and increased nuclear:cytoplasmic ratio). Urinary biomarkers: Novel protein and genetic markers are gradually expanding their diagnostic utility. They include tumor cell-associated antigens (via immunohistochemistry) and genetic abnormalities (via \202 uorescence in situ hybridization \200\224 FISH). Many identi \201 ed but few routinely available. Further proof of clinical utility is required. Commercially available tests include: (i) a FISH assay with probes for chromosomes 3, 7, 17 , and 9p21 and (ii) a quantitative immunoassay for nuclear matrix protein (NMP-22), a house keeping protein active during cell division. Cystoscopy: Size, number, position, morphology of tumors. Rigid cystoscopy allows biopsy. Photodynamic cystoscopy: a photoactive substance that accumulates in neoplastic cells (e.g. 5-aminolevulinic acid) is instilled and \202 uoresc es under light of the appropriate wavelength. Aids the identi \201 cation of carcinoma in situ (CIS). Biopsy/cystoscopic resection: Biopsy areas displaying abnormal urothelium. \200 Random biopsies may be necessary to det ect CIS, including of prostatic urethra. Inclusion of muscularis propria necessary to ensure accurate staging. Imaging: USS to exclude hydronephrosis (even if SCr normal \200\223as unilateral obstruction may occur). Not useful for staging. CT: for staging. In addition, upper tracts must be assessed for synchronous tumors by contrast-enhanced CT. MRI as good as CT for staging and may better delineate extravesical invasion. Bone scan if skeletal pain, i ALP, or i Ca 2+ . \200 CXR for lung metastases if muscle-in vasive (and if CT chest not undertaken during staging). PET: limited role in local disease, as 18F-FDG undergoes urinary excretion. May have a role in detection/monitoring of metastases. CHAPTER 9 Essential urology 752 Tumors of the bladder: pathology and management Pathology \200 TCC (90%) > SCC (5%) > ade nocarcinoma (2%) > sarcomas (rare) > small cell (rare). TCC has a range of phenotypic expressions: papillary ( 7 70%), sessile ( 7 10 \200\223 20%), nodular ( 7 10%), or carcinoma in situ (CIS). The usual growth pattern is papillary, projecting out into the bladder lumen. This may gradually invade deeper, breaching basement membrane, lamina propria, and, eventually, muscle, prior to distant spread. Often multifocal. 7 30% tumors are synchronous at presentation ( s to the \200\230 \201 eld change \200\231 effect of environmental exposures). WHO classi \201 es tumors pathologically as low-grade (formerly grades 1 \200\223 2) or h igh-grade (grade 3). Low-grade tumors rarely progress to more aggressive, muscle-invasive f orms (see Table 9.10). The term \200\230super \201 cial \200\231 tumor is misleading and best avoided. Low- and high-grade tumors follow different biological pathways, have different outcomes, and requi re different treatments, regardless of \200\230super \201 ciality \200\231 . 2 CIS does not imply early disease or a good outcome \200\224 it is often characterized by high-grade dysplasia and a poor prognosis. Many patients with CIS have coexisting papillar y tumors ( \200\230 pure \200\231 CIS in <10%). Staging and prognosis \200 The most signi \201 cant prognostic factors are: (i) depth of invasion (stage); (ii) histological grade; (iii) presence of CIS; (iv) previous recurrence s. Progression risk relates to grade. Low-grade <10% progression (rarely invade muscle). High-grade >30% progression. The majority of tumors (>70%) are non-muscle-invasive at diagnosis. \200 Non-muscle-invas ive tumors have a relatively good prognosis, with 5-year survival rates of >80%. Tumors are much more likely to recur than progress. 5-year s urvival deteriorates to <25% by stage T4. \200 Prognosis therefore depends on both stage and grade. As a rough guide, for super \201 cial tumors: \200 Ta low grade: prognosis very good. \200 Ta hig h grade: prognosis less good. \200 T1 low grade: prognosis good. \200 T1 high grade: pr ognosis poor. Diffuse CIS l higher recurrence rates and poorer prognosis. \200 7 50% with muscle-invasi ve disease have occult metastases at diagnosis. \200 Prognosis for those with distant dis ease is poor (<10% alive at 2 years). tumors OF THE BLADDER: PATHOLOGY AND MANAGEMENT 753 Table 9.10 TNM staging of bladder cancer T Primary tumor CIS Carcinoma in situ , high-grade dysplasia, con \201 ned to the urothelium Ta Papillary tumor con \201 ned to the urothelium T1 Invasion into the lamina propria T2 Invasion into the muscularis propria T3 Invasion into the perivesical fat T4 Involvement of adjacent organs (e.g. prostate, rectum) N Regional nodes N+ Lymph node involvement M Distant metastases M+ Distant metastases Management \200 The depth of bladder wall invasion determines treatment (non-muscle-invasive: Ta, T1, and CIS. Muscle-invasive: T2 \200\223 T4). Non-muscle-invasive \200 Transurethral resection (TURBT): Smaller TCCs may be resected as one piece with underlying muscle. Larger tumors require mor e extensive resection. Should be followed with a single dose of intravesical chemotherapy (e.g. mitomycin) to d re currence risk (administered within 6h of resection). Repeat TURBT at 7 6 weeks if: (i) residual tumor; (ii) no muscle in initial specimen ( l ri sk of understaging); (iii) high-grade disease. Subsequent treatment depends on the risk of recurrence and progression. Broadly: \200 Low-risk (Ta staging, <3 lesions, <3cm, low-grade dysplasia, papillary): follow with active surveillance. High-risk (T1 staging or above, CIS, >3 lesions, >3cm, high-grade dysplasia, non-papillary) : further intravesical treatment. Usually immunotherapy with bacille Calmette \200\223 Gu rin (BCG). Usually induction treatment weekly for 6 weeks (+/ \200\223 intermittent main tenance therapy for 1 \200\2233 years). Reduces progression risk by 7 25% (SE: cystitis, ha ematuria, fever, arthralgia, hepatitis, and pneumonitis). CHAPTER 9 Essential urology 754 Muscle-invasive disease (or failure of conservative treatment) Radical cystectomy with urin ary diversion \200 Bladder removed with local lymph node dissection. The prostate and sem inal vesicles are also removed in \231\202 (SE: impotence), and cervix, uterus, ovaries, a nd anterior vagina in \231\200 . Commonly performed as open surgery, but laparoscopic and robotic techniques are becoming well established. Operative mortality of 2 \200\2235%, but overall perioperative morbidity (cardiovascular, atelectasis, sepsis, bowel and urine leaks, bleeding, wound infections) hi ghly signi \201 cant ( 7 30 \200\223 60%). There is evidence that neoadjuvant chemotherapy has a role prior to surgery, and it should be considered in all suitable patients. Urinary diversion: Ileal conduit: a segment of ileum is used to create a stoma. \200 Orthotopic neobladder: pouch formed from bowel and connected to the urethra (prostatic urethral disease precludes this option). Continent cutaneous pouch: similar to neobladder, but externalization using bowel (often appendix) allows drainage via a catheter. Metastatic disease is treated with cisplatin-based chemotherapy. \200 In patients who are not considered to be candidates for cystectomy, bladder preservation with a radical TURBT +/ \200\223 chemotherapy may be an option. Radical external beam radiotherapy \200 Generally reserved for those un \201 t for surge ry, in a poor prognostic group, or needing palliation of local symptoms (e.g. haematuria). Follow-up See b p. 757. Bladder adenocarcinoma \200 Uncommon; 2% malignant bladder tumors. \200 Varied histolo gic patterns, but most often a glandular (enteric) morphology. Need to be differentiated from metastatic adenocarcinoma; e.g. prostate, colon. May arise from urachal remnant. \200 Tend to be aggressive with extra-vesical extension a t presentation. \200 Treatment is surgical, with or without adjuvant chemotherapy and radiotherapy. tumors OF THE BLADDER: PATHOLOGY AND MANAGEMENT 755 CHAPTER 9 Essential urology 756 Tumors of the renal pelvis and ureter Overview \200 Tumors can arise anywhere from renal calyces to the vesicoureteric junction. 70% occur in the distal ureter, 25% mid, and 5% upper. \200 Multicentric disease common, but bilateral tumors rare. \200 7 5% of patients with bladder cancer will develop an uppe r tract lesion (higher for CIS). 7 30 \200\223 40% of patients with an upper tract lesion will develop a bladder tumor ( l s to \201 eld transformation effect and downstream seeding). \200 Risk factors and gene tics re \202 ect those for bladder cancer ( b p. 750) \200 There are additional associat ions with Balkan endemic nephropathy ( b p. 582), aristocholic, or Chinese herb, nephropath y ( b p. 583) and Lynch syndrome. Clinical features \200 Frank haematuria (>60%). \200 Flank pain s obstruction (30%). \200 Lower urinary tract symptoms are uncommon. Many patients are asymptomatic. Investigations \200 Urine cytology is less sensitive than for bladder lesions. \200 Con trast CT (or retrograde ureterography) to demonstrate a \201 lling defect. The contralateral ureter must be evaluated. \200 Cystoscopy to assess synchronous bladder tumor(s). \200 Ureteroscopy 9 biopsy. Biopsy will determine histological grade but may understage. Additional investigations, as for bladder tumors ( b p. 751). Pathology \200 Benign tumors (e.g. \201 broepithelial polyps) are rare. \200 >90% are TCCs. Others: SCCs ( l risks include calculi, particularly staghorn calculi, and chronic i nfection), adenocarcinomas, small cell tumors, and metastases. Histologically identical to bladder tumors. \200 2 7 40% are invasive at presentation \200\224 a far higher proportion than for bladder tumors. Staging Described by the TNM system, comparable to bladder tumors. Management \200 Endoscopic/percutaneous procedures: \200\230 Kidney-sparing \200\231 techniques. \200 Require careful patient selection (e. g. solitary kidney, bilateral lesions, un \201 t for more aggressive surgery). Prospective surveillance for residual or recurrent tumor is essential. tumors OF THE BLADDER: PATHOLOGY AND MANAGEMENT 757 Nephrouretectomy: Remains the benchmark. \200 Laparoscopic outcomes now as good as open surgery. \200 The entire ureter is removed, including a cuff of normal bladder (retained ureteric stumps l tumor recurrence in 7 25%). Segmental ureteric surgery with re-implantation may be possible for isolated, distal, low-grade tumors. Adjuvant chemotherapy is often given for T3/4 or node +ve disease. \200 The role of topic al chemotherapy or BCG immunotherapy is less well de \201 ned than for bladder tumors. How ever, single dose intravesical mitomycin C post nephrouretectomy appears to decrease the ri sk of recurrent disease. Prognosis \200 Determined by stage, histological grade, and the patient \200\231 s age. \200 Molecular and cytogenetic markers may play a greater prognostic role in the future. 5-year survival 60 \200\223 90% for non-invasive disease. This falls to <5% for T4 tumors. Follow-up of transitional cell tumors \200 TCCs have one of the highest recurrence rates of any malignancy. \200 Follow-up is determined by tumor grade, tumor stage, and the nature of initial treatment undertaken. Although based on repeat cystoscopy and imaging, clinical assessment and urine cytology (low sensitivity, higher speci \201 city) also form part of surveillance. Urinary biomarkers are likely to play a more prominent future role. Bladder tumors \200 The majority of patients have an intact bladder and require long-term surveillance (i.e. large numbers, time-consuming, and costly). Non-muscle-invasive (example regimens) \200 Low-risk tumors: repeat cystoscopy at 3 month s. 6 \200\223 12-monthly thereafter. High-risk tumors: 3-monthly for the \201 rst year, 4-monthly for second, then 6-monthly f or 5 years (or recurrence or progression occurs). Muscle-invasive \200 After radical cystectomy, patients remain at risk of distant metasta ses as well as recurrence in the upper tracts and urethra. CT imaging of the chest, abdomen, and pelvis 6 \200\223 12-monthly is generally advocated ( X whether early detection of metastases confers a survival advantage remains unproven). Upper tract tumors \200 Post-nephrouretectomy, both cystoscopic surveillance (3-monthly f or the \201 rst year, then 6 \200\223 12-monthly) and imaging (contrast CT or retrograde ureterography) of the contralateral ureter is necessary. Renal-sparing treatment strategies mandate particularly stringent surveillance, as recurrence risk is higher. CHAPTER 9 Essential urology 758 Benign prostatic enlargement: general Background \200 The prostate is a walnut-sized glan d, surrounding the proximal urethra at the bladder apex. It comprises several zones, enclos ed in an outer capsule, and functions to secrete an alkaline seminal \202 uid. Benign prostatic hyperplasia (BPH), or hypertrophy, results from cellular proliferation in the peri-urethral transition zone and is a histological diagnosis. Benign prostatic enlargement (BPE) is the clinical term referring to increased gland size. Gland enlargement l bladder outlet obstruction (BOO) l lower urinary tract symptoms (LUTS). BPH is an unwelcome consequence of \231\202 ageing. 7 50% develop it by age 60 and 7 90% by age 85. Pathophysiology \200 Remains incompletely understood. \200 Heightened sensitivity to mu ltiple growth factors and cytokines appear important. Androgen dependency is particularly well described. 5 A -reductase converts testosterone l dihydrotestosterone (DHT) within the prostate. Prostatic DHT levels are not increased, but androgen receptor expression is demonstrably more abundant in hyperplastic glands. BPH is rare in \231\202 with hypogonadism. Proliferation (stromal > epithelial) occurs primarily in the peri-urethral transitional zone. Impaired apoptosis may also contribute to cell accumulation. \200 Twin studies suggest a partial genetic susceptibility. \200 LUTS result from: Bladder outlet obstruction. \200 Bladder dysfunction: i \201 lling pressures l bladder wall hypertrophy, trabeculation, poor compliance ( d smooth muscle, i collagen), detrusor o veractivity (sensitivity to small urine volumes), and, eventually, incomplete voiding. A 1 -adrenergic receptor stimulation in prostatic smooth muscle and the bladder neck l i smooth muscle tone. Clinical features \200 2 BPE adversely affects the quality of life of many \231\202 over age 50. \200 LUTS refresher: frequency, urgency, nocturia, poor or intermittent stream, dribbling, incomplete bladder emptying (see b p. 78). Not all men with LUTS have BPE (and not all men with BPE have LUTS). \200 Prostatic volum e and symptoms tend to increase over time. \200 More severe symptoms are commoner in blac k men. \200 Severity and response to treatment can be assessed with the international pro state symptom score (IPSS) (see Box 9.3). The \201 nal question relates to quality of lif e and is a strong determinant of the need for intervention. Erectile dysfunction is commonly associated with LUTS. BENIGN PROSTATIC ENLARGEMENT: GENERAL 759 Ask about medications (diuretics, anticholinergics, tricyclics, opiates) and lifestyle factors (caffeine, alcohol, excess liquid intake). A self-completed voiding diary undertaken over a few days can further assess symptoms, liqu id intake, and bladder capacity. Diaries can also serve as a platform for subsequent self-m anagement. Complications \200 Bladder dysfunction, post-void residual urine volumes, acute urinary r etention, recurrent UTIs, obstructive nephropathy, bladder stones, haematuria. Differential diagnosis \200 Prostate: prostate cancer, prostatitis, prostatodynia. \200 Bladder: overactive bladder (see b p. 765), bladder dysfunction (e.g. neurological disorder), tumor, stone, foreign body (e.g. stent). Urethra: stricture (previous trauma, STD). Box 9.3 International prostate symptom score (IPSS) Scoring system \200 Seven questions about LUTS. Answers are on a scale of 0 \200\223 5. \200 For questions 1 \200\223 6, the choice of answers is: not at all (score 0); less th an one time in \201 ve (1); less than half the time (2); about half the time (3); more th an half the time (4); almost always (5). Questions 1. Over the past month, how often have you had a sensation of not emptying your b ladder completely after you \201 nished urinating? 2. Over the past month, how often have you had the urge to urinate again less than 2 hours after you \201 nished urinating? 3. Over the past month, how often have you found you stopped and started again several times when you urinated? 4. Over the past month, how often have you found it dif \201 cult to postpone urination? 5. Over the past month, how often have you had a weak urinary stream? (Compare with your stream size at age 30.) 6. Over the past month, how often have you had to push or strain to begin urination? For question 7, the choices are: never (0); once (1); twice (2); three times (3); four time s (4); \201 ve or more times (5). 7. Over the past month, how many times did you most typ ically get up to urinate from the time you went to bed at night until the time you got up i n the morning? Add the scores to give the category of symptom severity (mild <8; mod- erate 8 \200\223 19 ; severe 20 \200\223 35). A further question addresses quality of life. \200 If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about it? \200 Delighted (0), pleased (1), mostly s atis \201 ed (2), mixed feelings (3), mostly dissatis \201 ed (4), unhappy (5), terrible (6). CHAPTER 9 Essential urology 760 Benign prostatic enlargement: investigation and management Physical examination \200 Palp able bladder. \200 Digital rectal examination (DRE). Size, consistency, contour, surface texture. Pain. Sphincter tone ( d if underlying neurological disorder). Normal prostate volume is 7 20g ( 7 2 index \201 ngers across). Neurological examination may be necessary. \200 BP: may be elevated if chronic retention and obstructive uropathy. BP will also help plan management with selective vs. non-selective blockade ( b p. 761). Investigations \200 Urinalysis and MSU for M,C+S. \200 PSA: BPH does not cause prostate cancer, but \231\202 at risk for BPH are also at risk for prostate cancer. PSA levels correlate with prostate volume, so PSA is less speci \201 c for cancer in an individual with BPH. \200 May help predict response to treatment. \200 Measurement is recommended in many guidelines. Discuss with patient, and interpret in conjunction with DRE. May be helpful if treatment with an 5 -reductase inhibitor is being considered, as these w ould be expected to reduce the PSA by 50% after 6 months. eGFR: Renal insuf \201 ciency is uncommon so not universally indicated at initial presentation (exception: high residual volume). USS: Prostate and bladder volumes may predict response to treatment. \200 Exclude hydronephros is if retention or d eGFR. Transrectal ultrasound (TRUS): For detailed volumetric assessment. Desirable prior to surgery and 5 -reductase inhibitors (see b p. 761). Consider if i PSA. Upper tract imaging: If haematuria, stones, d eGFR, large residual volume, upper tract infection. Maximal \202 ow rate (Qmax) and \202 ow pattern: Useful for initial assessment and to gauge response to treatment. \200 >15mL/s is normal. \200 The shape of the \202 ow pattern curve may help differentiate BOO from impaired bladder function. Urodynamics (pressure \202 ow studies): Invasive (urethral catheter and transrectal probe). \200 Differentiates BOO from detrusor dysfunction (BOO: i voiding pressures (>60cmH 2 O) and d Qmax (<15mL/s)). BPE: INVESTIGATION AND MANAGEMENT 761 Consider if complications, such as incontinence, or accurate prediction of surgical outcome is desirable (e.g. high-risk candidate). Flexible cystoscopy: If atypical features (e.g. haematuria), prior to invasive treatment, or if an alternative diagnosis (e.g. stricture) is being considered. Management Overview \200 Patients with minor symptoms (IPSS score <7), no complications, and an acceptable quality of life are managed with adaptive lifestyle measures and watchful waiting. Reassess at least annually. \200 Lifestyle measures: d liquid intake (particula rly night-time); modify diuretic therapy; d caffeine and alcohol; void prior to bedtime, tr avel, or meetings. Improve glycaemic control in diabetic patients. \200 Failed lifestyle measures, or moderate to severe symptoms (IPSS score \211 8) can be treated with drug the rapy. A 3 \200\223 6 point reduction in IPSS score can be expected ( 7 60% men report an i mprovement). Indications for surgery: acute urinary retention, recurrent macroscopic haematuria, recurre nt UTIs, obstructive nephropathy, failure of medical therapy. Drug therapy 1 receptor blockade \200 A 1 -adrenergic receptor-mediated smooth muscle tone in both prostate and bladder neck contribute to LUTS. There are several receptor subty pes, with the A 1a receptor most relevant in prostatic tissue. \200 Selective A 1a antago nists require less dose titration and may have fewer vascular side effects. \200 Tamsulosin 0.4mg PO od or alfuzosin 10mg PO od. Non- A 1a selective agents are still effective (and less expensive) but require more careful dose titration. \200 Doxazosin 1mg PO od (bedtime), titrate to maint enance 2 \200\223 4mg. \200 Terazosin 1mg PO od (bedtime), titrate to maintenance 5 \200\223 10mg. SE: postural d BP, dizziness, ejaculatory disorder, nasal congestion. \200 Rapidly improv e symptoms (within days) but do not demonstrably d the overall risk of acute retention or requirement for surgery. \200 Intraoperative \202 oppy iris syndrome (miosis, iris billowing, and prolapse) is more common during cataract surgery in those receiving A 1 -blockers (particul arly tamsulosin) and causes technical issues for the surgeon. 5 -reductase inhibitors \200 Inhibit 5 A -reductase 6 block prostatic conversion of te stosterone l DHT and impede gland growth. Improve LUTS through a reduction in prostate volume. \200 Greatest bene \201 t in those with higher initial prostate volume (>40g on DRE or USS) or progression of symptoms despite on an A -blocker. Peak effect is delayed for 3 \200\223 6 months. Continue long term. \200 d incidence of acute retention and the requirement for surgery. \200 Examples: \201 nasteride 5mg PO o d, dutasteride 0.5mg PO od. CHAPTER 9 Essential urology 762 Side effects: d libido, erectile dysfunction, ejaculatory disorder, gynaecomastia, but ofte n better tolerated than A -blockers. \200 May d PSA by 50% 6 caution when interpreting me asurements. \200 X 5 A -reductase inhibitors have been associated with a higher risk of h igh-grade prostate cancer in clinical trials, albeit with a lower incidence of prostate can cer overall (this may be a consequence of sampling a smaller prostate). Combination therapy \200 Since A -blockers provide rapid symptomatic relief and 5 A -redu ctase inhibitors gradually in \202 uence underlying pathology, concomitant use makes good sense, particularly where initial prostate volumes are high. \200 Combination l d progres sion, improved symptoms (and IPSS score), d risk of retention, and d requirement for surgery. Withdrawal of the A -blocker may be possible after 6 months. Anticholinergic agents \200 May be bene \201 cial where storage LUTS (urgency, frequency, nocturia, small urine volume s, urge incontinence) dominate symptoms without signi \201 cant obstruction or a residual volume. This clinical scenario is often described as an \200\230overactive bladder \200\231 . \200 Examples: oxybutynin, tolterodine, solifenacin, and darifenacin. \200 Generally eff ective and well-tolerated, although dry mouth common. \200 Also consider bladder training and biofeedback techniques. \200 (cid:2) May worsen obstructive (voiding) symptoms, incr ease residual volumes, and precipitate urinary retention. Phytotherapy \200 Plant extracts are widely used for both self- and prescribed treatment. \200 Suggested active components include polysaccharides, fatty acids, phytosterols, lec tins, and \202 avonoids. Anti-androgenic, anti-in \202 ammatory, and other effects have been postulated. Extracts of saw palmetto (American dwarf palm) and Pygeum africanum (African plumb tree) are the most common. X Evidence base is limited. Some studies demonstrate modest symptomatic improvement, whilst others show no bene \201 t over placebo. Minimal adverse effects. Phosphodiesterase-5 enzyme inhibitors \200 Sildena \201 l or tadala \201 l may improve mild to moderate LUTS (nitric oxide may mediate relaxation of the prostatic urethra). Role needs further clari \201 cation but may prove useful where coexisting BPE and erectile dysfunction. 1 There is a potential interaction between blockers and PDE-5 inhibitors causing postural hypotension. Invasive procedures See Table 9.11. BPE: INVESTIGATION AND MANAGEMENT 763 Transurethral resection of prostate (TURP) \200 The historical gold standard, although th e number performed is falling, as alternatives, including medical therapies, are introduced and re \201 ned. Involves the passage of a diathermy loop through a urethral sheath. Prostatic tissue is shaved away under direct vision. Prostate \200\230chips \200\231 are available for histology ( 7 5% incidental prostate cancer). \200 Requires hospitalization . Regional or general anesthesia. \200 Morbidity ( 7 20% l prolonged hospital stay) and m ortality ( 7 0.25%). \200 Good symptomatic and urodynamic outcomes. \200 Complications: Bleeding (leave catheter in place until cleared). \200 Urinary infection (prophylaxis is generally given). \200 Urethral stricture. \200 Absorption of hypotonic irrigation \202 uid through exposed veins l d Na + (now rare with saline irrigation for bipolar cautery). Damage to bladder sphincter mechanism. \200 Retrograde ejaculation into the bladder. \200 Urinary incontinence. \200 Erectile dysfunction (nerve damage). Open prostatectomy \200 Very large prostates (>100g). Inner core of the prostate shelled out via a lower abdominal incision. Laparoscopic technique is an alternative. Bladder neck incision and transurethral incision of the prostate (TUIP) \200 The main alt ernative to TURP for many years. Short GA. An incision is made to widen the prostatic ureth ra and bladder neck. Suitable for patients with smaller prostates if un \201 t for TURP. F ewer complications but retreatment often necessary. Newer techniques \200 See Table 9.11. \200 Longer-term outcome data for newer therapies are still emerging. CHAPTER 9 Essential urology 764 Table 9.11 Prostate: surgical techniques Non-TURP surgery See text. Bladder neck incision and transurethral incision of prostate (TUIP) Open prostatectomy Very large prostates. See text. TURP Monopolar Requires hypotonic glycine irrigation. Bipolar Normal saline irrigation. Laser techniques \200\224vaporization or ablation KTP (potassium titanyl phosphate) laser. So called \200\230green light \200\231 laser surg ery. Ambulatory setting with minimal anesthesia. Good outcomes. Gaining in popularity. Photoselective vaporization of the prostate (PVP) Similar to PVP, but with an alternative laser. Holmium laser ablation of the prostate (HoLAP) Laser techniques \200\224enucleation Laser used to cut and/or enucleate the prostate. Similar technique to TURP. Good symptomati c and urodynamic outcomes. Pros: d bleeding, \202 uid absorption, impotence and retrograd e ejaculation. d length of stay. Cons: irritative LUTS persists for a few weeks. Holmium laser enucleation of the prostate (HoLEP) Other Delivers energy via a catheter. Ambulatory setting with minimal anesthesia. Associated with signi \201 cant prostatic swelling (catheter required until this subsides). Repeat treatm ent or surgery may be necessary. High frequency radio waves l thermal injury. Ambulatory se tting. Good outcomes. Transurethral microwave therapy (TUMT) Transurethral needle ablation (TUNA) Prostatic stents are very rarely used (principally in a palliative setting). Mechanical methods Encrustation, pain, incontinence, and overgrowth of tissue (making removal dif \201 cult) are common. BPE: INVESTIGATION AND MANAGEMENT 765 The overactive bladder Introduction \200 An important syndrome de \201 ned by symptoms: urinary urgency (9 incontinence) dominates, usually with frequency ( \211 8x in a 24h period) and sometime s with nocturia ( \211 3x at night). Urgency is a sudden, overwhelming, desire to pass urine. It is an unpleasant symptom that has a debilitating impact on quality of life. Pathophysiology appears multifactorial, but involves detrusor overactivity. Possible mechanisms: increased muscarinic sensitivity, overactive afferent se nsory pathways and subtle urothelial dysfunction. Investigation \200 2 Infection should always be excluded: urinalysis, MSU for M, C+S. \200 Bladder diary, symptom questionnaires (many available), \200 Other: assessment of p ost-void residual volume (usually USS \200\224 further assessment may be necessary if >150m L), urodynamics (characteristic phasic increases in detrusor activity) 9 cystoscopy in atyp ical or refractory cases. Management \200 Lifestyle modi \201 cations Modify amount and timing of \202 uid intake, absorbent pads if incontinence, double void techniques (if residual volume). Bladder training. This is an organized regime of voiding that can be highly successful, but requires (persistent) patient motivation. \200 Pelvic \202 oor m uscle therapy improves urethral sphincter control and may be effective, esp. in younger patients. Use in conjunction with biofeedback electro des (abdominal, anal, vaginal) is common. Anticholinergics. Inhibit involuntary detrusor muscle contraction; examples: tolterodine, oxybutynin and solifenacin SE: dry mouth, constipation, blurred vision, confusion (1 elderly). \200 Contraindication s: BOO and narrow angle glaucoma B3 adrenergic agonists Recently introduced after success in clinical trials; e.g. mirabegron. Botulinum toxin. Inhibits acetylcholine release and therefore detrusor stimulation. Requires direct detrusor injection. Good symptomatic improvement in clinical trials (includ ing incontinence). Sacral neuromodulation. Surgical electrode insertion at S2-3 level. An external pulse generator con \201 rms ef \201 cacy prior to permanent implantation. \200 Symptomatic i mprovement in 2/3rds (may persist 3 \200\2235 years). \200 SE: pain at implant site, lea d migration, leg pain, urinary retention, altered bowel habit. Surgery (last resort). Augmentation entero-cystoplasty (with a GI segment, usually ileum) to i functional bladder capacity and d intravesical pressure. Ileal conduit formation in refractory cases. CHAPTER 9 Essential urology 766 Prostate cancer: general Background Although it is often stated that more men die with pros tate cancer than of prostate cancer, this still means that many men succumb to the dis- eas e every year. In addition, this belief may only hold true for populations where PSA testing is high and not where men present with symptomatic disease. Prostate cancer is the second commonest cause of cancer death in men in the UK after lung cancer. However, the clinical p henotype ranges from microscopic, slow-growing, well-differentiated tumors to aggressive ca ncers with rapid local invasion and distant spread. This has meant that screening for prost ate cancer has become a very controversial topic. Epidemiology \200 Incidence has risen steadily since the mid-1970s. Reasons: ageing population, improved cancer registries, improved diagnostic accuracy, incidental cancer his tology of prostate \200\230chips \200\231 at TURP. But, most importantly, the widespread use of PSA testing (and TRUS biopsies) has led to the diagnosis of cancers that would not p reviously have come to clinical attention during a man \200\231 s lifetime. Very rare age <40, uncommon age <50. Common age >80 (found at post-mortem in 80%). 7 1 in 6 \231\202 will develop the disease, and 7 1 in 25 will die from it. \200 Average age at diagnosis 70 \200\223 74, average age at death 80 \200\223 84. \200 A variation in the prevalence of prostate cancer around the world (Europe, USA, and Australia > Asia and North Africa) suggests genetic factors. Black men > white men > Asian men (possibly s to hormonal differences). Familial predisposition also occurs ( 7 5 \200\223 10% cases). Such patients tend to present 7 5 \200\223 10 years earlier. X Other risk factors may have a limited role: obesity, diet (high in animal fat, low in veg etables), and hormones (there appear to be no differences in serum androgen concentrations, but the use of 5 A -reductase inhibitors for BPH reduces prostate cancer incidence overall , albeit with an increase in higher-grade tumors). Genetics \200 There is evidence for a genetic component, but the identi \201 cation of speci \201 c genes has proved dif \201 cult. Risk is increased x 2 in \231\202 with \211 1 affected \201 rst-degree relatives. Risk increases with the number of affected family members, especially if relatives are diagnose d at a young age (<60). There is a high rate of disease concordance in identical twins. \200 Several single nucle otide polymorphisms (e.g. in the 8q24 and 17q regions) are associated with an increased risk (the more SNPs present, the higher the risk) . The presence of BRCA1 and (particularly) BRCA2 mutations appears to increase risk (and worsen prognosis). PROSTATE CANCER: GENERAL 767 Recently, a novel G84E mutation in the transcription factor HOXB13 in the 17q region has be en associated with a signi \201 cantly increased risk of hereditary prostate cancer. Pathology \200 High-grade prostatic intraepithelial neoplasia (PIN) is a precursor of malignancy. It is intermediate between normal prostate epithelium and cancer. 95% adenocarcinomas. 4% have transitional cell morphology (arising from prostatic urethral urothelium). Squamous cell and neuroendocrine tumors are v ery rare. 70% arise in the peripheral, 15 \200\223 20% in the central, and 10 \200\223 15% in the transitional zone. Many cancers are multifocal, involving multiple zones. Local invasion causes spread into the bladder neck (transition zone tumors) and ejaculatory ducts and seminal vesicles (peripheral zone tumors). Capsular penetration, with spread along the perineural or vascular spaces, occurs relatively late. Metastasizes to bone more commonly than any other site, causing sclerotic lesions. The natural history of the disease is extremely variable. Some low-grade tumors follow an indolent course, whilst others rapidly invade and metastasize. Clinical features Prostate cancers are often identi \201 ed in asymptomatic patients, foll owing an abnormal screening PSA level or DRE (or as an incidental pathologic \201 nding a t TURP). Local disease \200 LUTS (often late and more likely to be s to BPE), erectile dysfunction , haematospermia. Urinary retention, back or leg pain, and frank haematuria were more common in the pre-PSA era. Advanced disease \200 Weight loss and anorexia. \200 Anemia. \200 Bone marrow suppres sion. \200 Skeletal pain. \200 Spinal cord compression. \200 Leg swelling and pain s to venous and lymphatic obstruction. \200 Uraemic symptoms from obstructive uropathy. Physical examination \200 DRE: nodules, changes in texture, asymmetry. Obliteration of the lateral sulcus or seminal vesical involvement indicates locally advanced disease. (cid: 2) Many cancers are found in glands that feel normal. Furthermore, an abnormal prostate on DRE should always be investigated, even if the PSA is normal ( 7 20% patients). Distended bladder. \200 Abnormal lower limbs or neurological \201 ndings. CHAPTER 9 Essential urology 768 Prostate cancer: investigation Investigations \200 Urine for M,C+S. \200 PSA ( b p. 772 ). \200 U&E, eGFR, Ca 2+ , alkaline phosphatase (skeletal involvement). \200 Transrecta l ultrasound (TRUS): Used to evaluate abnormalities on DRE and to guide biopsy. \200 Tumors are often, but not universally, hypoechoic. \200 Also permits gland volume measurement. \200 Useful prior to focal therapy (e.g. cryotherapy) and for the detection of seminal vesicle invasion or extracapsular extension. \200 Biopsy is usually necessary, regardless of TRUS appearances, as TRUS alone is not suf \201 ciently sensitive. TRUS-guided biopsy: Indicated for tissue diagnosis in those with i PSA or abnormal DRE. \200 Performed as an ambulatory technique under LA. \200 Extended biopsy protocols, with more extensive sampli ng, is now the norm. These usually involve the removal of at least 10 \200\223 12 cores. Repeat biopsy may be necessary. \200 A transperineal (TP) approach is also commonly used and has the advantage of allowing additional samples to be taken (particularly when a TRUS biopsy has proved inconclusive). Complications: haematospermia (common), haematuria, pain, 1 infection, voiding dif \201 culties, PR bleeding. Imaging: USS pre- and post-micturition (with \202 ow rate) + upper tracts if signi \201 cant BOO or residual bladder volume. \200 Further imaging contributes to pre- treatment staging: Both CT and MRI can detect local tumor invasion and lymphadenopathy. MRI generally provides more accurate T staging. Endorectal MRI, via an endorectal probe, improves spatial resolution of MRI for zonal anatomy, extracapsular extension, and seminal vesicle involveme nt. Pre-biopsy 3-Tesla multiparametric MRI is increasingly used to identify suspicious areas th at can subsequently be targeted for TRUS or TP-biopsy. These scans can also generate a canc er risk score. MR spectroscopy imaging (MRSI), a technique that utilizes metabolite ratios within prostate tissue to distinguish normal from malignant tissue, has a n evolving role. Bone scan: if T3 or T4 disease, PSA >20ng/mL, skeletal symptoms, i Ca 2+ or alkaline phosphatase. Correlate with plain X-rays. Prostascint scan: a radiolabelled mAb to prostate-speci \201 c membrane antigen can locali ze soft tissue metastases. FDG-PET has only limited utility: tracer uptake is variable, and accumulation in the bladde r obscures the area of interest. PROSTATE CANCER: INVESTIGATION 769 Staging \200 Staging guides initial therapy and is undertaken using the TNM system. \200 In addition, histological grade is determined from biopsy specimens, using the Gleason score. Gleason grade is based on the extent to which the epithelium has a normal glandular structu re (1 \200\223 5). Experience and skill on the part of the pathologist is essential. Based on growth pattern and degree of differentiation, tumors are graded from 1 to 5 where grade 1 is the most and grade 5 the least differentiated. Adding together the values for th e two most prevalent patterns of differentiation derives a composite Gleason score, e.g. fo r a biopsy consisting of predominant grade 4 and secondary grade 3 disease, the composite s core is 4 + 3, or 7. 2 \200\223 4 = low-grade or well-differentiated; 5 \200\223 7 = moderate grade or