Urology 5th year, 3rd lecture (extended/detailed version) (Dr. Ali Kamal)
Urology<br />Neoplasms of the bladder<br />Ninety-five per cent of primary bladder tumours originate in :he epithelium; the remainder arise from connective tissue angioma, myoma, fibroma and sarcoma) or are extra adrenal phaeochromocytomas.<br />Secondary tumours of the bladder are not rare and most commonly arise from a neighbouring organ, particularly the sigmoid and rectum, the prostate, the uterus or ovary, although bronchial neoplasms also may spread to bladder.<br />Pathology<br />Benign papillary tumours. <br />Many histopathologists will not diagnose benign papillomas of the bladder, stating that most of them are merely better differentiated types of superficial bladder cancer. The papilloma consists of a single frond with a central vascular core with villi; it looks like a red sea-anemone (Figs 65.48 and 65.49). Inverted papilloma is a condition where the proliferative cells penetrate under normal mucosa so that the lesion is covered with smooth urothelium — it is benign.<br />Carcinoma of the bladder<br />Carcinoma arising within the bladder may be of three cell types: transitional, squamous and adenocarcinoma [or mixed owing to metaplasia in a transitional cell carcinoma (TCC)]. Over 90 per cent are transitional cells in origin. Pure squamous carcinoma is uncommon (approximately 5 per cent), apart from areas where bilharzia is endemic. Primary adenocarcinoma, which arises either from the urachal remnant or from areas of glandular metaplasia, accounts for 1—2 per cent of cases.<br />Transitional cell carcinoma<br />Aetiology. The first suspicion of a chemical cause for bladder cancer was raised by Rehn in 1894 when he recorded a series of tumours in workers in aniline dye factories. Hueper was able to show that 2-naphthylamine was carcinogenic in dogs. <br />Subsequent investigation demonstrated that the following compounds may be carcinogenic:<br /><ul><li>2-naphthylamine;
benzidine-derived azo dyes.</li></ul>Occupations which have been reported to have a significantly excess risk of bladder cancer are shown below<br />Occupations with an excess risk of bladder cancer<br /><ul><li>Textile workers
Rodent exterminators and sewage workers</li></ul>Bladder cancer became a prescribed industrial disease (No. 39) in 1953 and ex-workers may be entitled to compensation. Cigarette smoking is associated with a two to threefold excess risk, and certain genetic polymorphisms for N-acetyl tranferase, glutathione transferase and one of the cytochrome P45Os (CYP2D6) may increase the risk of occupationally acquired bladder cancer. In areas where S. haematobiumis endemic bladder cancer is more common, and this tends to be squamous in type. Balkan nephropathy has been associated with an increased incidence of upper tract urothelial tumours (see Chapter 63).<br />A series of genetic events has been clearly implicated in cancer formation that is outside the remit of this chapter. Activation of dominantly acting oncogenes such as ras and cerbB-2 has been reported in bladder cancer, as has the inactivation of tumour suppressor genes such as p53, p16 and retinoblastoma. Activation of other genes is responsible for the phenotypic changes seen in the cancer cell. These include the activation of enzymes which may dissolve the basement membrane such as the metalloproteinases (stromelysin, collagenases and elastase), lysosomal enzymes such as the cathepsins and others including urinary plasminogen activators; angiogenic factors [vascular endothelial growth factor (VEGF)] and other peptide growth factors such as the epidermal growth factor and its receptor also have a role to play. These changes are common to several tumour types including prostate cancer.<br />Tumour staging and grading <br />Study of the biological behaviour of transitional cell cancer of the bladder shows that they fall into the three following groups.<br />• Non muscle invasive tumours (pTa) and pT1 account for 70 per cent of all new cases. These tumours may be single or multiple. Histological examination may reveal invasion of the lamina propria (pTl) but not of the muscle or no invasion of lamina propria (pTa) —single papillary pTa tumours account for a significant proportion of bladder cancers and carry an excellent prognosis.<br />• Muscle invasive disease (accounts for 25 per cent of new cases). Such tumours carry a much worse prognosis as they are subject to local invasion and distant metastasis.<br />• Flat, noninvasive carcinoma in situ (primary cis — accounts for 5 per cent of new cases). Unless diagnosed and treated promptly, this carries a poor prognosis. <br />Superficial bladder cancer (pTa and pT1) <br />These are usually papillary tumours which grow in an exophytic fashion into the bladder lumen. They may be single or multiple and may appear pedunculated arising on a stalk with a narrow base, but if the’ tumours are less well differentiated they are more solid with a wider base. The mucosa around the tumour is often rather oedematous with angry-looking, dilated blood vessels. These areas may contain in situ changes (concomitant cis).<br />Some patients with bladder cancer have urinary infection, although this is more common with muscle invasive disease. Occasionally, calcium salts are deposited on these tumours, giving them a crusted exterior. The urothelium elsewhere in the bladder may also appear rather oedematous and velvety; this suggests a generalised ‘field change’ with the presence of widespread carcinoma in situ. The most common sites for superficial tumours are the trigone and lateral walls of the bladder.<br />After initial complete treatment by endoscopic transurethral resection (TURT) patients with pTa or pTl disease may develop two problems:<br />• 50—70 per cent develop recurrent tumours which may be single or multiple, and the recurrences may occur on one or on many occasions. Usually the recurrent tumours are of the same stage or grade as the primary tumour. Highgrade, multiple tumours with concomitant cis are most likely to develop recurrent disease;<br />• about 15 per cent will develop a recurrent tumour which is invading the bladder muscle. The risk of such progression increases with high grade, with pTl disease, with multiple primary disease and with concomitant cis. Many urologists now regard the presence of pTl G3 tumours as an indication for more radical treatment.<br />This behaviour provides the rationale for performing check cystoscopies. The factors which result in an increased recurrence and progression rates are:<br />• high grade;<br />• pTl disease;<br />•concomitant cis;<br />• multiple primary tumours;<br />• recurrent disease at the first check cystoscopy.<br />Patients presenting with a solitary grade 1 or grade 2 pTa tumour, without concomitant cis and which do not recur within the first 6 months have an excellent outcome.<br />Muscle invasive transitional cell carcinoma<br />The tumour with muscle invasion is nearly always solid (Fig. 65.51),although there may be a low tufted surface. These tumours are often large and broad based, having an irregular, ugly, sometimes ulcerated, appearance within the bladder. The incidence of metastases, whether from lymphatic invasion in the pelvis or blood-borne to the lung, liver or bones, is much more common and will cause the death of 3 0—50 per cent of patients.<br />In situ carcinoma<br />The histological appearance of irregularly arranged cells with large nuclei and a high mitotic index replacing the normally well ordered urothelium is known as carcinoma in situ. This may occur alone (primary cis) or in association with a new tumour (concomitant cis) or occur later in a patient who has previously had a tumour (secondary cis). This change may be appreciated macroscopically at the time of cystoscopy, although often is only diagnosed when a biopsy is examined under the microscope. The association of in situ carcinoma with papillary tumours increases the chance of recurrent disease and progression. It may cause severe symptoms of dysuria, suprapubic pain and frequency (hence its old name of malignant cystitis).<br />World-wide experience of this condition seems to indicate that symptomatic cis carries a high malignant potential. Fifty per cent of patients will die of bladder cancer.<br />Pure squamous cell carcinoma of the bladder<br />Squamous cell tumours tend to be solid and are nearly always associated with muscle invasion. This is the most prevalent form of bladder cancer in areas where bilharzia is endemic. Squamous cell tumours may be associated with chronic irritation caused by stone disease in the bladder as a result of metaplasia.<br />Pure adenocarcinoma<br />This accounts for approximately 1—2 per cent of bladder cancer. It usually arises in the fundus of the bladder at the site of the urachal remnant. Occasionally, primary adenocarcinomas arise at other sites and probably originate from areas of glandular metaplasia. Such tumours need to be distinguished from secondary cancer.<br />Clinical features<br />Painless haematuria is by far the most common symptom and should be regarded as indicative of a bladder carcinoma until proven otherwise. The haematuria may occur on only one or two occasions, and because the urine once again becomes clear patients only too often fail to declare the symptom to their general practitioner. Many months may elapse before it recurs and causes concern. The bleeding if more severe may give rise to clot formation and subsequent clot retention. It is fairly uncommon for the bleeding to be so profuse that emergency admission to hospital and blood transfusion is necessary. Occasionally, a pedunculated tumour or clot may occlude the bladder neck, causing retention of urine. The development of recurrent urinary tract infections, particularly in women in the later decades of life, should also arouse one’s suspicions.<br />Constant pain in the pelvis usually heralds extravesical spread. There is often frequency and discomfort associated with urination. Pain in the loin or pyelonephritis may indicate ureteric obstruction and hydronephrosis. A late manifestation is nerve involvement causing pain referred to the suprapubic region, groins, perineum, anus and into the thighs.<br />It is also important to assess the patient as a whole. Many are elderly men who have been life-long smokers and suffer from chronic obstructive airways disease or cardiovascular disease. Their suitability for anaesthesia must be borne in mind.<br />Investigation<br /><ul><li>Urine. </li></ul>Urine should be cultured and examined cytologically for malignant cells. This is not a good screening test for patients with haematuria as, particularly with low-grade tumours, malignant cells may not be identified unless a specimen obtained from a bladder washout is examined. False-positive results occur infrequently and are usually associated with stone disease. New tests are being developed based on the presence of antigens, such as nuclear matrix proteins, which may be good at detecting new or recurrent tumours.<br /><ul><li>Blood. Estimation of the haemoglobin and the serum electrolytes and urea should be carried out.
IVU. </li></ul>This should be performed on patients with haematuria. Occasionally, the preliminary film shows a faint shadow of an encrusted neoplasm of the bladder. The most common radiological sign is a filling defect. Occasionally, irregularity of the bladder wall may herald the presence of an invasive tumour (Fig. 65.52).Hydronephrosis may occur if a superficial tumour grows up the intramural ureter or if direct invasion of the ureteric wall occurs. Ultrasound scanning should be carried out if the kidney is nonfunctioning.<br /><ul><li>Cystourethroscopy. </li></ul>Cystourethroscopy is the mainstay of diagnosis and should always be performed on patients with haematunia. It can be done with a rigid instrument under general anaesthesia or with a flexible instrument under local anaesthesia. The urethra is inspected at the initial insertion of the instrument (urethroscopy) and the bladder is then examined in a systematic fashion (cystoscopy).<br /><ul><li>Bimanual examination. </li></ul>A bimanual examination with the patient fully relaxed under general anaesthesia should be performed both before and after endoscopic surgical treatment of these tumours. The bladder should be empty and the bimanual examination is executed with the right index finger in the rectum of a male and placed per vaginam in a female. The four fingers of the left hand push down on the anterior abdominal wall in the suprapubic region. Occasionally, a very large superficial fronded tumour may be felt as a soft but mobile thickening prior to resection. Superficial tumours are not usually palpable bimanually at the beginning and by definition are not palpable after resection. Once there is muscle invasion the differentiation between T2 and T3 disease depends on whether a mass is palpable bimanually at the end of the procedure (T3). Where invasion has spread into the prostate in a male or the vagina in a woman it is classified as T4a. If the tumour is fixed to the lateral pelvic side wall it is staged as T4b.<br /> <br />Treatment for carcinoma of the bladder<br /><ul><li>Noninvasive tumours</li></ul>Endoscopic surgery <br />It is not acceptable to take a tiny biopsy from the top of a papillary tumour and apply a fulgurating coagulation current to the rest unless a small recurrence is being dealt with. The tumour should be carefully resected in layers using a resectoscope. The base of the tumour is sent separately for histological examination. Small biopsies are taken near to and distant from the primary lesion to diagnose unsuspected cis. After removal of the tumour, two or three further loops of tissue from the base should be sent separately so that the pathologist can accurately determine whether there is lamina propria or muscle invasion. The base of the tumour is then coagulated, so achieving haemostasis. The appearance of pale yellow glistening fat will indicate a perforation of the bladder. Should this occur before the resection is complete, it may be prudent to stop the resection and place a catheter in the bladder for a few days. In this instance<br />the procedure could be completed some 2 weeks later. The bimanual examination is repeated at the end of each endoscopic procedure.<br />Patients with solid tumours should have adequate material resected for histological staging and grading. These patients will usually need some other form of treatment. It is likely that a debulking resection of these tumours is helpful prior to radiotherapy. Following these procedures an irrigating catheter is left in situ for 48 hours to prevent clot retention of urine. There is good evidence that a single dose of mitomycin C (40 mg in 60 ml of fluid) instilled into the bladder prior to catheter removal decreases the risks of recurrence in patients with pTa, PT1 grade 1 and 2 disease. <br />Follow-up. Most urologists agree that patients with a single, low- or medium-grade pTa tumour can safely be treated by resection alone and followed up by means of regular cystoscopies.<br />The treatment of patients with multiple low- or medium-grade pTa tumour can be by either means of resection alone or resection followed by a 6-week course of intravesical chemotherapy with mitomycin C, adriamycin or epirubicin.<br />The treatment of pTl disease is difficult. Many urologists, including many North American and European urologists, would offer immediate cystectomy to a patient with a high-grade pTl tumour — particularly if it was multiple or accompanied by cis, because of the 30—50 per cent risk of progression to muscle invasion. Others will treat such patients by means of endoscopic treatment followed by intravesical immunotherapy with intravesical bacille Calmette—Guérin (BCG) — although there is no firm evidence that this decreases the risk of progression. The treatment of solitary medium-grade pTl disease remains uncertain, but a reasonable approach would be endoscopic resection followed re-resection of the area in 6 weeks followed by intravesical chemotherapy with BCG.<br />Follow-up cystoscopies are essential; they may be carried out by means of local anaesthesia with a flexible cystoscope on by means of general anaesthesia if the urologist feels that the patient has a high risk of recurrence. They should initially be performed at 3-monthly intervals over the year; following this the time interval between cystoscopies can be determined according to the presence or absence of further disease. Thirty per cent of patients will never develop another tumour, so that after 2 years if the bladder has remained clear annual inspection may be adequate. For patients who go on to develop multiple recurrences within the bladder at each examination, the cystoscopies need to be maintained at frequent intervals so that the growths can be resected. These patients are at a greater risk from developing progression of their disease; whilst intravesical chemotherapy can decrease the recurrence rate, no reduction in progression rates has been found.<br />Intravesical chemotherapy and immunotherapy<br />Various agents have been used. These include thiotepa (which may be absorbed because of its low molecular weight and cause blood dyscrasias), mitomycin C, epirubicin and adriamycin. They are of equal efficacy and the cheapest should be chosen. They are administered by means of a urethral catheter and held in the bladder for 1 hour, the patients are turned from side to side and try to hold their urine for as long as possible. Usually the patients are treated weekly for 8—10 weeks and then re-cystoscoped. BCG is now frequently used as intravesical immunotherapy. It carries a greater risk of local side effects such as ‘cystitis-like’ symptoms and also risks of systemic side effects — including systemic BCGosis. Nevertheless, it is probably more effective than intravesical chemotherapy and is the treatment of<br />choice for cis. Currently, ‘booster’ doses of maintenance BCG treatment are being given in addition to the initial 6-week course.<br />Open surgical excision<br />This should be totally avoided. If by some error a bladder containing a tumour is entered, then the tumour may be removed with a diathermy needle and the base coagulated and the bladder closed. Postoperative radiotherapy to the wound will diminish the chance of tumour implantation.<br /><ul><li>Invasive tumours</li></ul>The treatment of cancer with proven muscle invasion remains a subject for debate. Whatever the modality of treatment employed, few centres have 5-year survival figures of more than 40 per cent. The controversy is centred around whether primary surgery (radical cystectomy), radical radiotherapy, or a combination of the two, provides the best result. There is a move towards primary surgical treatment in most centres. The use of systemic chemotherapy by means of a combination of agents using cis-platinum, methotrexate, adriamycin and vinblastine (MVAC) in addition to conventional treatment is presently being studied. -<br />Radiotherapy<br />Deep external beam X-ray therapy. External beam radiotherapy is usually given by means of high-powered linear accelerators. Radical radiotherapy giving 60 Gy over a 4—6-week period will produce a 40—50 per cent complete response. The difficulty with radiotherapy is in patients who do not respond at all or those who have a partial response, having a bladder with pTa or pTl tumour in it, and who are subject to recurrence. Patients with residual disease after radiotherapy should be offered ‘salvage cystectomy’ if they are fit. The protagonists of radiotherapy would claim that for most patients it saves the need to remove the bladder and allows men to retain potency. Radiotherapy is not always without complications, and during the course of treatment will cause urinary frequency and also diarrhoea. Late complications can leave the bladder contracted and fibrosed, in which case the bladder may need to be removed for palliative reasons. Late complications affecting the rectum should be uncommon, especially if lateral fields of irradiation are employed.<br />Local radiotherapy. For small invasive lesions, local radiotherapy can be delivered by open placement of a radioactive tantalum wire (iB2Ta) or iridium wire or the implantation of gold grains (t98Au). It is used infrequently today.<br />Surgery<br />Partial cystectomy. This should be limited to the treatment of small adenocarcinomas of the bladder.<br />Radical cystectomy and pelvic lymphadenectomy. This is now standard treatment for localised pT2—pT3 disease without evidence of secondary spread or of cis which has nor responded to BCG. Before contemplating radical surgery to remove the bladder, it is important to have evidence that surgical cure is attainable. A CT scan of the pelvis may over-stage the bladder if a recent resection has been carried out, although the finding of grossly enlarged pelvic, iliac or para aortic nodes on liver metastases will alter the decision for cystectomy. A bone scan [technetium-99m (S9mTc)] will help to show whether there is spread to bone.<br />Operation<br />Alternative drainage for the urine is necessary following removal of the bladder. The standard procedure is to perform an ileal conduit. Patients should be counselled about the onset of erectile impotence and absent ejaculation following the operation; they should also be told about alternative forms of urinary diversion which include continent urinary diversions and orthotopic bladder replacement.<br />Patients should be seen by a stoma care therapist who will help to advise the patient and will try different ileostomy bags to ensure that the correct site is chosen avoiding skin creases so that one does not end up with the disaster of a leaking urinary ileostomy. A decision is made about whether the male urethra is to be removed (depending on the estimated risk of recurrence within the urethra); a urethrectomy is usually indicated in patients with primary cis or those with tumour invading the prostate stroma. Many surgeons are now offering total replacement of the bladder after cystectomy (Fig. 65.53).<br />Preoperatively, the bowel is prepared with a balanced solution of polyethylene glycol (Golytely or Kleanprep). The patient should receive prophylactic antibiotics including metronidazole, cefuroxime and amoxycillin, and low-dose heparin.<br />The abdomen is opened through a long lower midline incision extending down to the symphysis pubis. The liver and the retroperitoneum are checked for evidence of metastases and the operability of the bladder is assessed. A bilateral pelvic lymphadenectomy is performed removing external iliac nodes, internal iliac nodes and the nodes in the obturator fossae. The vessels passing to the bladder from the side wall are ligated in continuity; these include the obliterated hypogastric vessels, the superior vesical artery, the middle vesical veins, and the inferior vesical arteries and veins. The ureters are then divided. The posterior ligaments extending from the pararectal area to the back of the bladder are ligated and divided, and the layer posterior to Denonvillier’s fascia is opened up. The endopelvic fascia is then divided on each side and the puboprostatic ligaments are divided. A ligature is passed between the dorsal vein complex and the urethra, and the former is ligated and divided. The urethra is then mobilised and divided. The ligaments lateral to the prostate are divided and the bladder is removed. In women, the uterus and anterior vaginal wall need to be included. Women must be counselled about the loss of ovarian and uterine function. -<br />An isolated loop of ileum is then prepared on its own mesentery, and continuity of the small bowel restored. The ureters are then implanted into the bowel and the ileostomy is created. Meticulous care must be taken to close all mesenteric windows, thus avoiding internal hernias. If the bladder is to be replaced orthotopically, a reservoir made from detubularised bowel (usually an ileocaecal segment or ileum) is created and anastomosed to the urethra after implantation of the ureters.<br />The operative mortality associated with cystectomy used to be considerable, but should be in the order of 2 per cent. Late complications include urethral recurrence (about 5—8 per cent) which is increased in the presence of multifocal tumours, cis and, particularly, invasion of prostatic stroma (Fig. 65.54).<br />Leukoplakia<br />This condition is simply squamous metaplasia of the bladder. Profuse production of keratin may result in the passing of white particles in the urine. It cannot be treated easily. Localised areas may be resected endoscopically. Diffuse leucoplakia of the bladder is premalignant and results in squamous bladder cancer. Careful cystoscopic assessment is required. The condition may require cystectomy.<br />Endometriosis<br />Endometriosis within the bladder wall is rare, but can have the appearance of a vascular bladder tumour or a tumour which contains chocolate-coloured or bluish cysts. The swelling enlarges and bleeds during menstruation. If medical management fails, by means of danazol or luteinising hormone-releasing agonists (LHRH), further treatment is usually by means of partial cystectomy or full-thickness endoscopic resection, depending on its site. The condition may be part of more widespread disease. Endometriosis is also a cause of ureteric stricture.<br /> <br /> <br /> <br /> <br /> <br />