BLADDER CANCER- Diagnostics

BLADDER CANCER- Diagnostics
Urine cytology is performed to detect cancer and inflammatory diseases of
urinary tract with specimen obtained via voiding or from bladder washing. Urine
cytology is more superior at detecting higher grade UC due to higher cells
shedding. The criteria for positive urine cytology are largely subjective and are
dependent on experience of pathologist. Low grade UC does not always exfoliate
in aggregates and cell changes might be subtle; hence the sensitivity can be as
low as 20%. For primary lesion urine cytology, it has an overall sensitivity 78%
with specificity 90% while on detection of residual UC after TURBT, the is
sensitivity 75% and specificity 85% and overall diagnostic accuracy of 66% cf to
exfoliative cytology (overall accuracy 49%).
Due to the low sensitivity (for diagnosis of low grade UC) and non-immediate
availability of test result of urine cytology and high propensity for recurrence of
UC, urinary biomarkers are being investigated for both diagnostic and prognostic
purposes. Biomarkers should be inexpensive, easy to use and interpret, and
provide results rapidly. Variety of potential biomarkers includes nuclear matrix
protein, bladder tumor antigen, fibrin/fibrinogen product, telomeric repeat
amplication protocols (TRAP), tumor associated antigens, hyaluronic acid, and
hyaluronidases. Two prospective RCTs showed sensitivity and specificity of
cytology; BTA TRAK and NMP 22 were 24% and 97%, 51% and 80%, 78% and
73%. A systemic review by Lotan concluded that all evaluated urinary markers
have higher sensitivity than cytology, both overall and after stratification by grade
and stage, but specificity if inferior to cytology overall. This is further confirmed by
meta-analysis by Glas demonstrated that cytology had the best specificity and
telomerase had the best sensitivity.
Photodynamic diagnosis (PDD) exploits effect of photosensitizer accumulating
preferentially in cancer cells, and fluoresce in visible spectrum when illuminate
with light of appropriate wavelength. Endogenous ALA is natural precursor of
photoactive intermediate protoporphyrin IX (PpIX); part of the haem biosynthesis
pathway. Early studies using ALA in bladder tumors confirmed good demarcation
between red fluorescence from malignant tissue and background reflected blue
light; correlation between fluorescence and histology findings with sensitivity of
100% and specificity of 69%. 5-aminolevulinic acid (ALA) accumulates at 20:1
ratio compared to normal tissue. Lipophilic derivatives of ALA; hexyl ester of ALA
(hexaminolevulinic acid, HAL) gives twice the fluorescence in half the time and
20 times lower concentration. The sensitivity of HAL is 96% compared to 73% for
white light cystoscope. Studies on PDD have shown significantly less residual
tumor post-resection, higher RFS at 2 year (89% vs 66%), improved treatment in
22% and economic advantage average recurrence of 0.3 in fluorescence group
cf to 1 in white-light group. However, false positive could arise due to excitation
by a tangential instead of perpendicular beam; preferential accumulation in
inflamed and scarred of mucosa and previous PDD instillation within 6 months.
When re-resection is performed, PDD has no additional value as it only detects
superficial disease.
Intravesical Chemotherapy
• Indications
• Agents Used ( Comparison of risk benefits & outcomes)
• Regimens (treatment vs maintenance)
Please discuss current worlds best practice
Aims
• Reduce recurrence
• Prevent progression
• Treat residual disease after TURBT
Indications
• Potentially all patients with superficial bladder cancer – one single post
operative dose
• “High risk” patients (high grade Ta/T1, CIS) – maintenance
Agents used
• many tried (over 35), a few effective including BCG, mitomycin C, thiotepa,
epirubicin, epodyl, doxorubicin, valrubicin, interferon, keyhole-limpet
hemocyanin, bropirimine, recently tried gemcitabine and taxanes
Studies
• individual studies a guide. Differences in patients, drugs, dosages, regimens.
• Meta-analysis completed
o BCG in Ta and T1 bladder cancer
o BCG versus Mitomycin C for Ta and T1 bladder cancer
o BCG versus Mitomycin C for superficial bladder cancer: recurrence,
toxicity and progression
o Combined analysis of EORTC and MRC trials for prophylactic treatment
of TaT1 bladder cancer
o BCG versus chemotherapy for CIS of the bladder
o Single post operative dose of chemotherapy and the risk of recurrence in
TaT1 bladder cancer
o Intravesical chemotherapy and the recurrence rate in superficial TCC of
the bladder (all agents)
Agent Used
BCG
Recurrence (vs TURBT)
Progression (vs TURBT)
Cochrane Review Ta and T1
585 patients, 6 RCT’s
67% reduction in incidence of
recurrences at 12 months
Lamm (Uro 2000)
29% vs 67% TURBT=difference 38%
36% vs 48% TURBT=difference 12%
Evidence less strong
Vs TUR, 26% vs 42% need cystectomy
2 metas positive
Sylvester 2.5yr f/u, 9.8% vs 13.8% progress
No evidence
Mitomycin C
39% vs 51% TURBT=difference 12%
No evidence
Epirubicin
44%
vs
61%
TURBT=difference
17%
No evidence
Thiopeta
No evidence
Doxorubicin 39% vs 55% TURBT=difference 16%
Suggests no significant difference between intravesical chemotherapy options in reducing
TCC recurrence
Complications
-locally occurring – direct effects on bladder
-systemic – absorption
some factors increase risk – TUR recently, traumatic catheterisation, active UTI
Agent
Minor
Major
Frequency/Urgency
71%
<5%
BCG
Cystitis 67%
Fever 25%
Hematuria 23%
Mitomycin
Irritative LUTS 3-30%
Palmar desquamation (contact
dermatitis)
Epi/doxorubicin
Irritative LUTS 13-56%
Thiopeta
Irritative LUTS 12-69%
Regimens
NO STANDARDISED PROTOCOL!
Agent
MW
Peri-op
Risk
use
group
Adriamycin 580
Yes
Low-int
Epirubicin 580
Yes
Low-int
Thiopeta
189
Yes
Low-int
Mitomycin 334
Yes
Low-int
BCG
NA
No
Int-high
Interferon
23,000 No
Salvage
granulomatous prostatitis 1%
granulomatous epididymo-orchitis rare
granulomatous hepatitis/pneumonitis
<1%
BCG sepsis 0.4%
Allergic reactions (arthritis, athralgia)
0.5%
Ureteral obstruction 0.3%
Contracted bladder <1%
Myelosuppression-rare
Contracted bladder
Extravasation – peritonitis, pelvic pain,
fibrosis, necrosis, ulceration
Rare <5%
Gastrointestinal upset
Fever
Hypersensitivity reactions
Up to 1/3 of drug absorbed
Leukopenia 8–55%
Thrombocytopenia 3-31%
Dropout Concentration
Cost
2-16%
3-6%
2-11%
2-14%
5-10%
Rare
$36
$595
$80
$130
$150
$6701340
50mg/50ml
50mg/50ml
30mg/30ml
40mg/20-40ml
1 vial/50ml
50100MU/50ml
Treatment vs Maintenance doses
Chemotherapy agents
• Single dose post operative decreases relative recurrence rate 39% (for single
tumours, 48.4% in TUR alone, 36.7% in TUR + chemotherapy)
• Maintenance doses
o In general up to 1 year
o Conflicting results
o Not routine
BCG
• Single induction course appears more effective than a similar course of
chemotherapy
• Maintenance therapy
o Controversial
o Some trials show no significant benefit but higher toxicity
o SWOG trial (Lamm, J Urol 2000) 660 pts, high risk, 6 week induction
course
• 550 pt randomised to no additional or maintenance BCG (6+3)
• median recurrence free survival improved (77 vs 36 months)
• 5 year survival no difference
• only 16% of patients completed the maintenance course
Worlds best practice
• weigh up benefits vs risk to individual patients
• TUR is important – resect all visible tumour, consider re-resection for high
risk large lesions
• One dose of intravesical chemotherapy peri-operatively within 6 hours. The
agent does not appear to matter
• Consider induction therapy
o ?only for high risk ?for all
o ?which agent – chemotherapy for intermediate risk, BCG for high risk
• Maintenance
o Appears to be helpful for BCG but appears to have toxicity
ƒ ?decrease time
ƒ ?decrease dose
o chemotherapy – may be useful
• Failure of therapy
o Salvage intravesical therapy
o Radical cystectomy option
Role of chemotherapy (adjuvant and neoadjuvant) and lymphadenectomy in invasive
bladder cancer
Chemotherapy
Neoadjuvant
cystectomy is the gold standard Rx localised muscle-invasive
bladder TCC
When considering neoadjuvant chemo remember up to 40%
clinical staging discrepancy
Toxicity and mortality associated with neoadjuvantchemo are
acceptable, however scant data on QOL available
Meta-analysis of cisplatin-containing combination neoadjuvant
chemo revealed a modest difference in favor of chemo: 5%
survival benefit (ABC collaboration 2003 NEJM)
Available data suggests that for ‘average risk’ cancer cT2,
benefit of chemo is at best modest. More substantial benefit for
high-risk disease eg cT3b
Quality of surgery is a confounder
Adjuvant
Advent of orthotopic bladder and decreased morbidity of
cystectomy have increased tendency of Urologists to operate
early and then consider adjuvant
Advantage local treatment performed immediately and then
pathologic result can then be considered
Available trials are small and provide insufficient evidence to
support routine use of adjuvant chemo
Result of larger collaborative international trials will be needed
before the true value can be assessed
Lymphadenectomy
Robust evidence to support the use of lymphadenectomy with
radical cystectomy as it increases survival
Micrometastatic disease present in between 2-10% in Ta/T1
disease and 25% overall in bladder TCC
Herr (Urology 2003) clearly showed significant survival benefit
in those who have lymphadenectomy whether node positive or
not, particularly if at least 10-14 nodes removed. This has been
validated by other Authors including Stein and Leissner (BJU
2000)
Konety (JUrol 2003) analysed data from SEER database over
2000 cystectomies and showed 60% reduced chance of death if
10-14 nodes removed
Theories are the removal of micrometastases and possibly
better technique
Standard is to iliac bifurcations, extended up to aorta, at present
no clear guidelines to suggest extent.
References
Campbells 9th
Sternberg et al. Chemotherapy for bladder TCC. Urol. 2006
Urinary Diversions
The development in urinary diversions has progressed considerably over the last 3 decades.
Beginning with Bricker with ileal conduits in the 1950s to cutaneous reservoirs in the 70s and
neobladders in the late 80s there has been a paradigm shift in the use of these methods for
diversion in cystectomised patients. It has come to a time in the present age where most Urologist
should be adept in performing such operations based on sound patient selections.
There are four domains that need to be considered before formulating a decision plan for urinary
diversion. They include: choice of bowel segment, sound selection criteria, options available for
urinary diversion and onco-surgical outcomes.
Most common bowel segments used involve either the distal ileum or colon. These have the least
effect on metabolic changes. While most metabolic abnormalities are clinically subtle, they may
assume significance in younger patients from prolonged exposure and in patients with renal
insufficiency. Jejunal segments are rarely used due to significant metabolic derangements and
stomach may have a place in patients with preexisting acidotic state.
The therapeutic goals are to provide a patient with a diversion that matches their medical,
physical and emotional needs. The key to a successful outcome is largely dependent on sound
patient selection. The most important aspect is to uphold sound oncological principles with
negative surgical margins. Baseline renal and hepatic function needs to be evaluated as continent
diversions have long urine contact time and may predispose to metabolic complications. Impaired
creatinine >2mg/dL precludes a continent diversion. If the renal function is borderline a creatinine
clearance should be > 60ml/min. Normal hepatic function is a prerequisite to deal with the
increased ammonia re-absorption. Patients should have good manual hand dexterity before
consideration of continent cutaneous diversion or neobladder, as intermittent catherisation is
required. Advance age, obesity, associated comordities, bowel disease or previous radiotherapy
are less relevant.
Three options are available for diversion post-cystectomy: conduit diversions, continent
cutaneous diversions (CCD) and orthotopic neobladders. Conduits are the oldest, simplest and
most commonly performed and remain the standard to which all other newer diversions are
compared. Terminal 15 cm of ileum should be spared to avoid B12 deficiency and bile salt loss.
External appliance is required and this may compromise patient’s body image. CCD requires a
reservoir from detubularised bowel segments for urinary storage as well as an efferent
catherisable aperistaltic limb. Importance of CIC cannot be overemphasized. Orthotopic
neobladder requires a formation of spherical pouch based on La Place’s law and a reliance on the
external urethral sphincter and pelvic floor for continence.
Finally complications are common in the early (within 30 days) and late (>30days) phases of
recovery. They can be divided into technical-surgical and metabolic complications. Technicalsurgical complications are further subdivided into stoma, diversion, ureterointestinal anastamosis
and bowel related complications. Metabolic complications include electrolyte and acid-base
derangements usually in the form of hyperchloraemic metabolic acidosis, sepsis, calculi, renal
deterioration, delayed malignancy and osteomalacia. Specific complications for neobladders
include daytime and nighttime incontinence and hypercontinence requiring CIC. For CCD, pouch
urolithiasis, incontinence and problems with catherization of the stoma are often encountered.
Most complications require re-operations to a greater or lesser extent and this must be discussed
with the patient in consultation prior to obtaining consent.
Case presentation
Recurrent T1 G3 TCC Bladder, Dr Adam Davies
Background history
52 year old male, Smoke, Otherwise well, Painless gross haematuria 3/52
Investigations
MSU – RBC, WBC, nil UTI, Cytology – likely high grade TCC
Creatinine – normal, CT Scan – thickening left bladder wall
Further investigations
Abdominal exam – NAD, CXR – clear, Flexible cystoscopy – tumour left bladder wall
Operation 1
Trans urethral resection bladder tumour, Histology – pT1 G3 N0 M0
Operation 2
Repeat cystoscopy at 6/52, Small recurrence posterior wall resected, Histology – pT1 G3
Commenced 6 weeks intra-vesical BCG
Operation 3
Check cystoscopy 6/52 post BCG, Erythema left lateral wall, histology – pT1 G3
Probability of progression?
pT1 G3 N0 M0, Single tumour > 3 cm, > 1 recurrence in 12 months, Nil CIS,
17% at 1 year, 45% at 5 year
Management options
BCG
Superior to chemotherapy for preventing recurrences, Intermediate and high-risk
tumours, Maintenance therapy
Salvage combination immunotherapy
Only if cystectomy not feasible, Consider in BCG failure, Only for low-risk or
intermediate-risk disease recurrence (TaG1, TaG2), Several regimes being trialled
Radio-chemotherapy
TURBT, radiation therapy , simultaneous chemotherapy, cisplatin, carboplatin and/or 5fluorouracil
Radical cystectomy
remains gold standard for salvage of failed intravesical therapy
a third of patients initially treated by endoscopic and intravesical therapy for high-risk
superficial TCC will require cystectomy
a third will die of their cancer
despite an initial response to BCG therapy, patients with T1 remain at risk for
progression and death
patients with T1 tumours who fail initial intravesical therapy are at greatest risk for
pathologic upstaging at time of cystectomy
prognosis is correspondingly poorer
Consider as first line treatment for young, otherwise healthy patients with high-grade T1
disease
5-year disease-free survival rate 85% for pathologic node-negative T1 tumors
Summary: Radiation Induced Bladder Cancer 1. Radiation treatment for prostate cancer may increase subsequent bladder cancer risk (relative risk 1.5) 2. Radiation induced bladder cancers are usually of higher grade 3. Cystectomy in irradiated pelvis is associated with higher mortality and morbidity 4. Overall survival appears to be similar Summary: Angiosarcoma 1. Radiation induced bladder angiosarcoma is very rare 2. Histological recognition often difficult without specific immunohistochemical staining 3. Associated with very poor prognosis 4. Poorly responsive to chemotherapy 5. Due to previous irradiation, surgery often becomes the only viable treatment options Bladder Angiosarcoma Risk factors Arsenic, thorium dioxide, polyvinyl chloride, radiation, and chemotherapeutic agents Post‐irradiation 22% of reported cases M:F 8:1 Presentation Most presented as large hemorrhagic masses difficult to resect with adequate margins in 7th decades Metastatic sites Lung and liver mets described Surgical options Cystoprostatectomy/cystectomy/partial cystectomy Radiotherapy treatment No accepted protocol, ~60Gy used May be limited by previous local irradiation Chemotherapy treatment Mesna, doxorubicin ifosfamide, and dacarbazine Angiogenesis inhibitor Thalidomide, ?multi‐kinase inhibitors Prepared by Rex Chan for Registrar Training week 2007 Bladder Cancer Case (Scott Leslie)
65 yo ♂
Macroscopic Haematuria
B/g: COPD
Sx: Smoker
Investigations:
Hb-123, Cr-89
U/A – blood++
MSU – no growth
Urine Cytology – Positive for malignant cells
CT IVP - 4cm enhancing mass left wall of bladder
- Left hydronephrosis
TUR(BT)
- Tumour resected down to detrusor
- Left ureteric stent inserted (? theoretical risk of upper tract seeding)
Complicated post-op by perforation at dome by tip of foley’s catheter
(? Conversion of T2 to T3 disease)
Histopath
- T2G3
Treatment options
- Cystectomy
- Chemoradiation
Treated with chemoradiation: 60Gy RTX and concurrent MVAC
chemotherapy
3 month check CE – residual muscle invasive high grade disease +
prostatic stromal involvement
Treated – Radical cystoprostatectomy + bilateral standard PLND +
urethrectomy.
Pt still smokes!
Bladder Cancer Case Presentation Trainees Week 2007
Mark Louie-Johnsun
75M 3/52 history of macroscopic haematuria
„ Background
– IHD: AMI X3 Rx Aspirin
ƒ No angina 5 yrs
– NIDDM
– Smokes 15/day
– Reasonable exercise tolerance (walk 1km)
Investigations
„ 2/3 positive urine cytology
„ MSU neg
CT and IVP – filling defect L lateral bladder and L renal pelvis
„ 12/06 Cystoscopy TURBT and L RPG
Solid looking lesion around L UO and superficial lesions L lateral
„ L renal washings positive cytology
Histo:
ƒ T1G3 (smooth muscle present)
ƒ Random biopsies no CIS
TREATMENT?? Upper tract TCC and T1G3 (focal) TCC
„ ?Rebiopsy
„ Priorities in Rx
– ? Rx upper tract TCC
– ? Intravesical BCG
– ? Synchronous Rx upper tract TCC / bladder
„ 2/07 Lap L nephroureterectomy
– Uncomplicated
– Histo
ƒ HG invasive TCC
ƒ “Tumour extend into muscle layer renal pelvis”
ƒ Tumour extend prox ureter and focal infiltration muscle
ƒ Renal parenchyma normal
5-6/07
„ 6X weekly course BCG
„ No complications
8/07
„ Cystoscopy
– Recurrent TCCs largest around L UO site of previous resection and BN
– Rx
ƒ TURBT to complete clearance
– Histo
ƒ Deep Bx: T1G3 (L UO tumour)
ƒ Random Bx and prostate urethra Bx NAD
ƒ No CIS
Further Rx??
„ Options
– Further course BCG
– Radical cystectomy and diversion
„ Further course BCG given
– Completed 4/6 (unable tolerate further due to irritative symptoms)
– Due for check cystoscopy this month
Case Summary Muscle Invasive Urothelial Ca in Patient Not Fit For Radical Cystectomy Ben Kwok 74M. Presentation with 3/12 haematuria + obstructive LUTS B/G: Heavy smoker, emphysema, poor exercise tolerance, past AMI x2 O/E ‐ Abdo unremarkable ‐ Prostate moderate size, smooth Investigations ‐ Creatinine 90 ‐ PSA 1.3 ‐ Urine m/c/s o Homogenous red cells Imaging ‐ Ultrasound o Left hydronephrosis +several solid mass lesions in bladder ‐ CT o Bilateral hydronephrosis + hydroureter L>R o No mass visible in bladder on CT Cystoscopy ‐ Extensive tumour bladder trigone, bladder neck and proximal prostatic fossa ‐ TURBT/prostate ‐ Unable to identify ureteric orifices to insert stent Histo ‐ High grade muscle invasive Patient declined radical cystectomy due to comorbidities Decision at MDTM to have radiotherapy + chemotherapy ‐ 64Gy in 32 fractions ‐ Cisplatin 40mg/m2 Treatment options for muscle‐invasive urothelial ca ‐ Cystectomy o 5yr survival o Overall 40‐60% o T1‐75% T2‐60% T3‐30% T4‐20% ‐ Radiotherapy o 5yr survival 40‐60% o Cochrane review 2001 suggested cystectomy has overall survival advantage c/w radiotherapy for muscle‐invasive cancer but older studies (1977‐1991) with older surgical + radiotherapy techniques ‐ Radiotherapy + Chemotherapy o 5yr survival 50‐60% ‐ Partial cystectomy +/‐ chemotherapy o T2 5yr survival 30‐80% in very selected patients ANGIOSARCOMA OF BLADDER
PRESENTATION:
32 year old fit and well ♀ G2P3 presents 6 months postpartum with
• macroscopic haematuria
• left flank pain
• preceeding irritative voiding symptoms
EXAMINATION:
Unremarkable
INVESTIGATIONS:
Blood workup normal
MSU: blood, no growth
Renal US: Posterior bladder mass with left hydronephrosis and hydroureter down to VUJ
MANAGEMENT:
Cystoscopy, JJ stent and biopsy shows angiosarcoma
Vascular tumour forming solid sheets/nests. Endothelial
cells are poorly differentiated with pleomorphic, large
hyperchromatic nuclei, prominent nucleoli and frequent
mitotic figures
Staging
PET scan: metastatic involvement of regional LN
MRI: involvement of anterior vaginal wall
Disease progression 5 months after diagnosis with
• Haematuria
• Renal Impairment
• Bilateral hydronephrosis
• Increasing vaginal mass
• PV bleeding
• Sacral pain
Palliative chemotherapy (epirubicin and ifosfamide) and radiotherapy
PRIMARY ANGIOSARCOMA OF BLADDER:
•
11 cases reported to date
•
Extremely rare vascular malignancy arising from blood vessel endothelium
•
Male predominence 8:1
•
5th to 9th decade
•
Linked to exposure to vinyl chloride, arsenic, therapeutic radiation
•
Most have metastasized at diagnosis
•
Very poor prognosis with 50% mortality at 12 months
Angiosarcoma of Bladder
Tanya Ha