Dickie Robinson Victoria Hopkinson M W Lau

Outline / Objectives Dickie Epidemiology Diagnosis Pathology Staging Victoria Haematospermia Cytology and alternatives to cytology Haematuria and key papers

Case 1 79 female – retired teacher WHO performance status 2 Presented via A&E with haematuria Irrigation for 2-3 days, no intervention required Flexible cystoscopy as an outpatient 1 week later

Case 1 cont.. Solitary tmuour in the trigone. Nurse endoscopic, new in the job, asks should I arrange any scans?

Upper tract imaging in bladder cancer FactorRR95% CIp Value Grade1.7( )ns CIS1.16( )ns T stage2.29( )ns Trigone tumor5.8( ) Bladder tumor size0.5( )ns Multiplicity0.48( )ns In this case also a judgment call as 79 years old and WHO 2. Palou – J Urol (3): Retrospective study of 1,529 primary NMIBC patients - examination of the upper urinary tract with excretory urography. 28 patients (1.8%) had synchronous UUTT, 17.9% were multiple and 46% were invasive. 7.5% of trigone tumours were associated with UUTT, but this only corresponded to 41% of the UUTTs first diagnosed (ie. if only scan trigonal tumours will miss 59% of UUTT) EAU guidelines 2013 on NMIBC –simply references the above paper.

Case 1 cont…. Wednesday morning, patient in surgical admission lounge having been listed for a TURBT. 1.Explain the consent process for TURBT 2.Key steps of a TURBT

Consent for TURBT Should commence in clinic / prior to day of surgery and be backed up with written information / website etc.. Common (greater than 1 in 10) Mild burning or bleeding on passing urine for short period after operation Temporary insertion of a catheter for bladder irrigation Need for additional treatments to bladder in attempt to prevent recurrence of tumours including drugs instilled into the bladder Occasional (between 1 in 10 and 1 in 50) Infection of bladder requiring antibiotics No guarantee of cancer cure by this operation alone Recurrence of bladder tumour and/or incomplete removal Rare (less than 1 in 50) Delayed bleeding requiring removal of clots or further surgery Damage to drainage tubes from kidney (ureters) requiring additional therapy Injury to the urethra causing delayed scar formation Perforation of the bladder requiring a temporary urinary catheter or open surgical repair Hospital-acquired infection Colonisation with MRSA (0.9% - 1 in 110) Clostridium difficile bowel infection (0.01% - 1 in 10,000) MRSA bloodstream infection (0.02% - 1 in 5000) BAUS – Bladder Tumour Resection – Procedure Specific Information for Patients

Steps in TURBT (modified from EAU guidelines on NMIBC 2013) The goal of the TURBT is to make the correct diagnosis and in Ta-T1 tumours to remove all visible lesions. It is crucial in the diagnosis and treatment of BC. Theatre team briefing, WHO checks, VTE prophylaxis, warming & antibiotics. EUA Visualisation of the of the urethra, entire bladder and U.O.’s. Bladder capacity. Small tumours (< 1 cm) can be resected en bloc. Larger tumours should be resected separately in fractions, including the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. Abnormal areas of urothelium (?CIS) - cold-cup biopsies or biopsies with a resection loop. Random (mapping) biopsies, should be performed in patients with positive urinary cytology and absence of visible bladder tumour. (Recommended biopsies: trigone, bladder dome, and from the right, left, anterior and posterior bladder walls). Biopsy prostatic urerthra in cases of suspected CIS or bladder neck tumours. In patients with palpable mass before TURB, EUA should be repeated after resection. Requirement for catheter +/- irrigation dependent upon findings. Document findings (EUA, capacity, size, multiplicity and location of tumours, residual tumour at end of procedure). Mitomycin-C for Ta-T1 tumours.

Case 1 cont.. 2 weeks later, asleep in MDT, rumbled and asked what the histology represents: Low grade papillay TCC. What is the difference between the WHO 1973 and 2004 classification of urothelial bladder cancer?

WHO 1973 vs Current U.K. guidelines recommend pathologists report using both systems to allow prospective audit of outcomes. It was hoped that 2004 system would be more reproducible. PUNLMP’s are not cancers (Harnden – BJUI :723-30) Conflicting evidence regarding comparisons of the prognostic power of each system.(MacLennan – E Urol (4): and Chen – PLosOne (10):e471499)

TNM classification 75-80% NMIBC at presentation T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: ‘flat tumour’ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle – T2a Tumour invades superficial muscle (inner half) – T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: – T3a Microscopically – T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall – T4a Tumour invades prostate, uterus or vagina – T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral) N2 Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral) N3 Metastasis in common iliac lymph node(s) M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Molecular biological grading Placing tumours into categories according to their molecular phenotype will become the standard in the future, H&E grading is likely to become obsolete in prognostication. Occurring in breast cancer. Unlikely to be based upon ‘old fashioned’ ideas regarding biomarkers such as expression of p53 and cell cycle regulators etc.. It will almost certainly take the form of multiplexed sequencing. Robinson 2013

Urothelial carcinoma tumour groupings based upon hierarchical clustering of gene expression. Sjödahl G et al. Clin Cancer Res 2012;18: ©2012 by American Association for Cancer Research

Molecular pathways of development M Knowles 2006.

Case 2 69 male – retired army sergeant. Storage LUTS, pelvic pain and visible haematuria. Smoker, IHD, type 2 diabetes, walks with 2 sticks. What next? Had flexi cystoscopy shown solid tumour. EUA mobile bladder mass. TURBT – residual tumour.

Case 2 H&E sections of tumour.

Pearls of keratin in ‘classical’ description of SCC Entire tumour filled with whorls of keratin. IHC staining of SCC bladder cancer tissue for cytokeratin.

Histological types of bladder cancer Urothelial / TCC – 90% SCC – 5% – Higher incidence in areas endemic for schistosomiasis. Adenocarcinoma – 2% Other sub-types – 3%

WHO 2004 – Histological types of tumours of the urinary bladder 44 different sub-types listed! Benign Urothelial papilloma Inverted papilloma Papillary urothelial neoplasia of low malignant potential Malignant papillary Papillary carcinoma – low grade – high grade – with squamous – with glandular differentiation Malignant non-papillary Flat carcinoma in situ Invasive carcinoma Variants of invasive carcinoma – Nested pattern – Small tubular pattern – Microcystic pattern – Inverted pattern – Squamous differentiation – Glandular differentiation – Micropapillary – Sarcomatoid carcinoma – Clear cell urothelial carcinoma – Plasmocytoid – With syncitiotrophoblasts – With unusual stromal reactions Pseudosarcomatous stroma – Stromal osseous or cartilaginous metaplasia – Osteoclast-type giant cells – With prominent lymphoid infiltrate Squamous cell carcinoma – Usual type – Variant – Verrucous – Basaloid – With sarcomatoid features Adenocarcinoma (from bladder mucosa, urachal, with extrophy) – Usual intestinal type – Mucinous (including colloid) – Signet-ring cell – Clear cell Hepatoid Mixture of above patterns Adenocarcinoma NOS Tumours of mixed cell types Undifferentiated carcinomasa – Small cell carcinoma Large cell neuroendocrine carcinoma – Lymphoepithelioma-like carcinoma Giant cell carcinoma Undifferentiated carcinoma NOS Metastatic carcinoma

Variants TCC variants (80% all TCC have mixed differentiation) Nested – Can be confused with Vonn Brunn nests – M:F = 6:1 – Neo-adjuvant chemo ineffective – V poor prognosis (30% 3 year survival) Micropapillary – % – M:F = 10:1 – BCG ineffective – Neo-adjuvant chemo ineffective – Adverse phenotype Other non-TCC variants Small cell – Men >70 yrs – Consider metastatic – Chemo-radiothepy treatment of choice – V poor prognosis (20% 5 year survival) Sarcoma – M:F = 2:1 – Previous chemo or XRT other tumours – Normal overlying urothelium – Not related to smoking – Treatment with cystectomy

SCC Risk Factors Chronic urinary tract infection Schistosomiasis – Increased urothelial proliferation – N-butyl-N-(4- hydroxybutyl)nitrosamine is generated in very high levels in the urine. – Chronic infection with S hematobium converts nitrates to nitrites and subsequently to nitrosamines. Myths SCC in Egypt – only 27% of MIBC – was 80% in 1980 – improved eradication – increased smoking – similar pattern elsewhere Incidence in SCI is only <1% – latency 17 yrs – Previously quoted at 10%

Global distribution schistosomiasis

Scistosomiasis 5 different types classified into: – Intestinal (4) – Urogenital (1) Terminally spiked Treatment – Praziquantel two oral doses of 40 mg/kg in 1 day – Increases permeability of the schistoscomes membranes to calcium ions – Interferes with adenosine uptake and thus purine synthesis – SE related to immune response. 90% stomach cramps, diarrhoea, malaise Bulinus genus eggs/day 20% schistosmulum days

Epidemiology U.K. statistics – 2 nd most frequently occurring malignancy of the urinary tract, after prostate cancer and 7 th commonest cancer overall. – 4th commonest cancer in men – 11th commonest in women – new cases diagnosed in 2009 – 4907 deaths in 2009 The highest rates occur in developed countries with age standardised incidence rates (ASR) of 19.5 and 4.2 per for men and women. (wide variation in the reporting and registration of bladder cancer, particularly with respect to the variable inclusion of CIS and stage Ta transitional cell carcinoma (TCC) in registries). In the U.K. progressive decline since a peak in the early 1990’s – U.K ASR falling from 18.4 per in 1993 to 11.5 in 2008 – this decline is far more pronounced in men than women. Incidence of bladder cancer is predicted to rise in less developed areas of the world as smoking rates increase in these countries. – Tobacco use has increased by 16.1, 8.7 and 6.5% in Africa / Middle East, Eastern Europe / former Soviet Union and Asia / Australia between 1998 and 2008 respectively.

Average Number of New Cases Per Year and Age-Specific Incidence Rates per 100,000 Population, UK Please include the citation provided in our Frequently Asked Questions when reproducing this chart: Prepared by Cancer Research UK - original data sources are available from

European Age-Standardised Incidence Rates per 100,000 Population, by Sex, Great Britain Please include the ciation provided in our Frequently Asked Quesitons when reproducing this chart: Prepared by Cancer Research UK Original data sources: 1. Office for National Statistics. Cancer Statistics: Registrations Series MB Welsh Cancer Intelligence and Surveillance Unit Information Services Division Scotland. Cancer Information Programme.

European and Global Age-Standardised Incidence Rates per 100,000 Population 2008

Percentage of population smoking or diagnosed with lung cancer

Risk factors for bladder cancer Effect AgeIncreased risk with older age GenderMale 3 x  incidence Smoking2 – 6 x  incidence (risk related to exposure) OccupationRisk varies with occupation Family history2 x risk with affected 1°relative GeneticNAT1 and GSMT1 null genotypes associated with increased risk Chronic UTIIncreased risk ChemotherapyCycophosphamide only (related to duration and intensity of exposure) Radiation exposureLatency period yrs Ethnic originBlack lower risk but worse prognosis CoffeeIncreased risk (smoking confounding) AcetaminophenConflicting evidence Fresh fruit & vegProtective effect (stating the obvious!) AlcoholNo effect

There is no substantially increased risk of bladder cancer for most occupations that have been studied *historically responsible 2- napthylamine – but banned since 1950’s Agricultural workers have the lowest risk of all occupations. Ruelen – Scan J Urol and Neph (s218):64-78 OccupationRRAgent responsible miners1.31agent unknown bus drivers1.29diesel exhaust rubber workers1.29numerous agents* mechanics1.27mineral oils leather workers1.27tanning agents and dyes blacksmiths1.27metal fumes machine setters1.24mineral oils hairdressers1.23dyes

NAT2 and GSMT1 N-acetyltransferase 2 (NAT2) is an enzyme involved in the metabolism of aromatic amines. The status of an individual is designated as either a ‘slow or fast acetylator’ and has been implicated in bladder cancer risk. The slow acetylator genotype is associated with a 40% increased risk of bladder cancer. Glutathione S-transferase 1 (GSMT1) status, involved in the metabolism of polycyclic hydrocarbons and detoxification of reactive oxygen species, is also a significant risk factor with the null genotype conferring a 50% increased risk of bladder cancer, although this association is only strong in non smokers.

Case 3 53 year male barber. No previous history. 60 pack yr smoking history. 2 months history of storage LUTS. 2+ blood in urine. Examination normal. What would you do next?

TURBT – solitary tumour. No visible residual tumour end of resection. What does this histology represent? G3pT1 TCC – scant deep muscle in specimen. What else is required ?

Re-resection Residual tumour following resection of T1 tumours has been observed in 33-53% of patients. Tumour is often under-staged by initial resection. Probability that T1 under-staged and is ≥T2 is 4-25%. A second TUR should be considered when: – the initial resection is incomplete – when the pathologist has reported that the specimen contains no muscle tissue – high-grade tumour – T1 tumour 2-6 weeks after initial TUR. EAU guidelines on NMIBC 2013

Imaging in MIBC Imaging parameters required for staging MIBC are: 1.the extent of local tumour invasion 2.tumour spread to lymph nodes 3.the upper urinary tract and other distant organs.

Re- resection 6 weeks later – no residual tumour.

Staging in MIBC Current gold standard methodology is poor. Upstaging occurs at the time of cystectomy in around 40% of all cases and up to 60% in T2 tumours. EUA – very poor, although if fixed then significant finding. TURBT – under stages 20-80% compared to cystectomy pathology. Imaging Turker – BJUI :

Local staging of bladder cancer Multi-detector CT scanning – Overall 50-90% accuracy for local staging – sensitivity differentiate ≥T3 from ≤T2 up to 90% – specificity differentiate ≥T3 from ≤T % Recent study looking at MRI alone: – overall 63% accuracy for local staging. – sensitivity differentiate ≥T3 from ≤T2 90.5% – specificity differentiate ≥T3 from ≤T2 60% Rajesh – Clin Radiology (12): Both CT and MRI can be used. Timing in relation to TURBT is important. Unable distinguish T2 from T3a. Evidence referenced in EAU guidelines comparing MRI and CT is almost 20 years old!! Technology as moved on a little.

RCR – Recommendations on Cross-Sectional Imaging in Cancer Management 2006 MRI is superior to CT for staging bladder cancer, due to its ability to demonstrate muscle wall invasion or penetration. MRI is the imaging modality of choice for staging patients considered suitable for radical treatment, that is cystectomy or radical radiotherapy. In those patients who are not suitable for radical treatment or where there is clinical suspicion of locally advanced or metastatic disease, CT of the abdomen and pelvis is suitable of staging purposes. Again this guidance is very much out of date.

Nodal and distant staging Neither CT or MRI is able to detect the presence of malignant cells in normal or minimally enlarged nodes. Sensitivity and specificity of both modalities ranges from 50-90% with an inverse correlation. Short axis diameter 8mm pelvic and 10mm abdominal are significant (EAU guidelines 2013 – open to debate). Advantage of CT – shorter image acquisition, cheaper, allows evaluation of upper tracts and staging for distant metastases. EAU guidelines In patients with confirmed muscle-invasive bladder cancer, CT of the chest, abdomen and pelvis is the optimal form of staging, including excretory-phase CT urography for complete examination of the upper urinary tracts.

FDP PET CT ( 18 Flurodeoxyglucose positron emission CT) Evolving evidence of it’s role in staging. Trial of 96 patients. Underwent standard CT and FDP PET CT. Upstaging in 19.8% & downstage 2.1%. Caused a change in management in 13.5%. Switch from curative to palliative intent in 8.5%. Detection of second malignancies that changed management in 4.6%. Mertens – BJUI : Royal College Radiologist Guideline: Evidence-based indications for the use of PET-CT in the United Kingdom 2012 Does not even mention bladder cancer – let alone give an opinion on its use.

Case 4 57 year old – works for HMRC, currently investigating spurious expenses claims by Mr. Dukic Previous prostatitis. On tamsulosin. Otherwise well. Deterioration in his LUTS. Non-visible haematuria in primary care.

Small prostate PSA 0.84 MSU – no growth Flexible cystoscopy normal USS – multiple renal cysts KUB AXR – normal Cytology – suspicious for malignancy What next? CTU – poor opacification of the right ureter, cannot exclude ureteric lesion. Case 4 cont..

GA cystoscopy – normal, Bx’s taken. Bilateral URS – normal. Selective ureteric urine sampling – samples are processed for MC&S not cytology. What now? Secretary arranges repeat cytology prior to returning to clinic while you're on leave. Comes back to clinic – cytology highly suspicious. Biopsies from bladder wall – normal urothelium. What now? Reads the daily mail – reading about a chap in Baisingstoke who puts this dye in peoples bladders when he does cystoscopies. Case 4 cont..

Rink – E Urol :

Case 4 biopsy results CIS

How does fluorescence cystoscopy / photodynamic diagnosis (PDD) work) and what are the drawbacks? Photoactive porphyrins [5-ALA, HAL (esterised ALA for better uptake), Hypericil] instilled into bladder prior to cystoscopy. Accumulate preferentially in neoplastic tissue. Under blue light ( nm) they emit red fluorescence. Disadvantages – Cost of equipment and HAL (particularly in the NHS as the concept of spending money to save money in the long term does not exist!!) – Time: catheterisation and administration of HAL required prior to cystoscopy. – False positive, particularly at re-resection. PDDDetails 5-ALA 5-aminolevulinic acidPre-treat for 3 hrs HAL (Hexvix®) HexaminolevulinatePre-treat 1 hr

Hexyl Aminolevulinate–Guided Fluorescence Cystoscopy in the Diagnosis and Follow-up of Patients with Non–Muscle-invasive Bladder Cancer: A Critical Review of the Current Literature. E Urol : Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) PDD increased the detection of: – papillary tumours by 7–29% – CIS by 25–30% Reduced the rate of residual tumours TURBT by an average of 20% compared to WLC alone. Superior recurrence-free survival (RFS) rates. Recurrence-free rates at 12 and 24 months were 10.9–27% and 13–24% higher with PDD than WLC. RFS intervals increased by 6-9 months with PDD, compared to WLC. PDD did not appear to reduce disease progression. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. EAU guidelines 2013: Photodynamic diagnosis is most useful for detection of CIS, and therefore it should be restricted to those patients who are suspected of harbouring a high-grade tumour, e.g. for biopsy guidance in patients with positive cytology or with a history of high-grade tumour (published prior to review above).

How does narrow band imaging work? The basis of this optical technique is represented by white light being filtered into two discrete wavelengths: blue (415 nm) and green (540 nm). Easily switch between white light and NBI. These light bands are strongly absorbed by hemoglobin and only penetrate the tissue surface, therefore, the vascular structures appear dark brown (capillary vessels) and green (veins). Does not require pre- catheterisation and instillation.

CIS

Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis Zheng - BJUI : Eight studies including 1022 patient cystoscopies. NBIWLI Sensitivity overall Specificity overall AUC overall Sensitivity detecting CIS0.927 Specificity detecting CIS0.768 AUC detecting CIS0.939 NBI is an effective method for the identification of abnormal lesions including carcinoma in situ and can provide higher diagnostic precision of bladder cancer than WLI.

Confocal LASER microendoscopy. Subsurface imaging of tissue microarchitecture and cellular features. Optical sectioning of the tissue micron-scale resolution is achieved using a 488 nm laser as the light source and fluorescein. Differentiation between benign and neoplastic tumours and delineation of tumour boundaries.

Optical Coherence Tomography OCTutilises near infrared light to generate an image at micrometer scale. Able to distinguish normal from neoplastic tissue. Able to assess depth of invasion and tumour margin.

Flat mucosa lined by less than approx 7 layers of urothelial cells Covered by an umbrella cell layer. Normal Urothelium

Papillary Hyperplasia Characterized by slight “tenting”, undulating, or an elevated configuration of the urothelium of varying thickness, lacking nuclear atypia. Pathology

Papillary urothelial neoplasm of low malignant potential PUNLMP or G1 PUNLMP/G1 have an orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear atypia. The urothelium is much thicker than in papillomas and/or the nuclei are significantly enlarged and somewhat hyperchromatic. Mitotic figures are infrequent Recurrence rate: 27-47%, Grade Progression rate: 11% Stage Progression rate: 0-4%

Urothelial Papilloma /G1 Discrete papillary growth with a central fibrovascular core lined by urothelium of normal thickness and cytology. In contrast to papillary hyperplasia, discrete papillary fronds are identified. Relapse rate: 0-8% Grade progression: 2% Stage progression: 0%

Low grade papillary urothelial carcinoma G2 Characterized by an overall orderly appearance but recognizable variation of architectural and or cytologic atypia eg. variation of polarity nuclear size, shape, and chromatin texture. Mitotic figures are more frequent than G1 Recurrence rate: 48-71%, Grade Progression rate: 7 % Stage Progression rate: 2-12%

High grade papillary urothelial carcinoma G3 Architecturally, cells appear irregularly clustered. Cytologically, the nuclear chromatin tends to be clumped and nucleoli may be prominent. Mitotic figures, including atypical forms, are frequently seen Focal necrosis, a feature not seen with lower grade lesions. Recurrence rate: 55-85%, Grade Progression rate: n/a Stage Progression rate: %

G3 invasive Muscularis propria

Carcinoma in situ Flat lesion of the urothelium characterized by the presence of cells with large, irregular, hyperchromatic nuclei that may be either present in the entire thickness of the epithelium or only part of it. Mitotic activity is frequently observed. Note urothelium is becoming detached from the lamina propria. Recurrence 80% Stage progression 40%

r Pathology resource on bladder and prostate histopathology – images – explanations of the different grades etc..