Bladder Cancer
What are the factors that play a role in the development of bladder cancer?
- inherited or acquired alterations of DNA
lead to induction of oncogenes or suppression of tumour suppressor genes
lead to aberrations of normal mechanisms that regulate cell differentiation & proliferation
can result in abN repair of mutated cells or abnormal apoptotic pathways- inherited, acquired, or anatomic factors that regulate processes such as the metabolism of chemicals
and the excretion and delivery of those metabolites to potential target cells
- exposure to chemical carcinogens, viruses, or other stimuli (eg radiation)
EPIDEMIOLOGY
What are the epidemiological findings of bladder cancer?
- incidence increases with age } median age is ~70yrs of age
- ~3x more common in M
- 4th most common cancer in men after prostate, lung, colon (incidence)
2nd most prevalent (after PCa)
- 9th most common among women
- rarely found incidentally at autopsy
- increasing incidence over last few decades } incidence rising faster in men
- about 2x more common in Caucasian men compared to Black men
1.5x higher in white women
- blacks tend to present with more advanced stage cancers
- higher rates of non-TCC bladder cancers among blacks
What are the survival data on bladder cancer?
- higher 5 yr survival among M (esp when compared to black F)
F have 30% higher chance of mortality when compared to M
- stage by stage, better survival among whites blacks almost 2x more likely to die from bladder cancer
- Hispanics have the best survival rates, even for invasive and advanced disease
- overall mortality from bladder cancer is decreasing despite increasing incidence
decrease seen more among M
- better survival rates among younger patients
more indolent and lower grade in younger patients
same risk for progression though
ETIOLOGY AND RISK FACTORS
What are the RFs for developing bladder cancer?
1) cigarette smoking
4-fold increase in incidence } back to baseline risk after ~20yrs of non-smoking
specific carcinogen not identified } ? 4-aminobiphenyl
failure to stop smoking after Dx predicts worse outcome, even for superficial TCC
2) occupational exposure to chemicals
aniline dyes (fabrics), acrolein aldehyde (textile & rubber)
2-naphthylamine, 4-aminobiphenyl (benzidine)
aromatic amine exposure (autoworker, painter, leather worker, etc)
3) analgesics
phenacetin (similar structure to aniline dyes)
increased risk of renal pelvic TCC also
4) bacterial, viral, fungal, and parasitic infections
chronic UTIs associated with SCC
Schistosoma haematobium is associated with SCC and TCC
HPV associated with TCC only in immunocompromised hosts
5) bladder calculi
increased risk of SCC
6) chronic indwelling catheter
increased risk of SCC
>50% of SCI patients have invasive disease at presentation
7) pelvic RADs
2-4fold increase in incidence post pelvic RADs (cervical or ovarian Ca)
usually high grade & locally advanced at time of Dx
8) genotoxic chemotherapy
cyclophosphamide ↑’s risk of bladder Ca by 9-fold (highest RR)
high rate of progression } usually high grade & muscle invasive at time of Dx
acrolein aldehyde likely culprit for both hemorrhagic cystitis and bladder Ca
mesna may protect urothelium by binding to acrolein and neutralizing it
(must be given at time of chemo .. no benefit if after)
development of hemorrhagic cystitis DOES NOT correlate with Bladder Ca risk
9) Blackfoot disease
arsenic ingestion from contaminated water in south Taiwan
results in CV disease and other malignancies, including bladder TCC
10) Aristolochia fangchi
Chinese herb (Stephania tetranda) for weight reduction (Belgium)
associated with interstitial nephropathy & urothelial TCC (mainly upper tract TCC)
11) renal transplant recipients
*** NO STRONG EVIDENCE for caffeine, sweeteners, hereditary ***
What are the RFs for developing bladder TCC? }}} “COBRA SCARS”
- Cyclophosphamide - Smoking
- Occupational exposure to chemicals - Chronic UTIs
- Blackfoot disease - Analgesic abuse
- RADs to pelvis - Renal Tx recipients
- Aristolochia fangchi - Schistosomiasis haematobium
What are the RFs for developing upper tract TCC? }}} “COBRA SCALP”
- Cyclophosphamide - Smoking
- Occupational exposure to chemicals - Chronic UTIs
- Balkan nephropathy - Analgesic avuse
- RADs to pelvis - Lynch 2 syndrome
- Aristolochia fangchi - Papillary necrosis
Which ONCOGENES have been associated with bladder cancer?
1) RAS gene family (eg p21) associated with higher grade
Which TUMOUR SUPPRESSOR GENES have been associated with bladder cancer?
1) p53 (chromosome 17p) most frequently altered gene in human cancers
repair of damaged DNA and pro-apoptosis of abnormal cells
normal p53 induces expression of anti-angiogenesis factor
thrombospondin-1 (TSP-1)
regulated by MDM2, which degrades TP53
mutation of p53 associated with more aggressive cancers
2) retinoblastoma (RB) gene (chromosome 13q) RB protein normally keeps cell proliferation in
check via E2F
associated w/ more aggressive TCCs
3) p15, p16, p19, p27 proteins (chromosome 9) cell proliferation regulated via RB protein
abN proteins prevent RB protein from keeping cell
proliferation in check
assoc’d w/ low-grade, superficial TCC
MOST COMMON genetic abN’ity
What gene amplification & overexpression abnormalities are associated with bladder cancer?
- increased expression of EGF receptor } associated with more aggressive tumours
} normally there are high levels of EGF in urine, so
high receptor levels cause increased EGF signalling
- overexpression of ERBB2 oncogene product (p185) } associated with higher grade & stage
} also associated w/ higher recurrence
What is the significance of acetylation in bladder cancer?
- amongst smokers and those with occupational exposure, pts with slow NAT1 & NAT2 acetylator
genotypes are more likely to have bladder cancer
rapid acetylation of carcinogens results in detoxifying pathways
PATHOLOGY
What are the layers of the bladder?
1) urothelium 3-7 layers thick
2) BM
3) lamina propria contains muscularis mucosa AND blood vessels, lymphatics, nerves
4) muscularis propria inner longitudinal, middle circular, and outer longitudinal
5) serosa reflection of peritoneum
What is epithelial hyperplasia and metaplasia?
hyperplasia } increase in # of cell layers WITHOUT nuclear or architectural abnormalities
metaplasia } change in epithelium with squamous or adenomatous development
What is atypical hyperplasia?
- similar to epithelial hyperplasia but increase in # of cells WITH nuclear or architectural changes
- overactive atypia and atypia of unknown significance have VERY LOW MALIGNANT POTENTIAL
What is epithelial dysplasia?
- epithelial changes that are intermediate between normal urothelium and CIS (severe dysplasia)
- NO increase in # of cell layers or mitotic figures
- 15% risk of developing high grade TCC
What are Von Brunn’s nests?
- islands of benign-appearing urothelium in the lamina propria
- cystitis cystica is von Brunn’s nests in which urothelium in centre of nest has undergone eosinophilic
liquefaction
- cystitis glandularis is von Brunn’s nests in which urothelium has undergone glandular metaplasia
(goblet cells)
may be a precursor for adenocarcinoma of the bladder
What is an inverted papilloma?
- BENIGN proliferative lesion associated with chronic inflammation or BOO
- papillary fronds project into fibrovascular stroma of bladder
- usually covered by thin layer of normal urothelium
- may contain an area of cystitis cystica or squamous metaplasia
- rare case reports of malignant transformation } especially if glandular type
more commonly associated with COEXISTENT TCC elsewhere in GU tract or
with hx of TCC (high grade) } more so with upper tract TCC than bladder
What is a nephrogenic adenoma?
- lesion resembling primitive collecting tubule } single layer of epithelium (TCC is multi)
- metaplastic response of urothelium to trauma, infection, or radiation
- often associated with irritative voiding symptoms
- BENIGN but rare cases of transformation to mesonephric adenocarcinoma
Rx observation (recurrence common in some so consider cysto)
What is vesical leukoplakia?
- squamous metaplasia with marked keratinization, downward growth of rete pegs (acanthosis),
cellular atypia, and dysplasia
- N response of urothelium to noxious stimuli } common in trigone of women
- may progress to SCC in 20% of patients if keratinizing leukoplakia
What is pseudosarcoma?
- aka post-operative spindle cell nodule
- rare, BENIGN lesion resembling a bladder sarcoma
- reactive proliferation of spindle cells occurring several months after a LUT procedure or UTI
- must r/o leiomyosarcoma
What are the premalignant lesions for each type of bladder cancer?
TCC
- “CIS”
- atypical hyperplasia (increase in # of cell layers + nuclear abnormalities)
- dysplasia (epithelial changes that are intermediate b/w N urothelium and carcinoma)
- inverted papilloma (glandular type) } likely coexistent
SCC
- bladder leukoplakia (squamous metaplasia w/ atypia)
- squamous metaplasia with atypia
adenocarcinoma
- cystitis glandularis (usually near trigone and assoc’d w/ chronic UTIs, exstrophy
& pelvic lipomatosis)
- nephrogenic adenoma (rarely degenerates to mesonephric adenocarcinoma)
UROTHELIAL CARCINOMA
CIS
What is CIS?
- high grade, superficial urothelial carcinoma (FLAT)
- often a velvety patch of red } can also be cystoscopically invisible
- pleomorphic, dark staining, large atypical nuclei } larger on luminal side
loss of cell polarity + cell denudement + increased nuclear/cytoplasmic ratio
- may be asymptomatic or may present with severe irritative storage symptoms
- +ve cytology in 80-90% of CIS patients
- CIS is present in 25% of patients with high grade, superficial tumours (T1G3)
- 40-80% progress to muscle invasive cancer
- CIS is present in 20-75% of high grade, muscle-invasive tumours
- CIS rarely primary disease (1-4%)
- ~20% with diffuse CIS treated with cystectomy have microscopic muscle-invasive disease
CIS of bladder
Urothelial carcinoma (TCC)
What are the features of urothelial carcinoma that are different from normal urothelium?
- increased # of epithelial cell layers
- loss of cell polarity
- increased nuclear-cytoplasmic ratio
- prominent nucleoli
- abnormal cell maturation from basal to superficial layers
- clumping of chromatin
- increased # of mitoses
What are the patterns of tumour growth seen with urothelial carcinomas?
- papillary (70%)
- sessile
- infiltrating
- nodular
- mixed
- flat intraepithelial growth (CIS)
What is the grading system of urothelial carcinomas (ISUP)?
strong correlation between grade and stage
- most high grade lesions are muscle-invasive
grade correlates with prognosis } stage correlates with survival the strongest
many believe low grade tumours have different origins than high grade tumours
- low grade may be from loss of suppressor genes on chromosome 9q
- high grade may be from abnormalities in p53, RB, p16 (suppressor genes)
1) papilloma } grade 0
} normal urotheliium (≤7 cell layers thick)
} benign but must r/o concomitant TCC almost never recurs after resection
2) well-differentiated } former grade 1
} thickened urothelium, only rare mitotic figures, slight anaplasia
} mild disturbance of base-to-surface cellular maturation
} mild increase in nuclear-cytoplasmic ratio
} PUNLMP when mucosally confined
3) moderately-differentiated } former grade 2
} thickened urothelium, a few mitotic figures, slight anaplasia
} moderate disturbance of base-to-surface cellular maturation
} loss of cell polarity
} moderate increase in nuclear-cytoplasmic ratio
} LOW-GRADE } loss of chromosome 9q suppressor genes
4) poorly-differentiated } former grade 3
} frequent mitotic figures
} no differentiation in base-to-surface maturation
} marked nuclear pleomorphism
} high nuclear-cytoplasmic ratio
} HIGH-GRADE
p53, RB, chromosome 9p abnormalities } found in CIS but NOT Ta
What is the significance of metaplastic elements?
eg squamous or adenocarcinomatous elements
- presence doesn’t change primary classification of tumour as urothelial carcinoma
- found in 30% of muscle-invasive tumours
NORMAL UROTHELIUM
PAPILLARY UROTHELIAL CARCINOMA
MUSCLE INVASIVE UROTHELIAL CARCINOMA
SCC
What is the epidemiology of SCC of the GU tract?
- accounts for ~5% of bladder cancers } much more common in Egypt
bilharzial (Schistosomiasis haematobium)
- usually younger patients
- less male predominance (only 2:1)
- associated with chronic infection/inflammation
- cancers are exophytic, nodular, fungating lesions
- usually low grade
- low incidence of LN or distant mets } has p53 & chromosome 9 (P16) abN’ities like TCC
- similar prognosis, stage for stage, with TCC
usually poor prognosis b/c of advanced disease at presentation
- urine cytology useless
- bone is the most common site of mets
What is the histogical findings of SCC?
- keratinized islands that contain eccentric aggregates of cells called squamous pearls
- grade DOES NOT correlate well with prognosis
What are the RFs for bladder SCC?
“Some Say Schisto Can Cause Bladder Disease”
- Smoking
- Stones/FBs
- Schistosomiasis haematobium
- Chronic UTIs
- Chronic indwelling catheter
- BCG
- Diverticula (bladder)
?cyclophosphamide
BLADDER SCC (squamous pearls)
Adenocarcinoma
What is the epidemiology of adenocarcinoma of the GU tract?
- account for <2% of primary bladder cancers
- can also occur in intestinal conduits, augments, pouches, etc
- majority represent mets from GI tract, breast, lung } r/o colon primary
- usually arise in trigone or in dome (urachal)
- most common type of bladder Ca in exstrophy & associated w/ pelvic lipomatosis
develop in response to chronic inflammation and irritation
- most are poorly differentiated and invasive
- more often associated with cystitis glandularis than CIS
- generally poor prognosis due to advanced stage at presentation
stage for stage, similar to TCC
What are the RFs for adenocarcinoma of the bladder? }}} “UCC CUBE”
- Urachal cyst/remnant
- Cystitis glandularis
- CIS
- Chronic inflammation
- Ureterosigmoidostomy
- Bladder augment
- Exstrophy of bladder
What are the classifications of adenocarcinomas of the GU tract?
1) primary vesical
2) urachal
3) metastatic
What are urachal carcinomas?
- very rare tumours arising outside the bladder
- usually adenocarcinomas but can also be TCC, SCC, or even sarcomas
- sharply demarcated from normal bladder epithelium } tumour is found in bladder wall
- may present with bloody or mucoid discharge from umbilicus
if tumour invades bladder may present with mucosuria
- may present as palpable mass after forming mucocele
- often have stipled calcifications on xray
- POOR PROGNOSIS } worse than primary bladder adenocarcinoma
- histologically invades deeper and wider than expected
often compromises results of partial cystectomy
- mets to iliac & inguinal LNs, omentum, liver, lung, bone
Rx partial cystectomy + resection of entire urachus
How common are metastatic adenocarcinomas of the bladder?
- most common form of adenocarcinoma of bladder
- primary sites include rectum, stomach, endometrium, breast, prostate, and ovary
ORIGINS AND PATTERNS OF DISSEMINATION
What are the main patterns of spread of urothelial carcinoma?
1) direct extension } involves a) angiogenesis
fibroblast growth factors (FGF) & VEGF
b) proteolysis of basal lamina
collagenase type 4 (an MMP; inhibited by TIMPs)
urokinase plasminogen activator (u-PA)
c) increased cellular motility
reduction of adhesion molecules such as E-cadherin
d) proliferation
increased EGF receptor expression
e) escape from local surveillance mechanisms (immune system)
2) metastatic spread } ~5% of all low-grade superficial disease will progress to mets
} ~20% of high-grade disease (including CIS) will progress to mets
} mets rare without muscle-invasion
3) lymphatic spread } extent of primary + LN status affects survival after surgical excision
} obturator (75%) & pelvic (65%) LNs most common, presacral (~25%)
paravesical (15%) is worst prognosis
4) vascular spread } 5yr survival in patients with distant mets is very low
5) implantation } can spread into abdo wounds, denuded urothelium, resected prostatic fossa,
or traumatized urethra
} occurs most commonly with high-grade tumours
What are the 2 main theories on the origins of urothelial carcinoma?
1) field change disease
2) original lesion + clonal seeding (recurrences)
What are the 3 main mechanisms of local invasion?
- en bloc spread (invading broad front) 60%
- tentacle-like invasion 25%
- lateral spread only 10%
How common is prostate involvement in muscle-invasive disease?
- ~40% of cystectomy patients
- prostatic urethra is usually site of involvement
40% have concomitant stromal invasion
~6% have prostatic stromal involvement WITHOUT prostatic urethral involvement
- presence of prostatic stromal invasion also predictive of subsequent distant mets 80%
What are the common sites of distant bladder metastasis? }}} “LL BAG”
- Liver (40%)
- Lung (35%)
- Bone (27%) } much more common with bilharzial SCC of bladder
- Adrenals (20%)
- GI tract (15%)
NATURAL HISTORY
What is the natural history of urothelial carcinomas of the bladder?
- ~75% present with superficial disease
~55-60% present with low grade Ta tumours
- most develop recurrences } ~20% recur with high grade disease
- ~5% progress onto ≥T2 disease
- most young patients (<30yrs) present with TaG1
~20% present with high grade superficial tumours
- 30-50% with T1G3 will progress on to ≥T2 disease
- ~25% present with ≥T2 disease
almost 50% have occult distant mets } clinical mets seen within 1yr in most
- 2% has upper tract disease at initial presentation
PROGNOSTIC INDICATORS
What are the RFs for recurrence or progression of superficial disease?
- grade } #1 RF for progression
- stage
- presence of CIS
- multifocality } #1 RF for recurrence
- cysto at 3months post-TURBT
- interval between prior recurrence
- lymphatic invasion
- tumour size (>3cm)
- papillary vs solid
- presence of nested variant (micropapillary variant) } very bad
- p53 status
What other prognostic indicators are being researched?
predicting poor outcomes
- +ve Ki67 staining bad prognosis
- chromosome 17p deletions (p53) progression
- p53 nuclear accumulation invasive (most promising)
- reduced E-cadherin levels invasive
- elevated EGF receptors invasive
- amplification of HER2/Neu oncogene progression
- chromosome 9 deletions recurrence and BCG failure
- elevated hyaluronidase activity high grade disease
- high urine fibronectin invasive and predicts poor BCG response
predicting better outcomes
- chromosome 9q deletions superficial disease
- heterogeneous staining of EMA better survival
- elevated TGF-β expression in tumour less aggressive
Lewis x blood group antigen bladder cancer
What are the markers of proliferation?
- nondiploid fractions \
- increased DNA-synthesizing S phase fraction } higher percentage of proliferating cells
- increased PCNA / correlates with aggressiveness
What are the markers of apoptosis?
- survivin levels inhibits apoptosis and so is upregulated in many cancer
DIAGNOSIS
How does bladder cancer present?
- painless hematuria most common symptom (found in 85%)
- irritative symptoms (frequency, urgency, dysuria) 2nd most common symptom
associated with CIS or invasive TCC
- flank pain } ureteral obstruction
- lower limb edema
- pelvic mass
- abdo pain, bone pain
- constitutional symptoms
What are the AUA guidelines on microscopic hematuria?
microscopic hematuria = ≥3 RBC/hpf from a fresh MSU on 2 of 3 samples
1) high-risk patient
microscopic hematuria x1 warrants FULL UROLOGIC EVALUATION
a) hx and P/E
b) urine cytology
c) upper tract imaging
d) cystoscopy
high risk includes:
- smoking hx - occupational exposure
- hx of gross hematuria - age >40yrs
- hx of urologic dz - hx of irritative symptoms
- hx of UTI - analgesic abuse
- hx of pelvic RADs
2) low-risk patient
if suggestion of benign cause (UTI, intercourse, menstruation, vigorous exercise)
then REPEAT U/A 48hrs AFTER CESSATION OF ACTIVITY
otherwise:
a) UPPER TRACT IMAGING
b) URINE CYTOLOGY
3) presence of significant proteinuria (>1g/day), RBC casts, or renal insufficiency warrants
REFERRAL TO NEPHROLOGIST
4) if -ve evaluation, repeat U/A, URINE CYTOLOGY, and BP check at 6, 12, 24, 36 months
What are the CUA guidelines (2008) on microscopic hematuria?
microscopic hematuria = ≥3 RBC/hpf on 2 u/a
if urinalysis performed after recent exercise, menses, intercourse, etc should REPEAT AFTER
STOPPING ACTIVITY and if negative, no further work-up required
1) presence of proteinuria, RBC casts, or dysmorphic red cells +/- elevated serum Creat
warrants REFERRAL TO NEPHROLOGIST
2) ALL PATIENTS SHOULD GET MINIMAL WORK-UP
a) urine cytology
b) upper tract imaging } U/S is 1st line
3) >40yrs old, +ve or atypical urine cytology, or +RFs (SOLAR–C)
RFs include smoking, occupational exposure, irritative LUTS, analgesic abuse, pelvic RADs,
cyclophosphamide exposure
SHOULD GET CYSTO
4) <40yrs old, N cytology, no RFs
repeat urinalysis + urine cytology + BP checks at 6, 12, 24, 36 months
- no f/u required after 3yrs of N tests
reassessment ONLY if gross hematuria, +ve or atypical cytology, or irritative LUTSWhat is the role of urine cytology?
high specificity (low false positives)
- usually positive only with high-grade disease and CIS
can have ~20% false negative rate
- cancer cells are more cohesive in well-differentiated, low grade disease
cells are not shed in urine
- can see 1-10% false positive rate
from urothelial atypia, cystitis glandularis, inflammation, or changes due to RADs or chemo
urine cytology NOT A GOOD SCREENING TOOL } poor sensitivity (>20% false -ves)
+ve cytology in face of TaG1 tumour may mean concomitant CIS somewhere else
Are washings better than voided cytology?
- washing gives more surface epithelial cells so may be better
- if flexible scope used however, this difference may be negated because far less epithelial cells
- washings ideal for sampling upper tracts and prostate
What is the value of flow cytometry?
overall, no added benefit over cytology
- can measure DNA content only in cells staining +ve for cytokeratins (epithelials)
- diploid tumours } low grade and low stage, better prognosis
- triploid to tetraploid tumours } poor prognosis
What is the value of image analysis?
analyzes DNA content in each cell & identifies cells with abN amounts of DNA via fluorescence pattern
EARLY DETECTION
What are the biases involved in the attempt to determine whether screening is beneficial?
- lead time bias } earlier diagnosis but no change in mortality
- length time bias } tendency to diagnose more indolent tumours with longer preclinical durations
- selection bias } tendency for participants in early detection programs to be more healthy & health
conscious
Is there any evidence for bladder cancer screening?
YES eg Messing et al (Wisconson trial)
- home dipstick screening for hematuria
- screened and unscreened had similar proportions of low grade (55%) and high grade (45%)
- low grade were almost all T1 or less in both groups
- 50% of high grade in unscreened were muscle invasive \
- 10% of high grade in screened were muscle invasive } decreased risk of muscle invasive
mortality was significantly reduced in screened group / disease and mortality
What is the argument against using cytology, flow cytometry, imaging analysis, and marker tests
to screen for bladder cancer?
- not sensitive for small tumours } would miss 10-20% of high grade tumours
- poor sensitivities for low grade tumours
- would miss significant amount of tumours, even though most of those would be superficial
- cost
What screening tools for bladder are being researched?
- Lewis x blood group antigen
- antigen M344
- DD23 antigen
- Hyaluronic acid (HA) or hyaluronidase in urine
- BLCA4 protein in urine
- NMP22 protein in urine (more sensitive than cytology)
- telomerase RNA in urine
- microsatellite nucleotide repeat analyses
- survivin protein in urine
- DNA FISH (highest specificity)
NOT adequate to replace cysto for evaluation of hematuria
may be useful in replacing some surveillance cystoscopies in monitoring low risk superficial
bladder cancer but likely are NOT satisfactory for screening
may have promise in high risk groups eg aluminum or benzidine workers
What are the important points to remember during the initial TURBT?
- fulguration or laser ablation of suspicious lesions w/o Bx is NOT ADEQUATE in initial evaluation of a
bladder tumour
- try to send separate specimens
a) bulk of tumour
b) deep base + underlying muscle
- if unable to resect fully, obtain enough to make accurate histologic diagnosis
- resect without regard for the orifice, but don’t fulgurate
+/- stent
- paralysis necessary for lateral wall tumours to prevent obturator reflex
- tumours in bladder tics should be sampled rather than resected
What are the indications for random bladder Bx’s?
1) partial cystectomy (or diverticulectomy) is planned
2) +ve cytology with no visible tumours, only papillary lesions (Ta), or low grade TCC on path
3) ?? consideration of orthotopic neobladder } prostatic urethral Bx
systematic Bx’s best } dome, left lateral, right lateral, trigone, prostatic urethra
STAGING
What is the accuracy of staging bladder TCC?
- ~30% understaged
- ~10% overstaged
What is the recommended staging workup for bladder cancer?
1) primary TURBT
2) bimanual exam during TURBT
- if palpable before resection, likely deep T2 or more
3) for superficial disease
- no further imaging recommended } consider upper tract imaging
4) for muscle-invasive disease
- CBC, lytes, creatinine, LFTs and ALP
- CXR
- biphasic CT urogram } better if done before TURBT
} can only assess large LNs and large liver mets
- bone scan
- MRI } not significantly better than CT
} better in detecting bone mets than CT and bone scans
What is the role of fluorescent cystoscopy using intravesical 5-ALA (aminolevulinic acid)?
- can see tumours not seen by white light } uses blue light (375-440nm) high sensitivity
- reduces recurrence rates and may prevent disease progression
- problem is that is has low specificity (high false negatives)
What is the role of PET scans for bladder cancer?
- not good for staging because FDG reagent excreted in urine
- helps assess masses that are possible mets or possible local recurrences post-cystectomy
helps guide the need for Bx
What are the main regions of lymphatic drainage from the bladder?
- internal iliac
- obturator (most commonly involved)
- external iliac
- presacral
- perivesical (less involved than others)
What are the boundaries of the STANDARD staging lymphadenectomy?
- slightly above bifurcation of iliacs
- down to femoral canals
- lateral to genitofemoral nerves
- medial to bladder pedicles
How common is mets to the LNs?
- close to zero in low grade, superficial
- 5-10% in T1G3 disease
- 40% in T2 disease
What is the 1997 AJCC TNM staging of bladder cancer?
- T } Ta – papillary
Tis – flat CIS
T1 – lamina propria invasion
T2a – superficial muscularis propria invasion
T2b – deep muscularis propria invasion
T3a – microscopic extension into perivesical fat
T3b – macroscopic extension into perivesical fat
T4a – invading pelvic viscera (eg prostatic stroma, vaginal wall, rectum, uterus)
not fixed
T4b – invading pelvic side wall, abdo wall, bony pelvis
fixed
- N } N0 – no pelvic node mets
N1 – single node ≤2cm below common iliacs
N2 – single node 2-5cm or multiple small nodes (<5cm)
N3 – node >5cm
- M } M0 – no distant mets
M1 – distant mets
PREVENTION
What has been suggested for chemoprevention of bladder cancer?
studied as secondary prevention as well as primary prevention in high-risk groups
- vitamins } vitamin A, B6, E, Zn, Se
- polyamine synthesis inhibitors } DFMO (difluoromethylornithine)
- COX inhibitors
- dietary alteration } urinary acidification, soy, green tea extract, high fluid intake, low-fat diet
no consistent significant benefits seen
STOP SMOKING … PROVEN PREVENTION
NON-UROTHELIAL TUMOURS OF THE BLADDER
What is small cell carcinoma of the bladder?
- derived from neuroendocrine stem cells or dendritic cells
stain +ve for enolase
- may be mixed with elements of TCC
- very aggressive with early vascular and muscle invasion
- should also be evaluated for small cell carcinoma of lung or prostate which may have
metastasized to the bladder
Rx } requires multi-modal therapy chemo + surgery/rads
- chemo recommended first even if tumour seems confined (cisplatin-based)
- poor prognosis } only 65% cured after chemo + Sx even if localized
40% for chemo + Rads
What is carcinosarcoma of the bladder?
- rare, highly malignant tumour containing malignant mesenchymal & epithelial elements
mesenchymal elements } chondrosarcoma or osteosarcoma
epithelial elements } TCC, SCC, or adenocarcinoma
- usually in middle-aged men
- poor prognosis
- should not be confused with urothelial cancers with prominent spindle cell component
Rx } multimodal therapy GC chemo + surgery +/- RADs
What are the most common primaries in metastatic bladder cancer?
- prostate - breast
- ovary - kidney
- endometrial - stomach
- colon & rectal - melanoma
- lung - lymphoma, leukemia
What is signet cell carcinoma?
- rare variant of adenocarcinoma } 2/3 originate in bladder and 1/3 from urachus
NON-EPITHELIAL BLADDER TUMOURS
What are the common non-epithelial bladder tumours?
5% of all bladder tumours
1) sarcoma (most respond poorly to chemo and Rads)
a) angiosarcoma and hemangioma bladder hemangiomas are rare
- can get malignant degeneration (rare)
angiosarcomas are very rare
- 20% come from previous hemangiomas
mets rapidly to hematogenous sites
Rx } laser or TUR of hemangiomas (can recur)
} partial cystectomy
b) leiomyosarcoma MOST COMMON mesenchymal bladder tumour
- also the most common sarcoma in kidney
2x more common in M
appears as submucosal nodule or ulcerating mass
r/o benign leiomyoma
poor survival (5yr disease specific is 62%)
Rx } aggressive surgical extirpation
c) rhabdomyosarcoma most common in young kids
embryonal type in kids (favorable histology – spindle or botryoid)
spindle cell, alveolar cell (bad histology), or giant cell type in adults
poor prognosis and don’t respond well to chemo or rads
Rx } aggressive surgical extirpation in adults
} CHEMO + RADs + surgery
d) other liposarcomas, chondrosarcomas, osteosarcomas are very rare
Rx } aggressive surgical extirpation
2) primary bladder lymphoma arises from submucosal lymphoid follicles
2nd most common non-epithelial bladder tumour
more common in women, usually in 40’s to 60’s
Rx } CHEMO + RADs, partial or radical cystectomy
3) neurofibroma benign Schwann cell tumour (stains for S-100 protein & type 4 collagen)
may be part of AD neurofibromatosis with variable penetrance
usually seen in kids or young adults
can rarely undergo malignant change into neurofibrosarcoma
4) pheochromocytoma usually from paraganglionic cells in bladder wall near trigone
usually seen during teens to 30’s
syncope on filling/emptying of bladder in 67% } hormonally active
10% are malignant
Rx } partial cystectomy TURBT contraindicated (HTN’sive crisis)
5) plasmacytoma, granular cell myoblastoma, malignant melanoma, choriocarcinoma, and
yolk sac tumours same behaviour as their counterparts in other body sites
Rx } same as counterparts in other sites of body
