Bladder Flashcards
How common is bladder cancer?
4th most common for men, 8th for women.
2nd most common GU cancer
What is the median age of dx and m:f ratio?
Median age 70y/o
M:F 3:1
What are the risk factors for bladder cancer?
- Smoking (RR 2-5 compared to non-smoker)
- Chemical exposure (industrial aromatic amines, polycyclic aromatic hydrocarbon, hair dye, chlorinated water,
arsenic) - Drugs (phenacetin-containing analgesia, cyclophosphamide)
- Schistosomiasis (a/w SCC instead of UC – lay ova in bladder epithelium, causes irritation)
- Chronic inflammation (chronic UTI, cystitis, stone)
- Radiation exposure
- HNPCC/ Lynch syndrome
What are the two hypotheses to explain the multifocality of bladder cancer?
Clonogenic hypothesis and Field change hypothesis
Describe the clonogenic hypothesis of multifocal bladder cancer
- Tumour as descendants of single transformed cell (monoclonal origin) that undergoes further genetic alteration, proliferates and spreads through the urothelial tract via intra-epithelial migration or intra-luminal seeding
- E.g. from smoking
Describe field change hypothesis of multifocal bladder cancer
- Urothelial cells undergo malignant transformation at multiple sites independently from local carcinogen exposure (polyclonal origin) and become the source of multifocal tumour
- E.g. local irritation e.g. from cyclophosphamide/ local recurrent UTI/ bladder stone
Macro features of Urothelial carcinoma
either flat, ulcerated, or papillary (sessile/ ulceration suggests HG)
What percentage of bladder cancers are Urothelial carcinoma?
> 90%
What is the micro appearance of Urothelial bladder cancer
atypical cells (spindle, pyramidal) invading basement membrane
What is the grading of urothelial carcinoma?
HG vs LG
based on: cytological atypia (polarity, nuclear size/ pleomorphism/ hyperchromatism), and
mitotic figure
What is the IHC of Urothelial carcinoma?
IHC: CK7+, CK20+, HMWCK+ (marker of urothelial origin), GATA3+, p63
What are the variants of Urothelial carcinoma associated with more aggressive behaviour?
Urothelial carcinoma with divergent differentiation
o Squamous/ basaloid
o Trophoblastic
- Nested
- Micropapillary
- Sarcomatoid
- Plasmacytoid
- Poorly differentiated with rich giant cells
What trial established 21Gy/3# QOD as non inferior to 35Gy/10# for symptomatic improvement in palliative bladder cancer?
MRC-BA09 Duchene G
PhIII RCT 1992-1997
What is the pathogenesis of Urothelial bladder cancer?
Arises from deletion of chromosome 9 then progresses though 2 divergent phenotypic pathways:
hyperplasia vs dysplasia
What type of urothelial cancer arises from the hyperplasia pathway? What proportion of total is this?
Low grade non invasive papillary tumour
70-80%
What type of urothelial carcinoma arises via the dysplasia pathway?
What proportion does this represent?
Cis becoming invasive high grade tumour
20-30%
Describe the process and mutation associated with the hyperplasia pathway in pathogenesis of Urothelial ca
- deletion in c/s 9 occurs
- Progress via hyperplasia to LG pTa tumour (70-80% of cases)
- Characterized by activating mutation in HRAS gene and FGFR3
What is the risk of non invasive recurrence and transformation to a high grade invasive tumour with a LG papillary non invasive tumour?
70% risk of non invasive recurrence
15% risk of transformation to invasive/high grade
Describe the pathogenesis of invasive high grade urothelial cancer.
What gene changes are associated with this?
- deletion of c/s 9
- Arise from flat dysplasia → HG CiS → to invasive cancer (20-30% of cases)
- Characterized by structural and functional defect in p53 and Rb tumour suppressor gene
What are the types of non invasive bladder changes that exist?
Dysplasia
Carcinoma in situ
Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
Non invasive papillary carcinoma (Ta)
What is the risk of progression of dysplasia to CiS?
20%
What is the macro appearance of CiS?
flat, grossly erythematous, no mass
What is the micro appearances of Cis?
flat lesion, epithelium often denuded, with large, irregular, hyperchromatic
nuclei, prominent nuclear pleomorphism, high N/C ratio, high mitotic figure
o Less important: loss of polarity, nuclear crowding, irregular thickness of
epithelium
What is the IHC of CiS?
CK20+, p53+, E-cadherin-
o HMWCK distinguish dysplasia (basal staining only) from carcinoma in situ (stain all urothelial cells)
What is the natural history of Urothelial papilloma?
Usually seen in younger patients
rarely recur after excision, rarely progress to higher grade
lesions
What is the macro appearance of Urothelial Papilloma?
Benign exophytic lesion
What is the micro appearance of Urothelial papilloma?
Delicate fibrovascular stalks lined by normal urothelium; cytologic atypia may
be present; no mitotic figure
What is the biological behaviour of Papillary urothelial neoplasm of low malignant potential?
up to 30% will progress to a higher grade lesion
What is the microscopic appearance of a papillary urothelial neoplasm of low malignant potential?
overall same as papilloma, except thickened urothelium (So Delicate fibrovascular stalks lined by thickened urothelium);
no cytological features of malignancy (no mitotic figures, no prominent nucleoli)
What is the micro appearance of non invasive papillary carcinoma (Ta)
How is grade established? Why is grade important?
- Increased architectural and cytological atypia
- LG/ HG based on degree of atypia
- Grading prognostically important (LG 10yr CSS 98%; HG 10yr CSS 40%)
What is the pathogenesis of SCC?
- Arise from squamous metaplasia
- Seen in the setting of chronic irritation (e.g. recurrent UTI, schistosomiasis, neurogenic
bladder, in-dwelling catheter, recurrent bladder calculi, other causes of injury to the urothelial lining)
What proportion of bladder cancers are SCC?
approx 3%
What is the macro appearance of a bladder SCC?
whitish in appearance (due to keratin), bulky, polypoid, necrotic
What is the micro appearance of a bladder SCC?
formation of keratin pearl, intracellular bridges, CK5/6+, with adjacent squamous metaplasia/ dysplasia, can be well/ moderate/ poorly differentiated
Must not show component of conventional urothelial carcinoma (if present, tumour should be classified as urothelial carcinoma with squamous differentiation)
What is the IHC of SCC?
- CK5/6+, p63+
- Negative for urothelial markers – GATA3-
What are other histologies of bladder cancer?
- Adenocarcinoma
- Small cell carcinoma
- Sarcoma
- Lymphoma
- Melanoma
- Metastases
What IHC markers can differentiate bladder from prostate cancer?
Bladder: (prostate all negative)
CK7 + (Cytokeratin marker expressed on epithelial cells)
CK20+ (“”)
p63+ (basal cell nuclei marker)
HMWCK + (basal cell cytoplasm marker)
GATA3 +
Prostate: (bladder all negative)
PSA +
AMARC +
Prostein +
What clinical features should a bladder biopsy/TURBT path report include?
- Previous bladder cancer
- Previous treatment
- Cystoscopy appearance – papillary, polypoid, red/ erythematous area
- Operative procedure: - not specified/ TUR/ biopsy
- Site of biopsy
o Renal pelvis
o Ureter
o Bladder, specific sites
o Prostate/ prostatic urethra
What macro features should a bladder biopsy/TURBT path report include?
- Specimen site – renal pelvis, ureter, bladder (specific site), prostate/ prostatic urethra, other
- TUR size (in gram or mm)
What microscopic features should a bladder biopsy/TURBT path report include?
- Histological type
- Histological subtype/ variants (for urothelial carcinoma), and percentage
- Non-invasive carcinoma
- not identified
- Cis flat- multifocal, focal
- papillary carcinoma, non invasive
- Histological grade
- Urothelial carcinoma – low grade, high grade
- Squamous cell carcinoma – G1/ WD, G2/ MD, G3/PD - Status of muscularis propria – present/ absent
- Extent of invasion
- Sub-staging of T1
- LVI
What is the common clinical presentation of bladder cancer?
Painless gross / microscopic haematuria (DDx for painless haematuria: cancer, trauma, benign; glomerulonephritis)
Gross haematuria ~10-20% risk of bladder ca
Obstructive/ irritative symptoms, or pain less common
What does T1 denote
Invades through the bladder urothelium into underlying lamina propria
What does T2 denote in bladder cancer
Muscle invasive
T2a- inner half of the muscularis propria
T2b- outer half of the muscularis propria
In bladder cancer, what does T3 denote
Invades peri-vesical tissue
In bladder cancer, what does T4 denote
Invades into adjacent structures
e.g. prostate, SCs, vagina (T4a)
What are patient factors which affect prognosis
Age
ECOG
Sex (females do worse)
Ongoing smoking
What are tumour factors assoc with worse prognosis in bladder cancer
Stage (most important factor)
Grade: high grade = worse
Lymph node status
Some Histological variants do worse:
1. carcinoma with rhabdoid features
2. carcinoma with micro papillary features
3. plasmacytoid carcinoma
4. sarcomatoid carcinoma
5. small cell carcinoma
6. undifferentiated carcinoma
Lesion size (larger is worse)
Carcinoma in situ presence (increases recurrence risk, so worse)
multi centricity is worse
interval to recurrence- shorter is worse
What treatment factors are assoc with prognosis in bladder cancer
extent of TURBT
What is the role of TURBT in bladder cancer
- First step in diagnosis for everyone
- Therapeutic for Ta/CIS/T1 non-MIBC
(Ta is non invasive papillary carcinoma)
What is the role of radical cystectomy in bladder cancer?
standard of care for:
MIBC
Multiple recurrent superficial tumours
High Grade T1 with CiS
Variant Histology
Performed with bilateral pelvic LND
What nodes are dissected at min in a pelvic LND with radical cystectomy?
obturator, external iliac, internal iliac, common iliac
When is adjuvant intravesical therapy used in bladder cancer?
Used for Cis, HG Ta/T1, recurrent disease, multifocality
Initiated 3-4 weeks after TURBT, given weekly for 6 weeks
What are the agents used for adjuvant intravesical therapy?
BCG
Mitomycin C
What is the effect of intravesical BCG in HG T1 bladder cancer?
Reduced recurrence rate from 80% to 35%
reduces progression to MIBC from 35% to 20%
What type of neoadjuvant chemotherapy regimen is used prior to surgery?
Cisplatin based
Dose-dense Methotrexate, Vinblastine, doxorubicin (Adriamycin), Cisplatin (DD-MVAC)
OR
Gemcitabine, Cisplatin
OR
Methotrexate, cisplatin, vinblastine (MCV)
What is the chemotherapy used concurrently for definitive chemoRT?
Weekly cisplatin (35mg/m2) (TROG)
5-FU (500mg/m2) D1-5, D16-20 + mitomycin-C (12mg/m2) D1
(suitable for patients with
impaired renal function) (BC2001)
What chemo is used in the metastatic setting in bladder ca?
Gem/Cis
DD-MVAC
What is the indication for RT in bladder cancer?
definitive treatment as part of organ preservation therapy
Definitive ChemoRT
or as part of Trimodality schema (Maximal TURBT -> CRT)
Palliative
What are the definitive RT dose options
64Gy in 32 fractions, 2Gy per fractions, 5 fraction per week
55Gy in 20 fractions, 2.75Gy per fractions, 5 fraction per week
What immunotherapy trials are running in bladder cancer
ANZUP- PCR-MIB trial
- in follow up
- pembrolizumab added to chemoRT
UK- PLUMBB trial (stopped as having high rates of toxicity)
- Pembro +hypofractionated RT
