Urinary Tract

Pathology:
Urinary Bladder, Bladder time.

Renal Pelvis &

Urethra
John F. Madden, M.D., Ph.D.
Spring 2010
First set of benign
conditions to
discuss.

Cystitis
 Infectious cystitis
• “Ascending” infection due to enteric bacteria
Most conditions of

•
ureteritis and
>95% of cases due to E. coli pyelonephritis are
also ascending
infections

• Klebsiella, Proteus, etc. in predisposed pts

important for patients on immunosuppression
(transplant patients, neutropenic patients)

• Yeast, viruses (CMV, polyoma, adenovirus)

with immunosuppression
We keep bacteria out of urinary tract
Fungal cystitis is
unusual except in
chronic

• Favored by obstruction
by peeing. Therefore obstruct the
urinary flow = infection. Female catherization and
anatomy (shorter urethra) puts them patients on multiple
at greater risk. Risk for males is antibiotics. Usually

• Prostatism, congenital anomalies, stones

obstruction of the prostate develop yeast
(candida) infection.

Older men due to BPH are at risk of Stones favors infectious

obstruction and cystitis cystitis.
 Pathogenetic
UTI is a spectrum of sequence is
degrees across which reflective in the
ascending infection has
Urethral assembled itself across
diagnostic
sequence. On
various areas of the
colonization urinary tract
wards diagnosing
cystitis is done by
a urine culture and
Asymptomati quantitatively
determine the
c bacteriuria diagnosis.

(<104/ml)

Occurs for various

“Urethral
reasons, but does not
warrant treatment
syndrome” Numerical criteria to

(104–105/ml) diagnose cystitis.

This number is of a
single species.

Cystitis
(≥105/ml)
Grey zone often
associated with
burning symptoms.
So, often urethritis
("urethral syndrome")
precedes cystitis.

Pyelonephritis
Case of bacterial
cystitis. This
patient had a
catheter.
Hallmarks of
severe acute
infection:
- yellowish grey
pus on bladder
- erythema /
hemorrhage due to
infection
Microscopically:
- reactive hyperplasia of
bladder epithelium
-hallmarks of infection (pure
PMN or PMN w/ mixed
chronic inflammatory cells
depending on stage of
inflammation)
- Whenever bladder gets
ulcerated and urine enters
stroma beneath epithelium,
the urine attracts eosinophils
Interstitial (“Hunner’s”) cystitis
AKA "Bladder Pain
Syndrome" There are a couple of other
non-infectious kinds of
cystitis. Interstitial cystitis is
one of them. Frustrating
diagnosis / unknown etiology

• Idiopathic (? autoimmune, mast cell

dysfunction) cystitis
• Typically, women in later adulthood
• Hematuria, pain
Superficial to
transmural ulceration

• Extensive ulceration, often transmural,

with fibrosis Chronic, recurrent, mild

•
to severe w/possible
transmural ulceratoin.
dDx: infection, cancer Supposedly an
autoimmune process

Many mast cells

found in infiltrate.
No epithelium and
plenty of ulceration. Not high powered,
therefore can't see
mast cells.

Difficult to treat
due to unknown
etiology.
Ulcerating, no
PMN, mast cells,
chronic
inflammation.

Difficult to know
how to treat these
patients.
Sometimes
steroids are given.
 Hemorrhagic cystitis
Kind of cystitis Another kind of
associated with cystitis. Inpatient
cytotoxic and outpatient
chemotherapy chemotherapy
agents / RT. Blood patients are the
found in urine. prime target.

• Complication of chemo-therapy
or therapeutic pelvic irradiation
Can be PO therapy

• Cyclophosphamide, others
(such as
cyclophosphamide)
or intravenous.
Both can cause
hemorrhagic

• Can cause severe hemorrhage

cystitis.

Often require a
cystectomy to control
the bleeding
Severe
hemorrhagic
cystitis. Surgical
case where the
patient was losing
lots of blood and a
cystectomy was
necessary.
Histology shows a
lot of reactive,
proliferation and
granulation tissue.
Lots of nuclear
atypia, which you
may mistake for
cancer, but it is
due to the chemo /
RT.
 Malakoplakia &
Xanthogranulomatous pyelonephritis
Xanthogranulomatous

•Chronic bacterial infection with

pyelo is similar to
Malakoplakia of the
urinary bladder. Both
are entities that result
ineffective clearance of organisms from chronic bacterial
infection and ineffective
clearance of bacteria.

•
Occurs often when you
have stones in the renal
Proteus often involved pelvis or patients who
are paraplegic w/o

•“Pseudotumor” bladder control who

constantly develop
cystitis.

•Sheets of histiocytes packed lysosomes

•Malakoplakia has Michaelis-Gutmann
bodies Difference between the two is that
Malakoplakia have calcified / fossilized
Lysosomes have
shreds of partially
bacteria in the lysosomes creating these digested bacteria
bodies.
Case of
xanthogranulomatous
pyelonephritis
presenting as a renal
tumor. This patient
had the kidney
removed. The
physician thought this
was clear cell RCC,
but it is simply a mass
of histocytes
mimicking a tumor.
Entirely reasonable to
excise this kidney,
although a partial
nephrectomy would
be more advisable.

These people
usually have large
renal calculi
 Picture of the
histocytes. This is
a case of
Malakoplakia. You
can see the
histiocytes and
under EM it would
be packed with
lysosomes.

Reddish smudge
are the Michalis-
Gutmann bodies
 Malakoplakia can
present in bladder
or kidney. In each
case it would raise
the suspicion of
cancer.

another Michalis-
Gutmann body.
When a normal cell type
undergoes differentiation to
another cell type = metaplasia.
It does so due to insults. At
times these areas undergo
biopsy and report states
"squamous cell metaplasia". It
is a common benign change
and you don't want to mistake
it for a carcinoma. Metaplasia
is not neoplasia. It is not
cancerous and does not
necessarily precede cancer.

Urothelial metaplasia
 Urothelium has
incredible ability to
undergo
metaplasia.

• Urothelium takes on characteristics of some

other type of epithelium

• Often a response to chronic inflammation

• Benign
 Transitional
epithelium.
Usually ~7 cell
umbrella cells layers thick,
umbrella cell on
top.

basal cells

Normal urothelium
Benign metaplastic Sort of metaplasia
change. that is common in
the bladder and
appears as a
domed mass on
the bladder and is
often biopsied in
fear of cancer.
Odd name since
we frequently have
no cystitis, but do
have a cystic
change.
Normal invagination
of the urothelium
underneath
submucosa that
undergoes central
cystic change,
inflates, and causes
a mass.

Cystitis cystica
Normal submucosal nests of urothelium (“von
Brunn’s nests”) develop central cystic change
 Cystitis cystica
can undergo
secondary
metaplasis to look
like colon.
Causing cystitis
glandularis.
Negative for
malignancy. May
be spontaneous or
associated w/
inflammation.

Most bladder
cancers are
those of
urothelium. We
may see
adenocarcinoma
arising due to this
type of
metaplasia.

Cystitis glandularis
Transitional cells convert to mucinous
columnar type
 Common in
bladder, especially
w/ patients who
have
schistosomiasis.
Theory is that the
squamous
epithelium is more
protective than the
typical urothelium,
hence the
metaplasia during
chronic irritation.

Again, rarely we
see squamous
carcinoma of
the bladder due
to underlying
squamous
metaplasia

Squamous metaplasia
Transitional cells convert to squamous
cells under chronic irritation
 Not metaplasia. It
is thickened
hyperplastic
urothelium due to
irritation.

Urothelial hyperplasia
 Disease where you get a
mass / lump / tumor in
bladder / urethra / ureter,
that looks just like kidney
epithelium. Called
adenoma since some ppl.
consider it a tumor
(misnomer), but other ppl.
consider it metaplasia.
Ppl. with chronic irritation
get this condition at a
higher rate. Theory (in at
least the transplant
population) is that this
represents bits of kidney
that break off, float, and
re-implant.

“Nephrogenic adenoma”
 Bladder carcinoma.
This applies equally to
carcinoma in the
urothelial lined portion
of the urethra which for
males extends out to
the proximal part of the
penile urethra and for
females to the distal

Urothelial third of the urethra.

After that point
squamous epithelium
takes over. The ureters
and renal pelvis are

(transitional also lined with

urothelium.

cell)carcinoma
 Various exposures

• Most common carcinoma of urinary

to environmental
carcinogens is
typically the cause.
Unlike RCC, which

bladder (85%) seems to just

occur.

• Y > X, white > black

More common in
males. More
common in the
white race.

• Known risk factors Single most important risk

factor for bladder cancer

• Smoking → ~50% of U.S. cases

• Aromatic amines
Hair dye (in the past),
no longer permitted.

• Some occupations
Nickel industry.

Most of the cancer

is squamous in
these patients, but
some are urothelial

• Schistosomiasis (squamous>TCC)
 So, most bladder cancer
are urothelial carcinoma
(90-95%), the remaining
are squamous, adeno.
(due to the metaplasia
Bladder cancer is as explained previously
described by the
term
"polychronotropism"
(historically) due to

• Tends to occur multifocally

the following factors:

Because it is so closely

• Tends to recur
related to chemical
exposure, the chemical
gets concentrated in the
urine and is stirred around
in the bladder = multifocal.
In addition, it is typically
triggered by numerous
genetic hits = high
reoccurrence
 There is no one

• Molecular alterations in multiple regulatory

knockout genetic
change / gene
involved in bladder
cancer.
pathways are seen (Ras-MAPK, p53, Rb)

• Abnormalities of chromosome 9 (mostly del 9)

are a consistent, early finding
very common

• p16 (CDKN2A) underexpression (9p21-)

(Rb pathway) especially common
Also common

• One FDA-approved ancillary test

(UroVysion™ Abbott) detects aneuploidy 3, 7,
17, and loss of the 9p21 via fluorescence in
situ hybridization (FISH) in urine UroVysion is used as a
screening test for
bladder cancer.
 Not all that
important. For
those interested it
shows an early
view of where
some of these
del 9
genetic changes
occur. Early
cancers at top and
more invasive
cancers at bottom

Text

Molecular Pathways in Invasive

Bladder Cancer:
New Insights Into Mechanisms,
Progression, and
Target Identification
Anirban P. Mitra, Ram H. Datar, and Richard J. Cote
From the Departments of Pathology

JOURNAL OF CLINICAL ONCOLOGY REVIEWA

RTICLE

VOLUME24 NUMBER35 DECEMBER102006

• Symptoms

• Episodic painless
Bladder cancer:
hematuriaclinical
(80%)
In 80% of patients Bladder

• Diagnostic evaluation
cancer presents to medical
attention with painless
hematuria (text obscured by
slide title)

•
If you have cystitis there is
blood in the urine with pain.
Urinary cytology Least invasive way
to start workup is a
Unlike bladder cancer
which causes blood and no
urine sample.
pain

• Sensitivity modest, detects mainly high

grade lesions Urine cytology is not
good for early / low
grade cancer

• Okay for following patients with

established Dx

• Molecular tests You can perform the molecular

test as mention on previous
slide (UroVysion)
Gold Standard is
cystoscopy with
biopsy
 Bladder cancer in two broad
categories Several ways to
subcategorize bladder
cancer. One important

• by extent of invasion
Superficial
way is based on how
deeply invasive it is.
Two groups:
1. Superficial

•
2. Muscle Invasive

Non-invasive or Invasive into lamina propria

only

• Traditionally, treated by transurethral resection

• Muscle-invasive Much worse

prognosis

• Invasion into or through muscularis propria

• Treated by cystectomy and/or radiation

 Superficial is lower
grade, less

•Superficial
aggressive Two main histo
subtypes:
Papillary urothelial neoplasia: 1. Papillary:
Cauliflower mass
(lower grade risk)

• two histologic types

Majority of urothelial cancers
2. Non-papillary:
analogous to
dysplasia in the
cervix, flat lesion
(higher grade risk)

• Exophytic, cystoscopic resection often

possible

• On average, lower grade

• Non-papillary More
aggressive,
high grade

• 10-40% of urothelial cancers

• Cystoscopically occult
 Episodic twisting
usually low grade / off papillary tumor
lower risk of can lead to random
invasion hematuria.

flat carcinoma are

higher grade / high
risk of becoming
invasive

Roughly 25% of
pts belong to the
bottom two "flat"
kind. These are
more aggressive
Superficial papillary
urothelial neoplasia
bladder with lots of
papillary
carcinomas

Both of these papillary

carcinoma examples
are fairly advanced
and invasive.

couple of smaller
papillary
carcinomas
non-invasive
papillary carcinoma
in the renal pelvis
Bladder cancer exception
(for historic reasons):
Whether invasive or pre-
invasive, lesions of the

Warning!
bladder are called cancer.
Pre- or non-invasive
"cancer" have very good
prognosis and rarely
progress to invasive
disease.

• By convention, papillary neoplasms of

urothelium are always called
“carcinoma” even if non-invasive

• Why call this “carcinoma”?

• Comparison with colonic adenoma
Superficial non-
invasive papillary
"carcinoma" of the
bladder, low grade,
excised
cystoscopically.
Microscopic view
of a pre-invasive
bladder carcinoma
urothelium on
these papillae are
seen as fingers w/
fibrovascular cords
lined with
urothelium that is
slightly thickened

Apoptosis occurring
around here

Atypical enlarged
cells.
Papillary urothelial neoplasia:
grading When these
papillary urothelial

•Papilloma
neoplasms are pre-
invasive can be
divided into low
grade and high
grade. The
majority of the
papillary are low
grade and don't

•(Low malignant potential)

progress.

•Low grade UC
•High grade UC
Example of a low
grade one
Another example
of a low grade one
Example of a high
grade one
Superficial papillary urothelial neoplasia:
natural history Since papillary
neoplasia is usually low
grade and doesn't
progress, they typically
present as episodic
hematuria, urologist will

• Frequent recurrence
perform a cystoscopy,
snips the cauliflower
lesion, pathologist
labels it as low grade,
and it may recur. None

• Infrequent
of these tumors develop
an invasive component.
So this patient must
keep coming back to
have these papillae
snipped out every six

progression or months.

invasion
Superficial papillary urothelial neoplasia: recurrence
All grades of
papillary neoplasia
tend to recur. After
a couple of years
at least half of the

G3
ppl have had
recurrence of the
tumor.

low grade

G1
G2
intermediate grade

high grade
Superficial papillary urothelial neoplasia: progression
Low grade (out to Progression
(development of
15 years) well over
half have recurred,
low grade invasive component)
but 5% have is uncommon in
progressed these patients

intermediate grade

high grade
 Therapy for superficial
papillary urothelial neoplasia
• Cystoscopic resection
Alluded to on

• Periodic (lifelong) follow-up previous slide.

Keep snipping the
papillae out.

• Urine cytology

• Cystoscopy
Routine for urologist to give single
dose of mitomycin (intravesically)

• Intravesical therapy following cystoscopic resection of a

papillary urothelium neoplasm. This
pushes out the time to recurrence.

• Partial cystectomy for high-grade

Bladder-sparring surgery is not
tumors really done
So ... we have two
histological types. The
papillary ones that we
just discussed, and
here we have the "flat"
ones. These are rather
aggressive.

Superficial “flat”
urothelial neoplasia
Carcinoma in stiu
was term used in Does not form

Cheng et al. Cancer

cervical lectures characteristic
and is used to papillary fronds, but
describe these flat instead flat lesion
neoplasms

Atypia Dysplasia CIS

Carcinoma in situ of
the bladder. It does
not form papillae, but
has nasty looking
cytologically atypical
cells, nuclear
enlargement, and
nuclear
pleomorphism.
Non-papillary (“Flat”) urothelial neoplasia
(urothelial carcinoma-in-situ): natural
For "flat" urothelial
history neoplasia pre-
invasive or in situ,

• Over 70% have diffuse disease at

the situation is
very different than
that for papillary
neoplasm. Read

diagnosis the slide.

• Over 30% of CIS have undiagnosed

invasive disease at cystectomy

• Over 5% dead of (metastatic)

disease in 5 years after cystectomy
for CIS
 “Flat” urothelial neoplasia
(urothelial carcinoma-in-situ): therapy
immunotherapeutic What do we do if we catch it
agent. Attenuated form early? We can biopsy, but can't

• BCG
of mycobacterium TB. resect b/c it's multifocal.
Therefore use intravesical
BCG works not only for
chemotherapy /
flat urothelium neoplasia,
immunotherapeutic agent or
but also papillary type.
cystectomy.

• >70% durable response in CIS

• Intravesical chemotherapy
• Thiotepa/doxorubicin/mitomycin
• Interferon cytotoxic

• Cystectomy
 Spanish urologist
from Canada.

Dudes on the left

created BCG.
Veterinarian Noted early on that
patients w/ TB
developed cancer
at lower rates.
Therefore, ppl
realized that BCG
might have some
anti-cancer effects
as a vaccine.
Finally, in the
1970's Alvaro
Morales instilled
BCG directly into
the bladder with in-
situ carcinoma
causing regression
of carcinoma and
durable responses.
It works great in
high proportion of
pts. Often need to
repeat treatment in
six months.

Alvaro Morales
Guerin & Calmette
 We discussed the lower grade
papillary type and higher grade
flat type. Either of these two
types can evolve into muscle-
invasive urothelial carcinoma
(the flat kind at a higher rate).
Once muscle involvement
occurs it is very hard to
distinguish papillary versus flat
type.

Muscle-invasive
urothelial carcinoma
Muscle invasive at
higher rate
Visual flow chart of
what we discussed
and the potential
treatments. You
can see that for
muscle invasive
carcinoma the gold
treatment is
cystectomy.
Here is a muscle
invasive carcinoma
presenting as an
ulcer. This is a
cystectomy
specimen.
Here is an invasive
carcinoma of the bladder
that probably started as a
papillary carcinoma and
evolved into a large
carcinoma which invades
muscle.
 This is what
invasive carcinoma
looks like. Very
high grade,
malignant
appearing cells.

These are muscle

fibers and it
infiltrates through
through the
muscularis propria.
The depth of
invasion determines
staging.
 Bladder cancer Over the years the
mortality has been
decreasing due to
better chemical
hygiene and better

mortality diagnosis.

Bladder cancer
occurs
predominantly in
Deaths per 100,000

men, possibly due

to previous
smoking statistics

Year
 Bladder cancer survival (1988- Survival is great for

2002) low grade papillary

disease and dismal
for patients with
distant disease at
diagnosis.
Percent surviving

Years since diagnosis

Bladder cancer stage distribution (1988-
Fortunately most are
2002) diagnosed at time when
it is localized. Good
alarm is the hematuria.

Percent of cases
 Therapy for invasive
urothelial carcinoma
•Radical cystectomy
Therapy for invasive urothelial
carcinoma (gold standard) is radical
cystectomy.

•Partial cystectomyShould be called bladder sparring.

They resect as much tumor as
possible via the transurethral
approach and then the person gets

• Transurethral resection
systemic and intravesical therapy.

•Chemotherapy
• MVAC (methotrexate +
Deleted on bottom of slide:
MVAC (methotrexate +
vinblastine + adriamycin +
cysplatin)