{09863} Schistosoma hematobium egg, bladder

{24020} urothelial dysplasia with squamous metaplasia; in the background of urothelial neoplasia, squamous metaplasia means little or nothing

Bladder schistosomiasis Eggs have calcified KU Collection

Schistosomiasis of the bladder Yutaka Tsutsumi MD

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.

Have you ever read about comedian Roscoe "Fatty" Arbuckle and the coca-cola / champagne bottle (or whatever)? To this day nobody knows exactly why Virginia Rappe's bladder ruptured. Mr. Arbuckle's career was ruined. The story does not show humankind at its finest. I would urge you to read up on the case, when you get a chance. It may cause you to reach the same decision that I have, i.e., that in a case involving allegations of weird (and even wildly improbable) sexual abuse, our criminal justice system simply cannot distinguish guilt from innocence.

{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 From Chile In Spanish

Bladder carcinoma in situ Very anaplastic, no invasion KU Collection

Papillary urothelial carcinoma Low-grade KU Collection

Urothelial carcinoma Pittsburgh Pathology Cases

Urothelial carcinoma Pittsburgh Pathology Cases

Bladder cancer WebPath Photo

Urothelial carcinoma Not invading yet WebPath Photo

Urothelial carcinoma Papillary growth WebPath Photo

Naming urothelial tumors is confusing and aggravating because no one truly knows the natural history of lesions that are always removed as soon as they are discovered, and where it isn't really possible to tell a recurrence from a second primary (and 70% of survivors will get a second urothelial primary).
Hence, there have been several different systems of nomenclature, and certain lesions that are "benign" in some are "malignant" in others.

The new WHO/International Society of Urologic Pathologists system is now standard, and this is what we'll teach you. Review J. Clin. Path. 61: 3, 2008.

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 flat lesions typically have loss of RB1 and p53.

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 FLAT LESIONS are most likely to present with discomfort, if they are symptomatic at all. The reason for this is that the integrity of the epithelial barrier is somewhat compromised, and salty urine contacts the nerves of the mucosa. (Remember how much potassium hurts when it contacts an exposed nerve?)

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.

Flat urothelium:
FLAT UROTHELIAL HYPERPLASIA is said to be present when it is "flat and >7 cells thick" (i.e., there are more than 7 layers of nuclei, some say 8 -- remember that of course the nuclei aren't really layered, and that a tangential cut will make there appear to be more).

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.

REACTIVE UROTHELIAL ATYPIA will be diagnosed when the pathologist recognizes nuclear changes of rapid epithelial regeneration (i.e., big nuclei, marginated chromatin, and obvious nucleoli) without any sign of anaplasia. Usually the number of layers is still normal
Of course, this means there's been instrumentation, or a stone, or an infection, or whatever. This has no premalignant potential.

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.

Of course, this is probably premalignant. You watch these patients.

UROTHELIAL CARCINOMA IN SITU of the bladder features obviously anaplastic cells in a flat urothelium.
There may be full-thickness, obvious anaplasia. In this case, the urothelium actually tends to be thin, and the cells tend to come apart.

Or there may only be a few anaplastic cells among healthy-looking cells ("pagetoid").

* 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.

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.



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.

A variant is the INVERTED PAPILLOMA, a smooth-surfaced bump with epithelium complexly infolded deep within it. ("A glove with the fingers pushed inside and collapsed.") There is no atypia, no desmoplasia, and there's a good top layer to the epithelium. So it shouldn't be mistaken for cancer.

PAPILLARY UROTHELIAL HYPERPLASIA: Like flat urothelial hyperplasia, with some papillary growth but not good fibrovascular cores.

PAPILLARY UROTHELIAL TUMOR OF LOW MALIGNANT POTENTIAL (* 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. These tumors seldom turn invasive.

* The PUNLMP remains controversial. For an update, see J. Urol. 175: 1995, 2006.

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".)

You'll learn the new staging systems on rotations. One of the common tough calls in pathology is, "Is this papillary urothelial carcinoma of the bladder still confined to the epithelium (Ta) or down into the lamina propria (T1)?"

Spotting superficial invasion:

• cells are scrambled, not lined up neatly


• the border isn't smooth (like smooth basement membrane)


• paradoxical differentiation (the invasive cells look LESS anaplastic than in the papilary lesion)


• stromal reaction (i.e., denser collagen lines up around tumor cells)


• inflammation


• tumor in the muscularis mucosae (see it using an actin stain)


• stromal retraction artifact ("the tumor cells are in a lymphatic with no endothelium")


• no nice parallel array of blood vessels just past the edge

*  Immunohistopathology helps make the hard calls.
Carcinoma in situ is likely to stain for p53 and/or cytokeratin 20, and to have a high division index as shown by MIB-1 / Ki-67.

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.

Also watch ErbB-4; staining for this oncogene product is an ominous sign (J. Urol. 179: 353, 2008).

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).

Finding the malignant areas to biopsy using laser-induced autofluorescence: J. Urol. 159: 1871, 1998.

Most recently, 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). Patients under surveillance for recurrence are alsfollowed 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).

RISK FACTORS for urothelial carcinoma include cigaret smoking (2-4x base risk), exposure to certain chemicals in industry (outstandingly the dye industry, outstandingly such aromatic amines as α-naphthylamine, auramine, and benzidine), abuse of phenacetin, carbon black (Lancet 358: 562, 2001), that now-infamous Aristolochia Chinese herbal "weight loss" pill from the early 1990's (NEJM 342: 1686, 2000 -- most of the victims now have urothelial dysplasia or worse, didn't get to the US), exposure to cyclophosphamide, Lynch's nonpolyposis colon cancer family syndrome (x14, J. Urol. 160: 466, 1998), and having a longstanding indwelling catheter (i.e., paraplegics and quadriplegics).

Long-term use of hair dye, or being a long-term hairdresser, seem to be risk factors (2x and 5x respectively: Mut. Res. 506: 21, 2002; Int. J. Ca. 91: 575, 2001).

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. These were 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).

Patients with superficial bladder cancer usually do well, especially with today's treatment, which often includes intravesical BCG. PROGNOSIS in invasive urothelial carcinoma depends on grade-and-stage (correlate pretty well most of the time). For the less-ugly, low-stage cancers, prognosis correlates with other markers of malignancy, including loss of ABO antigens (* demonstrated by some of your lecturer's Chicago friends), aneuploidy, and activation of known oncogenes.

BCG in the bladder After therapy Yutaka Tsutsumi MD

* Future pathologists: How to "gross in" a bladder: J. Urol. 171: 1823, 2004; Cancer 100: 2470, 2004; Arch. Path. Lab. Med. 127: 1263, 2003.

You need to know of a few other bladder tumors.

ADENOCARCINOMA of the bladder is uncommon. Two types are distinguished primarily by location.

One arises from where the urachus used to be, high on the front of the bladder. The prognosis depends mostly on stage (Cancer 110: 2434: 2007).

The other arises around the trigone (usually) from "cystitis glandularis" (maybe) or "colonic metaplasia" (known to be premalignant).

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).

* 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).

* NEPHROGENIC ADENOMA is a papillary mass of loose, inflamed connective tissue with hobnail cells all over its surface. It's probably a curious reparative response rather than a true tumor, since it usually follows injury. 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

Urethra From Chile In Spanish

Urethra "Pathology Outlines" Nat Pernick MD

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.

Pathology of the Urinary Bladder (Major Problems in Pathology series)
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silverberg's Surgical Pathology


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. Health and friendship!

Drop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science Trivia Quiz -- have a chuckle!
Rudolf Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Part I
Part II