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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.
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I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:
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
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
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:
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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 eighteen 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 William Carey 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 William Carey for making it still possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!
OBJECTIVES:
The student will give a reasonable account of the origins, symptoms, signs, epidemiology, and anatomic pathology of the common bladder lesions.
The student will recognize the common cystoscopic and biopsy lesions.
KCUMB Students
"Big Robbins" -- Lower Urinary
Lectures follow Textbook
QUIZBANK: Lower urinary (all)
As men draw near the common goal,
Could anything be sadder
Than he who, master of his soul,
Is servant of his bladder?
Keep The Water Flowing.
Kidney & Urinary Tract
|
Kidney and Lower Urinary
|
Lower Urinary / Male
|
Urologic Path
|
Urinary Tract Malformations
|
Urinary Tract
|
Bladder Exhibit
|
INTRODUCTION: Easy unit.
{15588} normal bladder, gross
{15771} normal bladder, gross
{15772} normal bladder, gross
{15587} normal bladder and prostate, gross
{15114} normal bladder, histology
{15120} normal bladder, histology
{15326} normal bladder, histology
{25266} normal bladder histology
You remember that normal transitional epithelium (better, "urothelium") is designed to cover surfaces that change their areas rapidly ("transition").
Bladder urothelium should be six or fewer cells thick (really, strata of nuclei), less when the bladder is full. The superficial layer exhibits the famous protective layer of broad, flat "umbrella cells", while the basal layer is famous for its ability to flatten out.
* Urothelium in the renal pelvis tends to have fewer layers, usually 3-5.
Urothelium usually produces a bit of mucin, which explains those few bubbles in the toilet bowl. Often tumors that arise from urothelium produce mucin also. This does not make them "adenocarcinomas".
Uroplakin III stains normal urothelium and many urothelial cancers, being quite specific (Am. J. Clin. Path. 113: 683, 2000).
When urothelium turns to urothelial papilloma-carcinoma, it tends to do so in multiple places (Nowell's law again, since urothelial cells seldom divide, they are all the more readily overgrown by mutants with more of a propensity to divide). Forty percent of tumors are multiple at presentation. This has a lot to do with "frequent recurrences after surgery".
{14941} normal urothelium
{14937} normal ureter histology
{10022} normal urothelial, cytology
A STRICTURE is fibrous tissue partially or totally occluding the lumen of a narrow hollow organ, usually the ureter or urethra. They may be congenital, but is more often post-injury scarring (gonorrhea, instrumentation, stone).
URETER PROBLEMS
You know the anatomy. The muscle is interlaced, without real layers. Acute obstruction causes renal colic, which is often excruciating. Chronic obstruction is usually asymptomatic, though the kidney won't function and will eventually atrophy.
Places where stones, etc., hang up are (1) the pyelo-ureteric junction; (2) the pelvic brim; (3) the ureterovesical junction.
DOUBLE URETER (bifid ureter) is whole or partial duplication, with two pelvises in the kidney. No big deal. A few percent of folks have this minor variant.
{15711} bifid ureter, gross
Any obstruction to urinary flow (in the ureter or elsewhere) during fetal life will result in CYSTIC DYSPLASIA of the portion of the kidney that isn't being properly drained.
An INCOMPETENT URETEROVESICAL VALVE is a common birth defect that causes reflux and predisposes to kidney infections. It may stay open all the time, or open during micturition.
How to manage these children remains controversial. Many of these children undergo surgical repair, but the benefit of surgery over simply treating infection is not clear (Lancet 357: 1329. 2001); now that surgery can be done endoscopically, we may have a better idea (NEJM 366: 1218, 2012). When there is actual deformity of the ureter, the kidney disease is a mix of renal dysplasia (which is part of the birth defect) and actual damage from the bacterial infections.
* A variety of defects have been reported in valves that merely reflux during micturition, including findings as simple as lack of smooth muscle and as complicated as the lack of certain obscure electrical cells and their gap junction protein (J. Urol. 174: 1981, 2005.)
HYDROURETER (i.e., dilated ureter) has several causes
CONGENITAL
PREGNANCY ("estrogen relaxes smooth muscle", etc.)
OBSTRUCTION
Ureter cancer
Bladder cancer
Prostate cancer
Cervix cancer
Metastases in the para-aortic lymph nodes
Etc.
CHAGAS'S DISEASE
{18791} pyelonephrosis and pyoureters, gross
A very large ureter is called a MEGA(LO)URETER.
* "Follicular ureteritis" is an archaic name for big lymphoid nodules. "Ureteritis cystica" and "Brunn's nests" match their counterparts in the urinary bladder.
Almost all cancer of the ureter is "urothelial carcinoma", a better term than the old name "transitional cell carcinoma". Like cancer of the renal pelvis, this is a variation on bladder cancer, with the same risk factors and the same tendency to arise multifocally over the urothelium.
{10580} urothelial carcinoma, ureter
NON-NEOPLASTIC DISEASE OF THE URINARY BLADDER
You learned in physiology and neuroscience class about the various problems with voiding when the cerebral cortex and bladder are separated. When the bladder is inflamed, urinating can be uncomfortable, and often the bladder contracts with excessive force (urgency). See "Big Robbins" for a common-sense list of causes of bladder outlet obstruction.
Anatomic and clinical pathology have not explained "overactive bladder", a common problem especially in older women, with discomfort, frequency, urgency, and/or urge incontinence.
EXSTROPHY of the urinary bladder results from failure of the pubis to form properly. This is a messy problem for the surgeon to repair, and of course, infection and poor hygiene are terrible problems. Update Urol Clin. N.A. 31: 417, 2004. Thankfully, today most of these patients are spared kidney damage despite the risk of ascending infections (J. Urol. 168: 2579, 2002).
{10742} exstrophy of the urinary bladder
PERSISTENT URACHUS, if it is or becomes patent, results in urine dribbling out the navel. More often, urachal cysts remain. When an adenocarcinoma arises deep in the front of the bladder wall, it has probably arisen from urachal remnants.
CYSTOCELE is drooping of a portion of the urinary bladder downward into the more caudal areas of the pelvis. This usually follows childbirth. This may remain filled with urine after voiding, or obstruct the outlet, inviting infection in either case.
HYPERTROPHY OF THE BLADDER WALL results from obstruction, usually from prostatism. The muscle bundles ("trabeculae") become much more visible ("trabeculation").
{24445} hypertrophy of the bladder from prostatism, gross
DIVERTICULA OF THE BLADDER may be congenital, but more often result from a portion of the mucosa pooching out ("pulsion diverticulum") between two strands of hypertrophied muscle in a person suffering from chronic obstruction. This may produce the famous "double urination" (* pis à deux, they call it in France), and/or a place for stasis, inviting infection, and/or a place where bladder stones can form.
Purists: Obviously pulsion diverticula of the bladder are pseudodiverticula, just like in the colon.
If a cancer forms here, it has been considered very serious, since there is no muscularis propria (detrusor) to slow the invasion. New numbers with fairly good survival statistics (i.e., it's the malignant potential of the tumor rather than the presence or absence of a barrier): Urol. 50: 697, 1997; J. Urol. 170: 1761, 2003. More aggressive and unusual-type cancers are prone to develop here (Arch. Path. Lab. Med. 133: 791, 2009).
* Trivia question: Ehlers-Danlos IX predisposes to bladder diverticula.
BLADDER STONES usually result from infection, and are composed of magnesium ammonium phosphate.
{21030} bladder stones
Bladder Inflammation
|
CYSTITIS is usually of bacterial origin, and has the same story as common bacterial pyelonephritis, which it precedes. Urosepsis still kills many adults of both sexes.
The pathology is what you'd expect. Neutrophils abound in the acute phase. In longstanding disease, there is a chronic inflammatory infiltrate and there may be much fibrosis.
Vitamin C is occasionally still recommended by "natural healing" types to prevent bladder infections. It failed a major controlled study miserably (Spinal Cord 34: 592, 1996). The only work since a small positive study on pregnant women from Mexico, where vitamin C might be present (Acta. Ob. Gyn. Scand. 86: 783, 2007).
* The uncommon "emphysematous cystitis" is an unfortunate term for infections with bugs that have formed gas (South. Med. J. 91: 785, 1998). "Bullous cystitis" is an archaic term for a bladder infection with so much edema between the epithelium and the muscularis propria that it looks like water balloons.
"Encrusted cystitis" is fairly common nowadays, and is due to urea-splitters. It features magnesium ammonium phosphate plastered over the bladder mucosa. Almost all cases are caused by Corynebacterium urealyticum, and this is becoming a bane of the renal transplant service (Eur. Uro. 39: 446, 2001).
* All about symptomatic urinary tract infections on young women, with the risk factors of recent intercourse, use of diaphragm and spermicide, and past history of urinary tract infections: NEJM 335: 468, 1996 (still great).
During the 1980's, there was a push to antibiotic-treat all little girls with asymptomatic bacteriuria, often for a long time. This never made much sense to me and now it's not much discussed.
The folk wisdom that cranberry juice prevents and helps cure bladder infections is clearly true (JAMA 271: 751, 1994, others). It prevents E. coli from forming fimbriae (J. Urol. 159: 559, 1998), so they cannot bind to their sanctuaries on the bladder mucosa. It's the proanthocyanidins (NEJM 339: 1085, 1998). A concentrate is now available and seems to work well: Urology 76: 841, 2010.
* POLYPOID CYSTITIS is not a tumor at all, but a reactive overgrowth (collagen and/or extra ground substance) in response to ongoing inflammation (usually an indwelling catheter). It may be bullous (i.e., look like blobs) or papillary (i.e., look like weeds). Update Int. Urol. 34: 293, 2002.
CHEMOTHERAPY CYSTITIS results from cyclophosphamide ("Cytoxan") or busulfan ("Myleran") administration, and RADIATION to the pelvic area can also produce a vicious cystitis.
* Future pathologists: You'll learn to recognize "cytoxan cells", which have big hyperchromatic nuclei and scanty cytoplasm, but smudgy nuclear chromatin that lets you know they're not cancer. Review of the histopathology of chemotherapy cystitis: Am. J. Surg. Path. 28: 909, 2004.
* "Giant cell cystitis" should not be diagnosed. It's an old term for the presence of of giant urothelial cells in patients who have had radiation or chemotherapy.
(HUNNER'S) INTERSTITIAL CYSTITIS ("painful bladder syndrome") (Urology 49(5A): 14, 1997; Am. Fam. Phys. 64: 1199, 2001) is a poorly-understood process in which all three layers of the bladder become chronically inflamed.
Patients are mostly women, and they often have considerable pain and urgency. The pain must be due, at least in part, to excess permeability of the urothelium to the potassium in the urine (Urology 57: 428, 2001; the same is apparently true of the equally-mysterious, painful "urethral syndrome".)
Probably the bladder epithelium becomes over-permeable, but morphologic changes are not obvious and the altered molecular structure is only now being worked out by pathologists (J. Urol. 171: 1554, 2004; Am. J. Clin. Path. 125: 105, 2006.)
Bladder capacity is diminished, producing increased frequency. Nobody knows why.
Visible on cystoscopy are distinctive new-vessel formations ("glomerulations" cited above) that are now considered important in establishing the diagnosis clinically.
No histopathologic lesion is diagnostic. However, pathologists are now looking at several distinctive findings, each correlating with severity, and each requiring special stains.
A different pattern of cytokeratins in the epithelium, without any diffence in morphology (Am. J. Clin. Path. 125: 105, 2006).
VEGF and other stains showing the glomerulations (J. Urol. 172: 945, 2004), and S100 to demonstrate an often-striking increase in little nerve fibers in the mucosa (J. Urol. 177: 142, 2007).
No special stains are required to show the mucosal edema, hemorrhage, epithelial loss and/or granulation tissue in severe cases.
"Hunner's ulcer" is the advanced stage, with mucosal breakdown.
MALAKOPLAKIA is a curious macrophage-rich response to proteus infections. The cells seem to have some problem phagocytizing the bugs.
Grossly, you'll see soft ("malakos" in Greek) yellow plaques.
Microscopically, you'll see foamy, lipid-laden (* "von Hensemann's) macrophages with calcified spherules ("Michaelis-Gutmann bodies"). Nobody knows much about this.
* The cure is to use an antibiotic that penetrates macrophages (Lancet 339: 148, 1992); quinolones seem best (Arch. Int. Med. 156: 577, 1996).
{25276} malakoplakia, histology
{24004} malakoplakia, Michaelis-Gutmann bodies
BRUNN'S NESTS are little balls of urothelial-type cells in the lamina propria of the bladder. They are very common and probably mean nothing. Look for them and you'll probably find them in most bladders. CYSTITIS CYSTICA is like Brunn's nests, only with a hole in the middle. This is supposedly a Brunn's nest that is responding to irritation. In CYSTITIS GLANDULARIS, the cells of cystitis cystica produce mucin; if there are goblet cells, the pathologist will note "with intestinal metaplasia". These are all pathologists' curiosities rather than something to worry about, but you need to know the names as they will often appear on biopsy reports.
{25279} Brunn's nests, histology
{25280} cystitis cystica, histology
{24007} cystitis glandularis, histology
Von Brunn's nest, cystitis cystica,
and cystitis glandularis
Adami & McCrae, 1914
SQUAMOUS METAPLASIA in endemic areas usually results from infestation with Schistosoma hematobium. This is a terrible public health problem, and the bladder can be ruined by all the eggs in the detrusor.
{09863} Schistosoma hematobium egg, bladder
{24020} urothelial dysplasia with squamous metaplasia; in the background of urothelial neoplasia, squamous metaplasia means little or nothing
Schistosomiasis of the bladder
|
Don't forget AMYLOID and AMYLOIDOMA as causes of hematuria (the brittle amyloid-laden vessels crack.)
* STRESS INCONTINENCE ("I lose urine when I cough") is a common problem, especially in women who have borne children. The problem is usually in the structures that support the bladder outlet. Surgery often helps.
Rupture of the bladder from trauma is very serious.
* ROSCOE ARBUCKLE
To this day nobody knows exactly why Virginia Rappe's bladder ruptured (if it even did). Having looked over the trial testimony (sent me by a cyberfriend interested in the case), it looks like a pathologist's overcall to me. I decided that Mr. Arbuckle was guilty only of hanging out with the wrong people But Mr. Arbuckle's career was ruined. The story does not show humankind at its finest. Ever since I was a lay prison minister, my experiences have taught me that in cases involving allegations of weird (and even wildly improbable) sexual misbehavior, everyone goes crazy and our criminal justice system simply cannot distinguish guilt from innocence. |
Mr. Arbuckle |
{25306} amyloidoma, gross
{25307} amyloidoma, histology (including congo Red)
BLADDER TUMORS
UROTHELIAL CARCINOMA is the usual "bladder cancer" of older adults. It strikes around 40,000 men per year (4th most common cancer), and 14,000 women (9th most common cancer). Around 1/3 of cases eventually prove fatal.
{18788} urothelial carcinoma, gross
{21029} urothelial carcinoma, gross
{08858} urothelial carcinoma, histology
{08859} urothelial carcinoma, histology
{08860} urothelial carcinoma, histology
{08861} urothelial carcinoma, histology
{17200} urothelial carcinoma, histology
{17202} urothelial carcinoma, histology
{23987} urothelial carcinoma, histology
{24019} urothelial carcinoma, histology
{24082} urothelial carcinoma, cytology
{24083} urothelial carcinoma, cytology
{10034} urothelial carcinoma, cytology
{10040} urothelial carcinoma, cytology
Bladder Tumors
|
Bladder carcinoma in situ |
The 2004 World Health Organization / International Society of Urologic Pathologists system is now standard, it's got strong predictive value, and this is what we'll teach you. Reviews J. Clin. Path. 61: 3, 2008; Am. J. Clin. Path. 133: 788, 2010.
The genetics of bladder cancer and its precursor lesions is now well worked out (J. Urol. 171: 419, 2004; Arch. Path. Lab. Med. 130: 844, 2006). The "papillary pathway" (80%) and the "non-papillary pathway" (from flat carcinoma-in-situ, 20%) are distinct.
The papilary lesions typically have mutant H-ras and overexpressed EGFR.
* Messenger RNA studies can be obtained easily from the cells of bladder washings.
The best urine in which to look for cancer cells is the second-voided of the day (i.e., the cells have not deteriorated in the bladder). A hefty dose of oral vitamin C after first void (which goes out in the urine) helps preserve the cells.
For some reason, and unlike most other cancers, the grade of a urothelial carcinoma is unlikely to get worse over time; after therapy, it may even get better (i.e., we killed off all the really anaplastic cells): J. Urol. 169: 2106, 2003.
Urothelial tumors are either flat or papillary.
THE PAPILLARY LESIONS are most likely to present with hematuria, either grossly or on microscopic urinalysis. Of course this results from papillary fronds twisting off and bleeding slightly. Of course, any mass lesion (papillary or otherwise) can obstruct.
As long as this is the only problem, it doesn't mean much, other than Nowell's law is probably operating, i.e., a mutation has allowed overgrowth.
UROTHELIAL DYSPLASIA ("low-grade intraurothelial lesion / intraurothelial neoplasia") is diagnosed when there is some coarsening of the nuclear chromatin in the urothelium, the nuclei have perhaps lost their usual orientation with long axis perpendicular to the basement membrane, and perhaps there's a mitosis or two, usually in the lower layers.
Or there may only be a few anaplastic cells among healthy-looking cells ("pagetoid cancerization").
Or the cells might just be big ("large cell non-pleomorphic").
Or the cells might look like oat cells ("small cell in situ").
Or only a few malignant cells might be stuck to the wall here and there ("clinging"). Or the cancer cells might grow only along the bottom, the the upper urothelium be nice with good umbrella cells ("undermining cancerization").
* Future pathologists: A fooler is BK polyoma virus in the immunocompromised. Another is chemotherapy effect after mitomycin C and/or thiotepa. Let us worry about this.
Usually asymptomatic, CIS may be uncomfortable if it allows backleak of electrolytes, since the salty urine stimulates pain fibers in the submucosa.
On cystoscopy, if it is visible at all, it looks smooth and red (i.e., the lamina propria is inflamed because substances from urine leak through) or is sometimes detected only by sampling of the mucosa by biopsy. Today's fluorescence scans using porphyrins may show it to advantage.
Carcinoma in situ is notoriously unpredictable, and much more ominous than an actual mass lesion without invasion (J. Urol. 172: 882, 2004). Around 20-50% of known cases of carcinoma in situ turn into invasive cancer within five years (Am. J. Clin. Onc. 21: 217, 1998), and it can sometimes metastasize without an identifiable invasive mass. We believe that many (most?) invasive cancers start here rather than in papillary lesions; the numbers are still being sorted out.
I am almost sorry to have to add that even experienced pathologists are notoriously unable to agree on the diagnosis for particular lesions, especially telling reactive atypia from something nastier (Am. J. Clin. Path. 134: 862, 2012). I believe that using just H&E, it is impossible and special stains are required.
Tomorrow's pathologists will probably make heavy use of proliferation indicators (is there much staining with Ki-67/MIB-1, p53, and/or p16INK4a?), as well as fluorescent in-situ hybridization (polysomy of chromosomes 3, 7, and/or 17 and/or deletion of 9p21?)
Ki-67/MIB-1 seems to be most helpful so far. See J. Clin. Path. 65: 715, 2012.
Papillary urothelial (papillary / exophytic urothelial tumors / lesions):
UROTHELIAL PAPILLOMAS (grade 0 tumors) grow up from the mucosa ("like a glove with fingers"), have fibrovascular cores, and are covered with normal urothelium (i.e., no analasia, no more than 6-8 nuclear layers). They are almost always incidental findings.
PAPILLARY UROTHELIAL HYPERPLASIA: Like flat urothelial hyperplasia, with some papillary growth but not good fibrovascular cores.
PAPILLARY UROTHELIAL TUMOR/NEOPLASM OF LOW MALIGNANT POTENTIAL (* PUNLMP, the old "Grade I") are papillary lesions with good fibrovascular cores, and in which the surface epithelium the cells show minimal anaplasia and/or minimal architectural distortion and/or more than 7 layers without anaplasia. A few fused fronds perhaps, and if there are mitotic figures they're still low in the epithelium. These tumors seldom turn invasive but maybe a third recur.
LOW-GRADE PAPILLARY UROTHELIAL CARCINOMAS (* similar to the old "Grade II") have papillary growth with good fibrovascular cores, and urothelium similar to flat dysplasia.
This is a very common diagnosis. Even the umbrella layer is often intact in one of these "low-grade" tumors. Another helpful sign of cancer is loss of the usual "clear cytoplasm" seen in some cells in a normal urothelium.
These little cancers usually remain asymptomatic for years. About half will recur, about 10% will eventually turn invasive, and a few percent of these patients will die of bladder cancer.
HIGH-GRADE PAPILLARY UROTHELIAL CARCINOMAS (* "Grade III") are obviously anaplastic. There are fibrovascular cores, but the urothelium looks like flat carcinoma-in-situ. They have usually invaded before they produce symptoms. If discovered early (i.e., you screen everybody for hematuria every year), though, only a minority invade (Br. J. Urol. 83: 957, 1999).
As you'd expect, bladder discomfort, painless hematuria, and infection are typical presentations.
Regardless of grade, urothelial carcinomas are "superficial" until they extend among the inmost fibers of the muscularis propria. (There is seldom an obvious a muscularis mucosae in the bladder; if there is, invasion of this doesn't count against the tumor being "superficial".)
Spotting superficial invasion:
* Urothelial carcinoma in situ famously grows down the prostate ducts; it's easy enough to tell from real prostate cancer on H&E, and to be confident as to whether or not it's invaded the prostate stroma, the CK5 (for basal cells) / CK7 (for urothelium) stain is heplful (Am. J. Clin. Path. 138: 190, 2012).
Aggressive papillary lesions can be identified by staining for p53, high division index (Ki-67), and having cytokeratin 20-positivity throughout the epithelium rather just in the surface (as in normal urothelium). Great photos: Am. J. Clin. Path. 121: 679, 2004; Cancer 97: 1876, 2003. The correlation with the new grading system is excellent.
* Combining the four cell cycle regulators p53, pRB, p21, and p27 prognosticates urothelial cancers fairly well (J. Urol. 183: 68, 2010). There are a host of others: Am. J. Path. 180: 1808 & 1824, 2012; Arch. Path. Lab. Med. 136: 372, 2012.
High expression of p16(INK4a) as an adjunct to morphology in urinary cytology: Am. J. Clin. Path. 132: 776, 2009.
Even the precursor lesions of bladder cancer typically have abnormal staining patterns. In 1998 I predicted the success of the Lewis X antigen as a screening tool for urine; it's proved the most sensitive though least specific of a series of markers that now also include several other biotech-based assays (World J. Urol. 22: 145, 2004; Lewis is still good as a stain even for flat lesions J. Clin. Path. 64: 672, 2012).
Finding the malignant areas to biopsy using laser-induced autofluorescence: J. Urol. 159: 1871, 1998.
Multiprobe fluorescence in-situ hybridization has been introduced (J. Urol. 176: 44, 2006) and has proven far more sensitive (70% vs 35%) than traditional cytology, though cytology still picks up many lesions that fluorescence misses; both have very few false-positives (Cancer Genet. Cytogenet. 173: 131, 2007). The prototype is "Urovision" FISH kit which looks for aneuploidy in chromosomes 3, 7, 9p21, and 17 -- it also seems to work for the less common histologic types (Am. J. Clin. Path. 130: 552, 2008). Patients under surveillance for recurrence are also followed in this way (Am. J. Clin. Path. 127: 295, 2007); no one really knows what to do when there is a "molecular recurrence" but no visible recurrence, though the majority will have a recurrence within two years.
Cathepsin L may come into use for surveillance in patients with previous neoplasia (J. Urol. 179: 478, 2008). A host of cell-cycle-related proteins are now n use for prognostication (J. Urol. 187: 457, 2012). Somehow, the fact that HER2 gene amplification lights up most carcinom in situ, but not dysplasia or reactive atypia, escaped attention until 2011 (Am. J. Clin. Path. 136: 882, 2011).
RISK FACTORS for urothelial carcinoma include
The urothelium, of course, is exposed to many carcinogens, which we may think are concentrated in the urine; nobody should be surprised to learn that the more water you drink, the lower your risk of bladder cancer (NEJM 340: 1390, 1999).
Your lecturer, after reviewing the evidence, believes that allegations that cyclamates and saccharin cause bladder cancer in humans are rubbish, and the ban resulted from junk science and politics-as-usual. The artificial sweeteners given in preposterously large doses to experimental animals, and nobody has been able to show the expected epidemiologic links (big reviews for both NEJM 302: 537, 1980; JAMA 240: 349, 1978). Even the JAMA, not noted downplaying risks to the public, belatedly agreed the claims of a link between saccharin and cancer were groundless (JAMA 254: 2622, 1985).
BCG in the bladder
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* Leave the diagnosis of treacherous lesions like "nested urothelial carcinoma" (looks like Brunn's nests, almost no anaplasia, but too deep) and "microcystic urothelial carcinoma" (a ringer for cystitis cystica, almost no anaplasia, but too deep) to the pathology team.
* Future pathologists: How to "gross in" a bladder: J. Urol. 171: 1823, 2004; Cancer 100: 2470, 2004; Arch. Path. Lab. Med. 127: 1263, 2003.
ADENOCARCINOMA of the bladder (Arch. Path. Lab. Med. 135: 1601, 2011; Arch. Path. Lab. Med. 137: 371, 2013) is uncommon. Two types are distinguished primarily by location.
The other arises around the trigone (usually) from "cystitis glandularis" (maybe) or "colonic metaplasia" (known to be premalignant).
* Clear cell variant: Arch. Path. Lab. Med. 132: 1417, 2008.
SQUAMOUS CELL CARCINOMA of the bladder usually arises in squamous metaplastic epithelium, i.e., the patient has schistosomiasis. This is the great cancer menace in Egypt, and it is extremely aggressive and lethal. Even a significant amount of real squamous metaplasia in a urothelial carcinoma is ominous.
PHEOCHROMOCYTOMA: Urinating turns from a pleasure to a headache. Uncommon, but memorable.
* Children are prone to exotic mesenchymal tumors, especially RHABDOMYOSARCOMAS. To diagnose a rhabdo here, you'll want to see plenty of anaplasia, a cambium layer, and at least a few good round rhabdomyoblasts.
* Small-cell carcinoma of the bladder, which often arises in a more conventional-style bladder cancer, looks like oat-cell carcinoma of the lung on microscopy and electron microscopy, and is aggressive as you'd expect, though cures aren't unknown (Cancer 103: 1172, 2005). There is a large-cell neuroendocrine variant as well (Am. J. Clin. Path. 128: 733, 2007). Don't worry about these.
* The micropapillary variant of urothelial carcinoma looks like serous cystadenocarcinoma of the ovary (Am. J. Surg. Path. 18: 1224, 1994. It seems to be best treated by surgery (Cancer 110: 62, 2007).
* The treacherous, newly-described NESTED VARIANT looks like von Brunn's nests but with smaller cells. Despite a benign appearance, it's thoroughly malignant and invasive (Arch. Path. Lab. Med. 131: 1725, 2007).
* Another fooler: "Plasmacytoid" urothelial carcinomas, usually mixed with the more familiar tumors, have cells that looks like plasma cells but of course are not. These tumors spready over the peritoneal surfaces (J. Urol. 187: 852, 2012)
* NEPHROGENIC ADENOMA ("nephrogenic metaplasia") is a papillary mass of loose, inflamed connective tissue with hobnail cells all over its surface. It usually follows injury and probably represents seeding by renal tubular cells -- if the patient has had a kidney transplant, the cells have the sex chromosomes of the donor (NEJM 347: 653, 2002). Tubules resembling kidney collecting ducts and Henle's loops penetrate deep into it. As you would expect, patients present with bleeding. It is considered harmless. Update Adv. Anat. Path. 13: 247, 2006.
URETHRA
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In either sex: Patients complaining of urethritis symptoms need to be questioned about consumption of jalepiño peppers.
POSTERIOR STRICTURE: A man's problem. Often congenital. The urologist can help you.
URETHRAL CARUNCLE: A woman's problem, often developing later in life, near the opening of the urethra. Perhaps it begins with plugging of the ducts of the glands. It is an uncomfortable lesion with mixed inflammation of the lamina propria, and often with pseudoepitheliomatous hyperplasia of the overlying squamous epithelium.
I peed in the Rhine.
--George S. Patton
Marginal note, March 1945
* SLICE OF LIFE REVIEW
{14937} ureter (cross section), normal
{14938} ureter (cross section), normal
{14939} ureter (epithelium), normal
{14940} urinary bladder, normal
{14941} urothelium, normal
{15032} urethra, normal
{15033} urethra, normal
{15108} ureter
{15109} ureter
{15111} ureter
{15112} ureter
{15113} bladder, urinary
{15114} bladder, urinary
{15119} bladder, urinary
{15120} bladder, urinary
{15122} bladder, urinary
{15325} ureter, normal
{15326} bladder, normal
{15327} bladder, normal
{15588} bladder, normal
{15771} bladder normal unfixed, inner surface
{15772} bladder normal unfixed, inner surface
{20930} urethra
{20931} urinary bladder
{25172} urethra, normal
{25174} urethra, normal
{25266} bladder, normal
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about this topic in 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!
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