
* Future oncologists: Etidronate is a new drug treatment for refractory bone pain -- it seems to work
by preventing formation of new bone.
With the focus on early detection, it's worth remembering that low-grade, low-stage prostate cancer,
treated very conservatively, doesn't seem to shorten life expectancy (JAMA 274: 626, 1995).
Nowadays, of course, you can follow the course of treated prostate cancer with serum prostate
specific antigen, the same stuff as you use for screening: Mayo Clin. Proc. 69: 69, 1994.
To date, no one has produced any "evidence-based" support for any of a host
of "alternative and complementary" remedies for prostate cancer (Urol. Clin. N.A. 33: 237, 2006).
{21031} prostate cancer, gross
{18767} prostate cancer, gross; looks yellowish
{03236} hydroureter in prostate cancer
{08865} well-differentiated prostate cancer
{23979} well-differentiated prostate cancer, Gleason 2
{08866} prostate cancer, cribriform, Gleason 3
{08864} prostate cancer, Gleason 3
{23980} poorly-differentiated prostate cancer, Gleason 4-5
{23975} atrophy of the prostate, as, after removal of androgens
{23969} irradiated prostate; note radiation changes in vessel to right of center
Prostate Carcinoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Prostate Carcinoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
* Anthony Sattilaro, an MD who claimed
to be cured of prostate cancer by the "Zen Macrobiotic Diet" (even though he'd
undergone conventional therapy),
authored the very famous books "Recalled by Life"(1982) and
"Living Well Naturally" (1984). He died of his prostate cancer in 1989.
Quacks still claim he was cured and is alive.
LOOKING AT PROSTATE BIOPSIES:
You will look and feel smart if you know the following. Leave the final
call to your pathologist.
|
Benign |
Malignant |
| Low magnification? |
Architecture intact |
My team:
Pearly penile papules
Fournier's gangrene
Fournier's gangrene
Lymphadenectomy incision
Balanoposthitis
Pearly penile papules
Mumps orchitis