6 - NMIBC Flashcards
Patient presents with gross haematuria, how would you approach?
I would assess him early in the fast track haematuria clinic
Obtain history
1) Sx
- clarify duration, severity of haematuria
- painless or painful (dysuria, UTI Sx)
- loin pain, stone passage
- constitutional Sx
2) Risk factors for urothelial carcinoma
- occupational exposure
- smoking
- irradiation, cyclophosphamide use
- travel history and chronic infection
3) Risk factors for RCC
- obesity
- hypertension
- family history of HNPCC or RCC
4) Past medical history and surgical history
Physical exam:
- general and focused
- anaemic signs
- palpable bladder mass
- ballotable kidney
- DRE: prostate and bimanual palpable bladder mass
Urine dipsticks
MSU microscopy and C/ST
Bloods tests
FC and CT urogram with contrast
Dipstick testing for haematuria principle
Ortho Toli Dine (orthotolidine)
- Haemoglobin containe peroxidase
- Thus will oxidize orthotolidine (chromogen in dipstick) causing change in colour
➔ colour change from yellow to green
False positive and negative multisticks for Haematuria
False positive
1) Myoglobinuria
2) Oxidizing agents, bleach
3) Menstruation
4) Dehydration
False negative (NAAG)
1) Nitrite
2) High level of ascorbic acid (vitamin C)
3) Acidic urine pH <5
4) High specific gravity
Definition of microscopic haematuria
How prevalent is it?
3 or more RBC per high power field
- with sediment count:
- in the absence of an obvious benign cause
- From a single properly collected urine sample
Screening study ~6.5% of population
How to count RBC under microscopy
1) Sediment Count
- centrifuge at 3000g for 5min
- discard supernatant
- re-suspend the cells in saline
- examine under HPF 400x
- ≥3 RBC / HPF
2) Chamber count
- un-centrigued urine in commercial chamber
- 50 RBC/microL
Risk of malignancy with haematuria (gross vs. microscopic)
Edwards (BJUI):
- 4000 patients
- Gross haematuria: 20% CaB
- Microscopic haematuria: 5% CaB
Mishriki (Urology 2008):
- For asymptomatic dipstick haematuria
- 5% urological malignancy on initial workup
- PSA is recommended as 10% has prostate cancer
- Further investigations will NOT identify any additional significant urologic pathology over 13 years
What investigation for microscopic haematuria?
Based on AUA risk stratification
1) Low Risk
- Male <40yo OR Female <50yo
- <10pack year
- 3-10 RBC/HPF
- No additional risk factors
➔ Repeat urinalysis within 6 months (or FC + USG)
2) Intermediate
- Male 40-59, Female 50-59
- 10-30 pack year
- 11-25 RBC/HPF
- Additional risk factors
➔ FC + USG
3) High
- >60yo
- >30 pack year
- >25 RBC/HPF
- Hx of gross haematuria
➔ FC + CTU
➔ If initial workup negative, repeat urinalysis in 12 months later, and discharge if still NAD
What is the sensitivity and specificity for urine cytology
1) Sensitivity overall 30-50%, but depends on WHO grade
- high for HG / G3 disease (84%)
- low for LG / G1 disease (16%)
2) High specificity 90%
How to save urine cytology
- Whole voided urine or bladder irrigates (avoid MSU due to low cellularity)
- at least 25mL
- ≥3 specimens in order to increase sensitivity
- Mid-morning ideally (avoid EMU due to degenerated cells and cytolysis)
- Fresh ideally (otherwise fix in 50% alcohol with refrigeration)
What system used to report urine cytology?
The Paris system (2nd edition):
1) No adequate diagnosis possible (No diagnosis);
2) Negative for UC (Negative);
3) Atypical urothelial cells (Atypia);
4) Suspicious for HG UC (Suspicious);
5) High-grade/G3 UC (Malignant)
Pros and Cons of urine cytology
+) High specificity (90%)
+) Good sensitivity for HG/G3 disease (84%)
+) Non-invasive, easy to save
-) Low sensitivity for LG disease (16%)
-) Inter-observer variability and user-dependent
-) Subjective evaluation
-) Low cellular yield
Tell me what you know about urine markers for CaB
- Sensitivity (~70%) is usually higher at the cost of lower specificity (~70%) compared to urine cytology
- None has been accepted as routine practice by clinical guidelines for diagnosis or follow-up
A. Protein Based
1) NMP 22 (nuclear matrix protein)
2) BTA (bladder tumour antigen)
B. Cell Based
3) UroVysion (FISH to detect aneuploidy, chromosome 3 7 17 abnormalities, and loss of 9p21)
4) Immunocyst (cytology + immunofluorescence assay)
5) FGFR3 (Fibroblast Growth Factor Receptor 3)
6) TERT (Telomerase Reverse Transcriptase)
7) Microsatellite analysis
Four of the promising and commercially available urine biomarkers, Cx-Bladder, ADX-Bladder, Xpert Bladder, EpiCheck ➔ high sensitivity and specificity, but no RCT yet
What is enhanced cystoscopy?
Standard WL cystoscopy has sensitivity and specificity around 70%
New technology were developed to improve detection. Methods include:
1) Fluorescence Cystoscopy
- aka Photo Dynamic Diagnosis (PDD) or Blue light cystoscopy
2) Narrow Band Imaging (NBI)
3) IMAGE 1S (formerly known as SPIES Storz professional image enhancer system)
- Optical and digital adjustment of image to improve tissue differentiation & contrast of images
Tell me about PDD
(what’s the mechanism? what’s the pros and cons?)
PhotoDynamic Diagnosis
AKA Fluorescence cystoscopy AKA blue light cystoscopy
Mechanism:
- abnormal heme metabolism in cancer cells
- instillation of porphyrin such as 3 hours of 5-amino-laevulinic acid (ALA) or 1 hour of hex-amino-laevulinic acid (HAL)
- will be converted to protoprophyrin and preferentially accumulate in tumour tissue
- emits red fluorescence under blue light (Xenon lamp with blue filter)
Pros:
1) Improves diagnosis
- Kausch systematic review:
- 20% more NMIBC detection
- 40% more CIS detection
2) May reduce recurrence if PDD-guided TURBT
- Cochrane review: prolong recurrence over time, but also risk of progression
- However PHOTO trial RCT showed no improvement in recurrence rate (but likely underpowered)
Cons
1) Lower specificity than WL (specificity 60%)
2) False positive up to 40% (Kausch review) due to inflammation, BCG, or recent TURBT
3) Higher cost
4) Time consuming
5) Contraindicated if porphyria / pregnancy / infection
Tell me about NBI cystoscopy
(Mechanism and advantages)
Narrow band imaging
Mechanism:
- Enhance contrast between mucosa and microvascular structures without using dye
- by using wavelength between 415nm and 540nm, which is strongly absorbed by haemoglobin
- therefore vascular tumour tissue is shown to be dark brown and green
Advantages:
1) Improved tumour detection (Herr Study on NMIBC surveillance)
- 55% more tumours detected
- 17% more CIS detection
2) Reduce recurrence if NBI-guided TURBT
- Naito CROES Study Group RCT: 22% reduction in recurrence rate for low risk tumour
Sensitivity and specificity of WL vs enhanced cystoscopy
WL
- Sen 70%
- Spec 70%
PDD
- Sen 90%
- Spec 60%
NBI
- Sen 95%
- Spec 80%
What imaging modality for upper tract workup?
CTU if no contra-indication
Khadra Study (2000):
- IVU will miss 21% of UTUC
- USG will miss 43% of UTUC
Albani Study (2007):
- 415 patients for CTU vs. IVU
- Higher sensitivity with CTU for UTUC (95% vs. 50%)
Presentation of Bladder cancer
1) Painless haematuria
- Gross haematuria 20% CAB (Edwards BJUI 2011)
2) Microscopic haematuria
- 5% CAB (Edwards / Mishriki)
2) Storage LUTS in 20%
- urgency or suprapubic pain
- “malignant cystitis” is typical in CIS
3) UTI with haematuria, recurrent UTI in 0.5%
- due to necrotic infected elements in bladder
4) Incidental finding on imaging or cystoscopy
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Unusual presentation:
- Pneumaturia or faecaluria if fistula in T4 disease
- If urachal adenoCA, might cause umbilical blood or mucus discharge
- Advanced disease might cause LL swelling, constitutional Sx, metastatic Sx
Histological types of primary bladder carcinoma
1) Transitional cell carcinoma (95%)
2) Squamous cell carcinoma (4%)
- if schistosomiasis endemic region, 75% are SqCC
3) Adenocarcinoma (1%)
4) Other very rare
- spindle cell carcinoma
- paraganglioma
- melanoma
- lymphoma
- sarcoma
Proportion of patients with NMIBC
For bladder cancer (TCC):
>80% p/w non-muscle invasive Ta or T1 disease
~20% p/w muscle invasive disease (T2-4)
Risk factors of bladder cancer (TCC)
A. Environmental exposure
1) Smoking (2-4x increased risk, esp if slow hepatic acetylators)
- slow 20y risk reduction after quitting
- family history (1st degree relative 1.8x, likely related to shared smoking history)
2) Occupation (dye, rubber, hairdresser, painter, leather worker)
- aniline dyes
- aromatic amines e.g. 2-naph-thylamine, 4-amino-bi-phenyl (4ABP), benzidine
3) Excess BMI
B. Demographic factors
1) Male sex (but female more likely to have more advanced tumour, with poorer prognosis)
- 2.5 times more likely, maybe associated with bladder RU and smoking
2) Old age
- rare <50yo, mostly commonly 80s
3) Caucasian
C. Medication or Iatrogenic related
1) Cyclophosphamide chemotherapy
2) Pioglitazone (thiazolidinedione) was shown to cause CaB in PROactive trial in 2005 -> but remains controversial
3) Pelvic RT
4) Renal transplant (3x increase)
D. Genetics
1) NAT2 slow hepatic acetylator
2) GSTM1 (associated with ability to metabolize aromatic amines)
Risk factors of Bladder SqCC
SqCC may arise from keratinising squamous metaplasia, which is caused from chronic bladder irritation:
1) Long term foley, Neurogenic bladder, spinal cord injuries
2) Recurrent UTI/inflammation
3) Bladder stone
4) Schistosomiasis (i.e “Bilharzial” bladder cancer)
5) Smoking
DDx of adenocarcinoma in bladder
1) Primary adenocarcinoma of bladder
- 1/3 from urachus
- long term complication of bladder exstrophy and bowel implantation into the urinary tract (e.g. ileal conduit)
2) Secondary adenoCA from direct spread from GI tract
Occupations associated with bladder cancer
1) Rubber, leather worker
2) Paint or dye
3) Fossil fuels, coal miners, mechanics
4) Iron, Aluminium processing
5) Hairdresser
TNM Staging of CA bladder
Ta = non invasive papillary carcinoma (i.e. no stromal invasion)
Tis = carcinoma in-situ
T1 = invades subepithelial connective tissue (stromal invasion +)
T2 = detrusor muscle
- a = superficial (inner half)
- b = deep (outer half)
T3 = perivesical tissue
- a = microscopically
- b = macroscopically (extravesical mass)
T4 = outside bladder
- a = prostate, seminal vesicles, uterus, vagina
- b = abdominal wall or pelvic wall
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N1 = single LN in true pelvis (hypogastric, obturator, external iliac, presacral)
N2 = multiple regional LNs in true pelvis
N3 = common iliac LNs
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M1 = distant mets
- a = non regional LNs
- b = other distant mets
Histological variants of bladder TCC
1) Papillary in 70%
2) Mixed papillary and solid in 10%
3) Solid in 10%
- usually G3
- half are M1 at presentation
4) CIS in 10% (flat tumour)
- poorly differentitated carcinoma
- confined to epithelium, with intact basement membrane
- 50% occurs in isolation, 50% occurs with MIBC
5) Other variants
- micropapillary, plasmacytoid, sarcomatoid –> worse prognosis than HG TCC
Histological grading of NMIBC
WHO Grading in 1973 and 2014/2016
1973: better for risk group calculation due to higher prognostic value (based on van Rhijin IPD analysis in 2021)
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated
2014/2016:
PUNLMP (Papillary urothelial neoplasm with low malignant potential)
LG
HG
What is the value of the WHO 1973 and 2004/2006 Classification system for NMIBC?
They are Prognostic for Progression (NOT for recurrence)
NMIBC: Compared WHO 1973 vs WHO 2014/2016 prognostication
- WHO 1973 is actually a stronger prognosticator of progression than WHO 2014/2016
- A 4-tier combination (LG/G1, LG/G2, HG/G2, HG/G3) is superior to both
- Subgroup analysis showed similar prognosis between PUNLMP and TaLG, thus PUNLMP should not be used
Based on in-patient data analysis published in 2021 (European Urology Oncology)
Sample size: 5000
Centres: Europe and Canada
Patients: underwent TURBT +/- intravesical therapy
van Rhijn, B.W.G., et al. Prognostic Value of the WHO1973 and WHO2004/2016 Classification Systems for Grade in Primary Ta/T1 Non–muscle-invasive Bladder Cancer: A Multicenter European Association of Urology Non–muscle-invasive Bladder Cancer Guidelines Panel Study. European Urology Oncology, 2021.
(8/2021)
When to book CTU in newly diagnosed NMIBC patients?
Incidence of UTUC is low in NMIBC patient (1.8%)
Therefore role of CTU after diagnosing CaB is questionable.
EAU guidelines suggests arrange CTU in selected newly diagnosed CA bladder patients to r/o UTUC:
1) Trigone tumour (UTUC up to 7.5%)
2) Multiple tumour
3) High risk or very high risk tumour
What is the goal of TURBT of bladder cancer?
For NMIBC (TaT1 cancer), TURBT aims at:
1) Make correct diagnosis of NMIBC vs MIBC
2) Complete removal of all visible lesions
Recommended steps for TURBT
Based on EAU guidelines:
1) EUA - bimanual palpation under anaesthesia
- if palpable bladder mass, then suggestive of muscle invasive disease
2) Insertion of resectoscope under visual control, inspection whole urethra
3) Inspect whole bladder urothelium
- use enhanced cystoscopy if available (flouorescence cystoscopy, NBI)
4) Resection of tumour
- resection in fraction (exophytic part, tumour base with detrusor muscle, resection edge)
- consider en-bloc in suitable cases
- avoid cauterisation as much as possible to avoid tissue deterioration
5) Take biopsies
- from all abnormal looking urothelium
- if cyto +, Hx of HG/G3 disease, non-papillary appearance tumour ==> systematic mapping biopsies of normal mucosa (trigone, dome, left, right, ant, post)
- if bladder neck tumour, trigone tumour, suspected CIS, positive cytology with no bladder tumour ==> prostate urethral biopsy
6) Clear documentation if size, location, number
+7) Some recommended bladder irrigation for longer to washout any malignant cells
+8) Post resection bimanual examination
- to see if bladder mass resolved; if residual mass, then highly suggests residual invasive disease
How to assess quality of TURBT resection quality
Any presence of detrusor muscle is a surrogate criterion of resection quality
If absence detrusor muscle: associated with higher risk of (Detruosor +ve and -ve):
1) Residual disease
2) Tumour under-staging
- Herr : 15% vs 50% upstaging
3) Early recurrence
- Mariappan Study: 39% vs 70% (detrusor present vs absent)
Risk stratification of NMIBC
Based on the EAU 2021 NMIBC Scoring model:
Risk factors:
1) Age >70
2) Multiple papillary tumour
3) Diameter >3cm
Low risk:
- No CIS
- Up to T1LG/G1 with no risk factors
- Up to TaLG/G1 with 1 risk factor
Intermediate risk:
- No CIS
- Between low and high risk
High risk (following except very high risk)
- All CIS
- All T1HG or T1G3
- 1 risk factor + (T1G2)
- 2 risk factors + (T1 LG) or (Ta HG/G3)
- 3 risk factors + (T1 G1) or (Ta LG/G2)
Very high risk:
- CIS in prostatic urethra
- Variant histology (micropapillary, plasmocytoid, sarcomatoid, small-cell, neuroendocrine)
- LVI
- T1HG/G3 + (3 risk factors) or + (1 risk factor + CIS)
- T1G2 + (2 risk factors)
- TaHG/G3 + (3 risk factors + CIS)
- i.e. if HG/G2 or HG/G3 or recurrent then definitely not low risk*
- i.e. if CIS then high risk*
What is the benefit of immediate single instillation intravesical chemo after TURBT? What patients can benefit?
Sylvester’s meta-analysis from 2016 of ~2300 patients:
1) Reduces recurrence rate
- 5-year recurrence rate decreased from ~60% to 45% (ARR 15%, RRR 35%)
2) Does not improve survival or time-to-progression
It is applicable to patients with:
1) Primary tumour
2) Recurrent tumour with:
- recurrence rate ≤ 1 recurrence per year
- EORTC 2006 recurrence score <5
Note: Sylvester has published four meta-analyses for adjuvant chemotherapy of NMIBC:
