1. Haematuria and Urinary Tract Tumours
Mr C Dawson MS FRCS
Consultant Urologist
Edith Cavell Hospital

2. Haematuria Macroscopic vs Microscopic Painful vs Painless
Initial, terminal, or mixed with urinary stream

3. Microscopic Haematuria
“Excretion of abnormal quantities of erythrocytes in the urine”
Red blood cells identified by colour and shape (Yellow-red / biconcave)

4. Dipstick testing for haematuria
Hb from red cells catalyses conversion of indicator by peroxide
Test detects intact RBC’s, free Hb, and myoglobin
Oxidising agents - false positives
Reducing agents - false negatives
Oxidising agents such as hypochlorite. DEHYDRATION and EXERCISE can also cause false positive (Campbell p321)
Reducing agents - e.g. Vit C

5. Dipstick testing for haematuria
Dipsticks not sensitive for screening (miss 10% of patients with microscopic haematuria)
Best accomplished by microscopy of freshly voided, concentrated urine sample
> 3 RBC’s / hpf in a centrifuged specimen considered abnormal

6. Nephrologic vs Urologic haematuria
Look for casts and protein
Haematuria associated with ++ or +++ proteinuria should always be assumed to be of glomerular or interstitial origin
Most common glomerular causes of haematuria are
IgA Nephropathy
Mesangioproliferative GN
Focal segmental proliferative GN
Even heavy bleeding will generally not elevate the protein concentration significantly.
Haematuria associated with + + or +++ proteinuria should always be assumed to be of glomerular or interstitial origin
Casts - Tamm Horsfall mucoprotein is the basic matrix of all renal casts. Is always present in the urine and originates from tubular epithelial cells.
A cast is the precipitation of protein in the tubular lumen
When the cast contains only mucoprotein it is a hyaline cast. If cellular elements are present in the lumen of renal tubule at time of ppt then they can be entrapped and preserved. Casts containing entrapped RBC’s are diagnostic of glomerular bleeding which most likely represents glomerulonephritis. Casts with other cellular elements (usually sloughed renal tutule epithelial cells) are indicative of non-specific renal tubule and nephron damage. Granular casts are the result of further degeneration and breakdown of cellular elements (Campbell’s p322)

7. Investigation of Haematuria
MSU and Urinary Cytology
IVU [KUB and Renal U/S)
Cystoscopy [Flexible Cystoscopy]
Always do a DRE!
21% have a malignancy
10% have bladder cancer (99% TCC)
10% have Ca Prostate

8. Urothelial tumours of the Urinary Tract
Predominantly TCC (>90%)
SCC shows great variability worldwide
75% of bladder cancers in Egypt
only 1% of bladder cancers in England
Adenocarcinoma - <2% of primary bladder cancers
Primary vesical
Urachal
Metastatic

9. Epidemiology - Incidence
Bladder most common site
47000 new cases in U.S. in 1990
M:F 2.7:1
Men - 4th most common cancer (Prostate, lung, colorectal - 10% of all)
Women - 8th most common cancer (4% of all)
Median age of diagnosis yrs

10. Epidemiology - Mortality
10200 bladder cancer deaths in U.S. in 1990
Accounts for 5% of all cancer deaths in men, and 3% in women
Mortality rates in Whites similar to Blacks
Younger patients have more favourable prognosis (present with lower grade) but risk of disease progression is the same grade-for-grade

11. Aetiology Occupational Exposure to chemicals Cigarette smoking
Analgesics
Artificial sweeteners
Bacterial / Parasitic infections
Bladder calculi
Pelvic irradiation
Cytotoxic chemotherapy
Occupational exposure - accounts for 1/4 to 1/3 of bladder cases in the US. Latent period of yrs. More intense exposure shortens the latent period. Most are aromatic amines (e.g.. aniline dyes, 2-naphthylamine, xenylamine, benzidine). Occupations at risk - auto workers, painters, truck drivers, drill press operators, leather workers, dry cleaners, paper manufacturers, dental technicians.
Cigarettes - 4x higher risk in smokers. Risk correlates with no smoked, duration, and degree of inhalation. Approx 1/3 of all cases may be related to smoking. Chemical not yet identified, but nitrosamines and 2-naphthylamine known to be present.
Analgesics - Phenacetin: similar structure to aniline dyes. Assoc with increased risk of TCC. Associations with other analgesics not identified.
Artificial sweeteners: saccharin and cyclamate, in large doses, are bladder carcinogens in rodents. Little evidence for same effect in human studies.
Chronic cystitis - Increase risk of SQUAMOUS cell carcinoma.. Schistosomiasis related cystitis is large worldwide cause of SCC. Cystitis from any cause if long-term, can cause cancer - ? related to nitrite and N-nitroso compounds in the bladder
Pelvic irradiation x inc risk of TCC formation, typically high grade and locally advanced at presentation
Cytotoxics - Cyclophosphamide - 9x inc risk of bladder cancer. Most are muscle invasive at diagnosis. May be due to metabolite of cyclophosphamide

12. Theory of Carcinogenesis
Oncogenes
Deletion or inactivation of Supressor genes
Amplification of expression of gene products
Oncogenes
Altered genes coding for malignant phenotype
Several oncogenes in ras family have been found on chromosomes 1, 11, 12 in bladder cancer. Encoded ras protein may behave like one of the guanine nucleotide binding proteins that transduce signals from growth factors at the cell surface to induce proliferation. Expression of p21 protein may be related to histologic grade. C-myc oncogene expression may be correlated with invasion in superficial bladder cancer.
Deletion or Inactivation of supressor genes
These genes normally regulate cellular growth and differentiation
Amplification of the expression of genes that encode for growth factors or growth factor receptors which usually regulate the growth and diff of cell
Some evidence implicates each of these mechanisms in the aetiology of bladder cancer but in all cases the data is insufficient to prove a causal relationship

13. Clinical presentation
Painless haematuria (85% of patients)
“bladder irritation” (frequency, urgency, dysuria) - often associated with diffuse Cis or invasive cancer
Flank pain (ureteric obstruction)
Pelvic mass

14. Investigation Cytology IVU Cystoscopy Cytology
Need a reliable pathologist to correctly interpret specimens
First voided specimens should not be used (get cellular degeneration). UTI’s, catheters, calculi can all produce artefactual changes in urinary cytology, as can post-radiation, chemotherapy, intravesical BCG
IVU
Mandatory
Not a sensitive way of detecting small bladder tumours
Useful for upper tracts
Cystoscopy
Careful cystoscopy and bimanual examination
Abnormal areas should be biopsied
Random biopsy of: +ve cytology with normal IVP and cystoscopy, mucosa adjacent to papillary TCC, areas of Cis.
Retrograde ureterograms - required if upper tracts not well seen on IVU. Can also collect urine for cytology / brushings

15. Cystoscopic appearance of TCC
Carcinoma in situ
Papillary (70%)
Nodular (10%)
Mixed (20%)

16. TNM Staging

17. Bladder Cancer
The Good
The Bad
The Ugly

18. The Good T0/T1 superficial / exophytic papillary TCC
70% 5 year survival
15% Transformation each 10 years
Surveillance cystoscopy - more about spotting change than treatment
Opinions vary about how often a patient should be cystoscoped. To a certain extent a negative cystoscopy is a “waste of time”. Ideally the interval should be long enough not to inconvenience patient, but short enough to catch the new tumours before they can progress.
Most people cystoscope approx 3 monthly for first year, then 6 monthly for two years, then yearly, assuming nothing found - revert to start if find a tumour. Pay attention to grade of tumour found.

19. The Good...
Initial, low-grade, small tumours low risk of progression - TUR followed by surveillance
T1, multiple, large, recurrent tumours, or Cis in random biopsy - consider intravesical chemotherapy
T1 G3 - high rate of progression - consider cystectomy

20. The Bad Any Invasive TCC 25-30% 3 year survival
No real advance in 50 years
T2 / T3 - partial or radical cystectomy, radiotherapy, or combination of both
T4 - Chemotherapy, followed by radiation or surgery

21. The Ugly Diffuse Cis, overtly Malignant 78% risk of invasion
Intravesical chemotherapy preferred primary treatment for Cis - treatment effective in 30%. Intravesical BCG produces complete regression in 50-65% of patients
Radiotherapy and chemotherapy ineffective
Good review article in J Urol March 1995 by Hudson and Herr
“Carcinoma may be the precursor to solid tumours. Probably a spectrum between preneoplastic or precursor lesions, and frank penetration of the basement membrane. Cis may have short or long in situ phase, but is inexorably progressive and will become invasive if uncontrolled and given enough time.
Now appears that 2 forms of Cis exist -
1) focal Cis, single aneuploid cell line, lack of over expression of p53, cell surface receptors, or tumour antigens and expression of normal urothelial antigens = good prognosis.
2) Diffuse Cis, involvement of prostatic urethra, overexpression of p53, cell surface receptors, or tumour assoc antigens, or loss of normally expressed urothelial antigens = suggests poor prognosis in whom early, aggressive management is necessary i.e. either immediate cystectomy or 3/12 trial of intravesical BCG then cystectomy if BCG ineffective would be reasonable.”

22. Tumours of the renal pelvis and ureter
2-4% of patients with bladder cancer
[30-75% patients with upper tract tumours will develop bladder TCC]
Pelvic tumours
5-10% all renal tumours
5% all urothelial tumours
The High incidence of subsequent bladder cancer suggests the need for routine follow-up cystoscopy in patients with upper tract tumours. The explanation for the disparity between the relatively low incidence of subsequent upper tract tumours in patients with bladder cancer and the relatively high incidence of subsequent bladder tumours in patients with upper tract tumours may be related to seeding of tumour cells down stream, or to the fact that the bladder mucosa has a longer exposure time to urinary carcinogens than the renal pelvis and ureter, because the former functions as a reservoir and the latter as a conduit.

23. Tumours of the renal pelvis and ureter
Ureteric tumours 1-2% all urothelial tumours
Rare before 40 yrs, peak incidence 60-70
Bilateral involvement 2-5%
Association with Balkan nephropathy
Other aetiological factors similar to Bladder TCC
In the Balkan countries (including Bulgaria, Greece, Romania and Yugoslavia) there is an endemic nephropathy that is associated with a high incidence of upper tract urothelial tumours.
In these countries urothelial tumours account for 40% of all renal cancers. Balkan nephropathy associated TCC is more commonly bilateral (10%) and behaves in a more indolent fashion than the sporadic form of the disease.

24. Diagnosis of Upper tract tumours
Usually seen as a filling defect on IVU or retrograde
Cystoscopy mandatory to rule out coexisting bladder tumour
Cytology less helpful as may be normal in low grade tumours

25. Treatment of upper tract tumours
Renal pelvis - Nephroureterectomy with excision of cuff of bladder
Upper/mid ureter
Segmental resection if solitary or low grade
Nephroureterectomy if multifocal or high grade
Lower ureter - distal ureterectomy and reimplantation

26. Renal tumours

27. Benign Renal tumours Cysts account for 70% asymptomatic renal masses
Cortical adenoma
Oncocytoma
Angiomyolipoma (80% assoc with tuberous sclerosis)
The major import of most benign lesions lies in either their growth to a large size, creating clinical symptoms, or their differential diagnosis from renal tumours.
Cortical adenoma - commonly found at autopsy, are benign both clinically and histologically. However can be very difficult to distinguish radiologically from RCC’s so most diagnosed are treated by nephrectomy.
Oncocytoma - Invariably benign. Histologically consists of large eosinophilic cells with granular cytoplasm. Mitoses are rare, and the cells have a benign ultrastructure characterised by a profusion of mitochondria. Many RCC’s have oncocytic features and contain eosinophilic granular cells. Differentiation between a typical renal oncocytoma, and oncocytic renal cell carcinoma can be difficult. Grossly the tumours are tan/light-brown, well circumscribed, round, encapsulated, and containing a central dense fibrous band with fibrous trabeculae in a stellate pattern. This “cartwheel” pattern is often visible on CT or U/S. Commoner in males, incidence uncertain. 6% can be bilateral. Usually asymptomatic, may cause bleeding, especially larger ones. Partial nephrectomy satisfactory if diagnosis certain preoperatively, but radical nephrectomy safer.
Angiomyolipoma - 80% with these have some or all of stigmata of tuberous sclerosis (hereditary/familial disease characterised by mental retardation, epilepsy and adenoma sebaceum). Hamartomas may be found in brain, eye, heart, lung and bone. Renal hamartomas freq bilateral. Yellow/gray and have a propensity for profuse haemorrhage, large size and multiplicity. Microscopically - unusual blood vessels, clusters of adipocytes, and sheets of smooth muscle. Pleomorphism common. Because of multiplicity, conservative surgery is imperative. Distinctive CT appearance with density = fat.
Management - size of lesions assoc with propensity of symptoms, esp haemorrhage. Asymptomatic lesions <4cm may not req Rx, but must be observed. Persistently symptomatic tumours of any size - angio-infarction. Angio-infarction should be attempted as first line Rx for any haemorrhage into an angiomyolipoma. Partial nephrectomy may be required.

28. Renal cell carcinoma 3% adult cancers M:F 2:1
High incidence of carcinoma in patients with von Hippel Lindau disease
No specific causative agent detected
Von Hippel Lindau - Angiomatous cerebellar cyst, angiomatosis of the retina, and tumours or cysts of the pancreas.

29. Presentation Classic triad of pain, haematuria, and flank mass (rare)
More commonly just pain and haematuria
Symptoms of metastatic disease
Paraneoplastic syndromes
Renal carcinoma is typically unilateral, but bilaterality, either synchronous or asynchronous occurs in approx 2%.
Von Hippel Lindau - characteristically assoc with multiple and bilateral renal tumours
Paraneoplastic syndromes
1,25 - DHCC, Renin, erythropoietin, PTH-like substances, glucagon, hCG, insulin
Hypercalcaemia reported in 10% - ?aetiology. A peptide produced by the tumour that is analogous to the amino-terminal regions of a parathyroid hormone-related protein may be the causative agent.

30. Investigation Ultrasound - distinguish solid from cystic mass
CT - Staging, prior to surgery
MRI - less sensitive than CT for lesions less than 3cm
Angiography - tumour in solitary kidney if partial nephrectomy considered

31. Treatment
Radical nephrectomy remains only effective method of treating primary renal carcinoma
5 year survival
60-82% Stage I
47-80% Stage II
35-51% Stage III
Survival increased by pre-op radiotherapy in some studies

32. Tumour in solitary kidney / bilateral tumours
Partial nephrectomy gives excellent short term results (72% tumour free survival at 3 yrs)
Survival independent of whether tumour present in other kidney
Survival dependent on stage of local tumour

33. Treatment of metastatic disease
Chemotherapy
Hormonal therapy
Immunotherapy
“adjunctive” nephrectomy
Chemotherapy - Most drugs lack any therapeutic efficacy.
Hormonal therapy - Basis for hormone therapy of advanced renal cancer was the demonstration of its efficacy against and oestrogen-induced clear cell tumour in the adult Syrian hamster.
Progesterone therapy (Medroxyprogesterone acetate [Provera]) ) given twice weekly continues to be a method of management in the absence of more effective agents.
However, no proper study has proved the efficacy of these agents in the management of advanced renal carcinoma.
Immunotherapy - theory is that host immune functions play a role in tumour control and that these immune functions can be stimulated.
Several reports of small numbers of patients treated with BCG have shown some benefit. INTERFERON - Type 1 (alpha) interferon has been used in metastatic renal cancer and responses of 16.5% (complete), and 26% (partial) have been noted. Responses appear independent of preparation used, and correlate with those patients who have undergone previous nephrectomy, and who have a good performance status, a long disease-free interval, and lung-predominant disease. TCGF (IL-2) is a 15k dalton glycoprotein produced by Th cells. In vivo it generates LAK cells, and enhances NK cell function, augments alloantigen responses, and stimulates production of T cells with antitumour function. Variable responses have been produced, but id does seem that in some patients IL-2 can alter the natural history of the disease - probably 5% complete, and further 10-15% partially. NB side effects are awful! - fever, chills, malaise, nausea, vomiting, diarrhea, Renal and cardiopulmonary
“Adjunctive” nephrectomy - Anecdotal evidence that removal of primary tumour may lead to regression of metastases. However regression occurs in <1% after adjunctive nephrectomy, and such regressions are often short lived. One study of 73% patients followed for 5 years reported a spontaneous regression rate of 6%, so it is difficult to support a routine practice of adjunctive nephrectomy. Nephrectomy prior to to trial of interferon therapy has been suggested to improve outcome, but this has not been conclusively shown.