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

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

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

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

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

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)

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

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

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 67-70 yrs

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

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 40-50 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 - 2-4 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

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

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

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

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

TNM Staging

Bladder Cancer The Good The Bad The Ugly

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.

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

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

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.”

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.

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.

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

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

Renal tumours

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.

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.

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.

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

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

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

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.