Metastatic bladder cancer Five percent of patients have metastatic disease at the time of d iagnosis. Systemic chemotherapy TCC is a chemosensitive cancer; it is recommended for patients with u n- resectable, diffusely metastatic measurable disease. Combination is more effective than single-agent treatment. A complete response is seen in 15% of patients given methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), though 20% of patients develop neutropenia a nd 3% die of sep- sis. Median survival is 14 months. Most UK centers are using gemcitobine, an antimetabolite agent, alone or in combination with cisplatin. Complete responses are re ported in 25 \200\22340% of patients and it is better tolerated than MVAC, with 1% toxic de ath rate. Carboplatin may be used if cisplatin is contraindicated (i.e. performance status (cid:116)2 of GFR <60mL/min). Taxanes (paclitaxel and docetaxel) are microtubule disassembl y inhibitors; respons- es range from 25 to 80%, using these agents alone or in combination. Prognostic factors predicting response to chemotherapy include alka- line phosphatase, age >60y, performance status, and visceral metastases. Depending on the number of factors, medi an survival varies from 9 to 30 months.3 In future, molecular markers such as tumor p53 sta tus may be shown to predict chemosensitivity. Unfortunately, no biomarker is cur- rently av ailable to predict outcome, drive treatment decisions, or monitor response to treatment. Radiotherapy Roles for RT include palliation of metastatic pain, haematuria, and spinal cor d compression. Surgery There is no surgical role in treatment of extravesical metastatic disease. Palliati ve cystectomy or urinary diversion is justi \201 ed for severe local symptoms. 1 Advanced bladder cancer meta-analysis collaboration (2003) Neoadjuvant chemotherapy in in vasive bladder cancer: a systematic review and meta-analysis. Lancet 361:1927 \200\22334. 2 Grossman HB, Natale RB, Tangen CM, et al. (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859 \200\22366. 3 Bajorin DF, Dodd PM, Mazumbar M, et al. (1999) Long-term survival in metastatic transitio nal cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:31 73 \200\22381. CHAPTER 7 Urological neoplasia 290 Bladder cancer: urinary diversion after cystectomy The choice of urinary diversion requires consideration of both clinical and quality of life (QoL) issues. Patients planned for cyst ectomy should be in- formed of the possible options. Contraindications to the continent re- constructive procedures include debilitating neurological and psychiatric illness, short l ife expectancy, and impaired renal or liver function. These patients must be motivated and able to perform ISC. Contraindications to orthotopic neobladder include tumor in the prosta tic urethra, wide- spread CIS, and urethral stricture disease. The majority of patients report good overall QoL following urinary diversion. The reconstru ctive procedures were expected to be better for social functioning compared to the ileal co nduit; most QoL studies have not shown signi \201 cant differences, although patients with continent diver- sions generally score more favorably in terms of body image, social activ - ity, and physical function. Ureterosigmoidostomy Dating back to 1821, the oldest form of urinary diversion, whereby the ureters drain into the sigmoid colon, either in its native form or following detubularizat ion and reconstruction into a pouch (Mainz II). This diversion requires no appliance (stoma bag, catheter) so remains popular in devel- oping countries. In recreating a \200\230cloa ca \200\231, the patient may be prone to upper UTI with the risk of long-term renal deterio ration, metabolic hyperchlo- raemic acidosis, and loose frequent stools. The low-pressure a nd capa- cious Mainz II pouch reduces, but does not abolish, these complications. Ileal conduit This was developed during the 1940 \200\231s by Eugene Bricker of St. Louis; it remains the most popular form of urinary diversion in the UK. Fifteen cm of subterminal ileum is isolated on its mesentery and the ureters are anastomosed to the proximal end. The distal end is brought out in the right iliac fossa as a stoma. The native ileum is anastom osed to gain enteral continuity. Complications of ileal conduit are: Prolonged ileus. Urinary leak. Enteral leak. Pyelonephr iris. Uretero-ileal stricture. Stoma problems (20% \200\224skin irritation, stenosis, and p arastomal hernia). Upper tract dilatation (30%). - - - - Patients require stomatherapy support and some \201 nd dif \201 culty in adjust- ing the ir lifestyle to cope with a stoma bag. Metabolic complications are uncommon. In post-RT salvage patients, a jejunal or colonic conduit is used because of concerns about the healing of radiation-damaged ileum. The conduit BLADDER CANCER: URINARY DIVERSION AFTER CYSTECTOMY 291 may be brought out in the upper abdomen and patients require careful electrolyte monitoring due to sodium loss and hyperkalaemia. Continent diversion The advantage is the absence of an external collection device. There ar e two types of continent diversion. - A right hemicolon. The ureters drain into this low-pressure balloon- shaped reservoir, usua lly through an antire \202 ux submucosal tunnel. This is drained by the patient via a cont inent catheterizable stoma, such as the appendix or uterine tube (the Mitrofanoff principle ) brought out in the right iliac fossa. A similarly constructed pouch may be anastomosed to the patient \200\231s urethra to act as an orthotopic neobladder so that natural voiding c an be established and no stoma is necessary. Patients void by relaxing their external sphin cter and performing a Valsalva. This neobladder should require no catheter, unless the pouc h is too large and fails to empty adequately. In this case, the patient must be prepared to perform ISC. continent pouch is fashioned from 60cm of detubularized ileum or Popular ileal pouches include those of Studer (see Fig. 7.4), Camey II, and Kock. Ileocaeca l pouches include the Indiana and Mainz I. Which one is chosen often comes down to the surg eon \200\231s preference; they carry similar complication risks. Previously irradiated bowe l can safely be used to form pouches though complications are more likely. Complications relating to pouches and neobladders are divided into early (12%) and late (37%). They include: - Urinary leakage and peritonitis. - Pelvic abscess. - Stone formation. - Catheterizing dif \201 culties and stomal stenosis. - Urinary incontine nce and nocturnal enuresis (particularly with neobladders). Pouch ureteric re \202 ux and Ureteropouch anastomotic stricture. Late neobladder rupture. - UTI. Metabolic abnormalities include early \202 uid and electrolyte imbalances; later, urinary electrolyte absorption may cause hyperchloraemic acidosis and loss of small bowel may resu lt in vitamin B12 de \201 ciency. Metabolic acidosis is less likely in patients with norma l renal function; treatment is with sodium bicarbonate and potassium citrate. Annual B12 mo nitoring should be undertaken with supplementation if necessary. Adenocarcinoma may develop (5%) in intestinal conduit, neobladder, or sigmoid colon mucosa in the long term due to the carcinogenic bacterial metabolism of urinary nitrosamines. This tends to occur near to the in \202 ow of urine. It is, therefore, advisable to perform an nual visual surveillance of urinary diversions after 10y. If the urethra is in situ, annual urethroscopy and cytology is important. CHAPTER 7 Urological neoplasia 292 (a) (b) (c) (d) Fig. 7.4 (a) The distal 40 \200\22344 cm of resected ileum opened along the antimesenteric border with scissors. Spatulated ureters are anastomosed end to side with 4-0 running sutur e on either side of proximal end of afferent tubular ileal limb. Ureters are stented. (b) T he two medial borders of the U-shaped, opened distal ileal segment are oversewn with a sing le layer seromuscular continous suture. The bottom of the U is folded between the two ends of the U. (c) Before complete closure of the reservoir, a 8 \200\22310 mm hole is cut into the most caudal part of the reservoir (left). Six sutures are placed between the seromuscul ar layer of the anastomotic area of the reservoir and the membraneous urethra (right). An 1 8F urethral catheter is inserted. (d) Before complete closure of the pouch, a cystostomy tu be is inserted and brought out suprapubically adjacent to the wound. (Reproduced with permi ssion from Studer et al. 1996).1 1 Studer UE, Danuser H, Hochreiter W, et al. (1996) Summary of 10 years experience with an ileal low-pressure substitute combined with an afferent tubular isoperistaltic segment. Wor ld J Urol 14:29 \200\22339. This page intentionally left blank CHAPTER 7 Urological neoplasia 294 Prostate cancer: epidemiology and etiology Hormonal and growth factors and diet Growth of p rostate cancer (PC), like benign prostatic epithelium, is largely under the promotional in \202 uence of testosterone and its potent metabolite, DHT. Androgen ablation by orchidecto my results in programmed epithe- lial cell death (apoptosis) and involution of the prostate . PC is not seen in eunuchs or people with congenital de \201 ciency of 5A-reductase. Resp onse to castration therapy in the treatment of patients with PC may be subop- timal if the serum testosterone is not fully suppressed (<50nmol/L). Oestrogens, including phyto-estrogen iso \202 avones (genistein, daidzein) found in foodst uffs used in Asian and Oriental cuisine, have a similar nega- tive growth effect on PC. Thi s may explain why these races rarely develop (or die of) PC. Other possible dietary inhibit ors of PC growth include vita- min D, the antioxidants lycopene (present in cooked or proce ssed toma- toes) and polyphenols (pomegranate, blueberry, green tea, red wine), isothiocyan ates in cruciferous vegetables (sprouts, broccoli), and omega-3 unsaturated fatty acids pre sent, for example, in mackerel and other oily \201 sh. Conversely, arachidonic and linole nic acids and omega-6 polyunsatu- rated fatty acids (present in high-fat red meat) promote PC cell growth in vivo and increases risk of advanced PC in prospective cohort studies. Obe sity does not confer increased risk of PC diagnosis, but appears to be associated with more aggressive disease. Vegan and dairy-free diets are associated with lower circulating IGF-1; this is of interest because high serum IGF-1 levels have been associated with increased risk of developing PC. A pan-European study involving 142 000 men followed up for 8y showed high intake of dairy protein/cal- cium increased risk of PC (see also b p. 298). Other risk factors Age is an important risk factor for development of histological PC, the di- sease being rare below 40 and becoming increasingly common with rising age, according t o post-mortem studies. Prevalence of PC rises from 29% in the \201 ftfh decade to 67% in the ninth decade. This is paralleled 20y earlier by the presence of prostatic intraepitheli al neoplasia (PIN), the accepted premalignant lesion. However, most prostate cancer does no t become clinically recognized or life-threatening. Seventy- \201 ve percent of prostate c ancers are diagnosed in men >65y, the peak incidence is 70 \200\22374y. The in- cidence amo ngst men aged 50 \200\22359 has trebled since the 1970 \200\231s. Geographic variation, the disease is more common in western nations, particularly Scandinav ian countries (where low sunlight and vitamin D syn- thesis may be implicated) and North Am erica. The disease is rare in Asia and the Far East, but US migrants from Asia and Japan ha ve a 20-fold increased risk. This suggests an environmental etiology, such as the west- ern diet, may be important. Ethnicity: black men are at greatest risk, then Caucasians; Asians and Oriental races devel op PC uncommonly unless they migrate to the West. PROSTATE CANCER: EPIDEMIOLOGY AND etiology 295 The world \200\231s highest incidence is among African Americans and Jamaican; there are sc ant data available regarding native African men. A recent British study suggests that Afric an Europeans are at 3 times risk of developing PC compared to white men, although the risk of PC death is similar. Family history: 5% of PC are believed to be inherited. Hereditary PC tends to occur in youn ger (<60y) men who have a family history; genetic abnormalities on chromosomes 1q (HPC1 loc us), 8p (MSR-1 locus), Xp and Y; mutations of the BRCA2 gene on 13q are also reported. The risk of a man developing PC is doubled if there is one affected \201 rst-degree relative and is 4-fold if there are two. Men without sons are at greater risk than those that have f athered sons. Recently there has been an inter- est in a rare recurrent mutation in HOXB13, a homeobox transcrip- tion factor gene that is important in prostate development, located on chromosome 17q. Exercise appears to confer protection against PC. It is known to reduce serum IGF-1, insuli n, leptin, and testosterone while stimulating antioxi- dant protection pathways and immune function, thereby reducing harmful reactive oxygen species. Serum from exercised men on low -fat diet slows growth of LNCaP cells in vitro. Several case control studies have signi \201 - cantly associated exercise with reduced PC risk: in the largest of these, 47 000 men >65y were followed for 14y; 3h/week of vigourous exercise was associated with reduced risk of high-grade, metastatic, and fatal PC. In another study of 190 subjects undergoing biops y, men taking the equiva- lent of 1h of strenuous exercise per week were less likely to be diagnosed with PC, adjusting for PSA and other variables, and >1h of mild/moderate exercise reduced risk of high-grade diagnosis. Some controversy surrounds the possible increased risk of develop- ing PC conferred by sexu al activity, infectious agents, and vasectomy. The balance of data and opinion go against t hese putative risk factors at pres- ent. Exposure to cadmium has been suggested to raise th e risk of PC, but no new data have been upcoming since the 1960 \200\231s. High alcohol int ake appears to be associated with increased risk while smoking does not. However, smoking a ppears to increase the risk of fatal PC. CHAPTER 7 Urological neoplasia 296 Prostate cancer: incidence, prevalence, mortality, and survival Incidence The diagnosis of PC is on the increase, probably as a result of increasing use of serum PSA testing for both symptomatic and asymptomatic men, and the use of more extensive prostatic biopsy protocols . PC is the most commonly diagnosed male cancer (excluding skin) in the UK and USA. In 1999 , 24 714 men were diagnosed with PC in the UK, mean age 72y; by 2008, this had increased to 37 051. The lifetime risk of a man being diagnosed with PC is estimated to be 1 in 9. Risk factors and etiology are discussed on b p. 294. Prevalence While the incidence of PC continues to rise (now approximately 8% of all men), t he true prevalence of the disease is highlighted by post-mortem studies carried out on men who died of unrelated causes. These have demonstrated histological evidence of PC in 10% of men in their third decade, 34% in the \201 fth decade, and rising to 67% in the ninth de cade. It is feared that much of this \200\230latent \200\231 or clinically insigni \201 c ant PC could be detected by PSA screening and treated unnecessarily at the older end of the age spectrum. As the incidence of PC is high and 5y survival rates are around 70 \200\2238 0%, an estimated 215 000 men are alive in the UK who are diagnosed with PC. Mortality It is estimated that 3% of men die of PC. In 2008, 10 168 deaths were at- tribute d to prostate cancer in the UK, the second most common (13% of all) form of male cancer dea th. This compares with 8524 deaths due to co- lorectal cancer and 20 384 due to lung cancer . Because most deaths occur in men over 75y, however, the number of years of life lost per PC death is very low compared to less common cancers. Worldwide, PC claimed 258 000 lives i n 2008, the areas with greatest mortality were southern Africa and northern Europe. Mortality increased slowly in the UK and USA during the 1970 \200\231s and 80s, peaking in 1990 at 3% per year. However, in 1991, mortality started to decrease in the USA by 2% per y ear. In the UK too, there was a small reduction in mortality which stabilized at the turn o f the century. This could have been due to changes in the way death certi \201 cates were writ- ten or treatment, perhaps earlier use of hormone therapy for advanced disease, or inc reased treatment of localized disease carried out in the 1990 \200\231s. Survival Survival rates for PC have been improving for the past 30y. The detection of a gre ater proportion of latent, earlier, slow-growing tumors has had a bene \201 cial effect on survival rates. The relative 5y survival rate for men diagnosed in England in 2001 \200 \2232006 was 77% compared with only 31% for men diagnosed in 1971 \200\22375. The relative 10y survival rate for men INCIDENCE, PREVALENCE, MORTALITY, AND SURVIVAL 297 diagnosed in England in 2001 \200\2232006 was 60% compared with only 21% for men diagnosed in 1971 \200\22375 (Source: Cancer Research UK website: M http://info.cancerresearchuk.org/ cancerstats/types/prostate/). Indeed, it has been suggested that PC patients have an overal l improved life expectancy due to more intensive overall health care received. CHAPTER 7 Urological neoplasia 298 Prostate cancer: prevention The fact that as many as 32% of men in their \201 fth decade have histological PC, even though the disease is rarely detected clinically below the age o f 50y, suggests the opportunity for preventative strategies. Dietary and lifestyle intervention There are growing epidemiological and laboratory data su pporting dietary and lifestyle interventions, though randomized prospective trials are few and mostly small. High fat consumption results in increased production of insulin and IGFs. Diets rich in sat urated fat such as arachidonic, linolenic, and omega-6 fatty acids promotes PC cell growth in vivo and increases the risk of advanced PC in prospective cohort studies. Obese men gene rally have lower PSA, but higher risk for high-grade or extracapsular disease at presentati on, recurrence post-treatment, metastasis, and death. Soy products contain phyto-oestrogens, including the iso \202 avone, genistein. Genistein is a natural inhibitor of tyrosine kinase receptors and inhibits PC cell lines. Chinese Ame ricans have a 24-fold risk of developing PC compared to native Chinese, perhaps due to a di fference in their respective diets. Lycopene, present in cooked tomatoes and tomato products, is consid- ered to reduce risk of PC progression and inhibits cell lines. Selenium supplementation (0.2mg/day = 2 brazil nuts) was shown to reduce the risk of develo ping PC in a melanoma prevention trial. Selenium is a trace element required as an antioxid ant. It is found in relatively low concentration in European soil and can be assayed using toenail clippings. Vitamin E supplementation was shown to reduce the incidence of PC in Fin nish smokers. It is an antioxidant. However, a large prospective ran- domized North America n trial (SELECT) recently showed no risk reduc- tion using either of these agents alone or in combination. Vitamins A (retinoids) and D both inhibit growth of PC cell lines and vitamin D receptor po lymorphisms appear to predispose to certain indi- viduals to PC. Pomegranite juice appears to reduce PSA doubling time during relapse following radical prostatectomy for high-risk disease. Green tea contains polyphenol catechin and antioxidant compounds. A cohort study of >65 000 unscreened Japanese men followed up for 14y observed that the risk of developing PC was re duced proportional to the volume of green tea consumed; a randomized trial of men with PIN suggested less subsequent cancer diagnosed in men randomized to 600mg green tea catechin da ily. A large pan-European (EPIC) study of diet demonstrated consumers of vegetables (including v egetarians) did not exhibit a reduced incidence of PC; conversely, consumers of meat did no t exhibit greater risk of PC diagnosis. The same study did show that consumption of one por tion of cruciferous vegetables per week (e.g. broccoli) reduces the incidence of PC by 40%. Other bene \201 cial dietary ingredients include turmeric and black pepper. PROSTATE CANCER: PREVENTION 299 Studies from UK, Europe, and USA have shown that 25 \200\22340% of PC patients are taking s ome form of complementary therapy, most without informing their doctor. These can occasiona lly be harmful: for example, a \200\230Chinese herb \200\231 mixture called PC-SPES, now w ithdrawn, frequently caused thromboembolism. Smoking has been shown in population studies to be associated not with diagnosis, but with fatal PC. No de \201 nite link exists between vasec- tomy or sexual activity and PC. Studi es have suggested an increased risk associated with early sexual activity and a reduced ris k associated with frequent masturbation, but these require substantiation. Similarly, a pro - tective effect of regular physical exercise on PC has been suggested by laboratory and pr ospective cohort studies. Chemoprevention Antiandrogens Given that most PC is initially an androgen-dependent disease , interest in its prevention has focussed on antiandrogens. While non-steroidal antian- dro gens would have unacceptable side effects, the 5A-reductase inhibitors (5ARI) could be feas ible chemoprevention agents. The Prostate Cancer Prevention Trial recruited 18 000 men who had no clinical or biochemical evidence of PC and PSA <3ng/mL.1 They were randomized to pla cebo or \201 nasteride 5mg daily for up to 7y. The men were offered biopsy if they develo ped a rising PSA, an abnormality on DRE, or at the end of study. PC was detected in 24% and 18% of participants in placebo and \201 nasteride arms, respectively, suggesting that \201 nasteride reduces the risk of devel- oping PC by 25%. However, Gleason 7+ cancers were signi \201 cantly more frequent in the \201 nasteride arm. While this could be due to t he effect of the 5ARI on tissue architecture or a selection artifact due to gland shrink- a ge, there is as yet no license for prescribing 5ARI for PC prevention. The REDUCE study to assess the chemopreventative effects of dutasteride has yielded similar results in a popula tion of men with PSA 3 \200\22310ng/mL and a history of previous negative biopsy.2 Table 7. 13 compares these two studies. Careful interpretation of these data suggest 5ARI do not red uce the risk of clinically signi \201 cant PC developing. Statins Statins are HMG-CoA reductase inhibitors, a commonly prescribed class of medication s that reduce cholesterol levels and prevent cardiovascular events. Statins can induce apop tosis and growth arrest in PC cell lines by suppressing IGF-1 receptor expression; they als o reduce in \202 ammation in PC tissue. In a population-based cohort of men aged 40 \200 \22379y followed for 17y, 38 of 634 statin users (6%) were diagnosed with PC, compared with 186 (10%) of 1813 non-statin users. In other studies, statin use signi \201 cant- ly redu ced risk of elevated PSA, needle biopsy and high-grade PC, and correlated to duration of st atin use. In a cohort study of 7042 treated PC patients followed up for 4y, any statin or N SAID use reduced the risk of all-cause mortality. CHAPTER 7 Urological neoplasia 300 Table 7.13 A comparison of PCPT and REDUCE studies PCPT (2003): \201 nasteride vs placebo REDUCE (2010): dutasteride vs placebo Number; age recruited 18 882; >55y 8231; 50 \200\22375y Patient characteristics Normal DRE; PSA <3ng/mL PSA 2.5/3.0 \200\22310ng/mL; 6 month, 1 previous negative biopsy Duration of study/time of protocol-driven biopsy 7y/7y 4y/2y and 4y Number of cancers (%) 803 (18) vs 1147 (24); p<0.001 659 (20) vs 858 (25); p<0.001 Gleason 7 \200\22310 cancer (% of all cancers detected) at biopsy 280 (37) vs 237 (22); p<0.001 220 (33) vs 233 (27); p=0.81 Gleason 7 \200\22310 cancer, % detected at subsequent RP (correctly predicted at biopsy) 31 (70) vs 19 (50) N/A 1 Thompson IM, Goodman PJ, Tangen CM, et al. (2003) The in \202 uence of \201 nasteride on the de- velopment of prostate cancer. N Engl J Med 349:215 \200\22324. 2 Andriole GL, Bostwick DG, Brawley OW, et al. (2010) Effect of dutasteride on the risk of pros- tate cancer. N Engl J Med 362:1192 \200\223202. This page intentionally left blank CHAPTER 7 Urological neoplasia 302 Prostate cancer: pathology of adenocarcinoma PC was \201 rst described by Venetian anatom ist, Nicolo Massa, in 1536, at a similar time to the \201 rst anatomical drawings of the prostate by Vesalius in Padua. In 1786, John Hunter demonstrated that castrating young male ani- mals prevented the growth of the prostate. In 1817, the \201 rst good descrip- tion of a PC was made in London by George Langstaff in a paper on cases of Fungus Haematodes; 1 853 saw the \201 rst histological description of PC by J Adams. In those times, PC was co nsidered a rare disease due to the shorter life expectancy of the population and poor detec tion methods. By far, the most common (>95%) prostatic malignancy is adenocarci- noma, carcinoma of the a cinar or ductal epithelium. The basal cell layer is absent and the basement membrane is bre ached by the malignant cells which invade into the prostatic \201 bromuscular stroma. Mac roscopically, they tend to be hard and white, though a soft mucin-producing variety exists. The prostatic urethra, ducts, or stroma may be invaded by tran- sitional cell carcinoma of the bladder (see b p. 266 on Bladder cancer pathology and b p. 364 on Urethral cancer). Pr ostatic sarcomas, most common of which is the rhabdomyosarcoma, are rare and mostly seen in childhood. Secondary deposits (metastases) from other sites are rare. Adenocarcinoma of the prostate Most (75%) adenocarcinomas are located in the peripheral zon e and most (85%) are multifocal. The mean number of cancers in a radical prostatec- tomy sp ecimen is 7. Twenty percent arise more anteriorly in the transition zones and 5% in the emb ryologically distinct central zone. The tumor spreads locally through the \202 imsy prost atic capsule (this is absent at the apex and base of the gland) into surrounding tissue, at which time it is termed \200\230locally advanced \200\231. The disease may involve the ur ethral sphincter, corpora of the penis, seminal vesicles, or trigone of the bladder, includ - ing the distal ureters, but rarely invades through Denonvilliers fascia to involve the re ctum. Local spread is often along the course of autonomic nerves, so-called perineural inva sion. The most frequent sites of metastasis are bone and lymph nodes of the obturator fossa e, internal, external and common iliac arteries, and presacral regions. Soft tissue metasta ses in lung, liver, testis, and brain are less common. Bone metastases are characteris- tic ally sclerotic, rarely lytic. The axial skeleton (spine, ribs, and pelvis) are most commonl y affected, followed by the proximal long bones, clavicles, and skull. PC is a complex disease, exhibiting genetic as well as morphological heterogeneity, increas ing with stage and grade. Epigenetic changes such as inactivating hypermethylation of the d etoxifying enzyme, GSTP1 gene, are observed in 90% of PC and 70% of PIN lesions, suggesting this may be an early event in carcinogenesis. Up to 50% of PC carry a rearrange- ment of c hromosome 21, whereby a translocation results in the fusion of an androgen-dependent protea se, TMPRSS2 and the ERG transcrip- tion factor (which then itself becomes androgen-dependen t). It is pos- tulated that this \200\230gene fusion \200\231 rearrangement could be an ea rly step in PROSTATE CANCER: PATHOLOGY OF ADENOCARCINOMA 303 prostate tumourigenesis. Frequent changes include somatic loss of alleles on chromosomes 16 and 18, inactivation of tumor suppressor genes, pTEN (chromosome 10q) and MSR-1 (chromosom e 8p), p53 (chromo- some 17p) and activation of c-myc and bcl-2 protooncogenes. Evidence is also gathering on the potential tumourigenic role of a subset of pros- tatic basal epithel ial cells that are thought to be immortal, undifferentiated stem cells. CHAPTER 7 Urological neoplasia 304 Prostate cancer: grading Adenocarcinoma of the prostate is graded by the Gleason system (Fi g. 7.5), developed in 1966 by Minneapolis pathologist, Dr Donald Gleason. Using low power m icroscopy, adenocarcinoma is graded 1 to 5 according to its gland-forming differentiation. Since most PCs are multifocal and hetero- geneous, allowance is made by adding the two domi nant grades to give a score between 2 and 10. If only one pattern is observed, that grade i s doubled to give the score. This system is used to grade needle biopsies, TURP, and radica l prostatectomy specimens. Gleason scores 2 \200\2236 are considered well differentiated, 7 is moderately differentiat ed, and 8 \200\22310 are poorly differentiated. In practice, 75% of PC is graded 5, 6, or 7 ; less than 5% are graded 2 \200\2234; and 20% are graded 8 \200\22310. Gleason 8 \200\2231 0 PC is usually referred to as high-grade, though sometimes even 7 is considered high-grade because of the presence of pattern 4. Among expert pathologists, there is good interobserv er reproducibility with Gleason scoring. However, scores assigned to needle biopsies are ra rely less than 3 + 3 = 6, since grades 1 and 2 are rarely if ever observed. In 30 \200\2234 0% of cases, needle biopsy scores are lower than those assigned to the subsequent radical p rostatectomy specimen while overgrading by needle biopsy is uncommon (5%). If a minority pa ttern 5 is seen, patholo- gists will mention this as a tertiary grade in their report since it carries a worse prognosis than the same Gleason score without it. The importance of the Gleason score is that it correlates well with prog- nosis, stage for stage, however the patient is managed. Indeed, it remains the most important prognostic ind icator, following radical curative treat- ment. Cancers of the same Gleason score have a wo rse prognosis if the predominant grade is higher (for example, 4 + 3 = 7 is worse than 3 + 4 = 7). Some men with low-grade tumors develop high-grade tumors after several years. This is probably due to clonal expansion of high-grade cells rather than dedifferentiation of tu mor cells. In general, large volume tumors (for example, the \200\230index \200\231 tumor in a multifocal primary PC) are more likely to be of high-grade than smaller tumors, but oc casionally, exceptions are seen. Finally, caution must be taken when Gleason-scoring tissue that has been subject to certain interventions, including RT and androgen depriva- tion therapy. It is recognized that PCs treated with androgen ablation exhibit changes similar to those seen in cancers of Gleason score 8 \200\22310. It is possible that treatment of BPH with 5ARIS could adversely affect the Gleason score of cancer present in the gland. Pathologists are, therefore, keen to know relevant clinical details and are reluctant to provide Gleason scores for such patients. Although cytological features play no part in this grading system, the diagnosis requires a bsence of acinar basal cells, including absence of immunohistochemical staining for basal c ell markers p63 (a homologue of tumor suppressor gene, p53) and cytokeratin 34BE12. In addi tion, posi- tive staining for the A-methylacyl CoA racemase (AMACR or racemase) enzyme, ove rexpressed in PC and PIN, is used routinely by pathologists to help make the diagnosis. PROSTATE CANCER: GRADING 305 Other prognostic indicators As well as Gleason score, tumor stage and PSA level are indepen dent predictors of PC prognosis. Tissue molecular markers, such as overex- pression of PCA3 and p53, have been shown to correlate with adverse outcome following radical prostatectomy . Fig. 7.5 A diagrammatic representation of the Gleason grading system for prostrate cancer. The grade depends on the structure of the prostatic glands and their relationship to the st romal smooth muscle. CHAPTER 7 Urological neoplasia 306 Prostate cancer: staging and imaging Tumor staging is by the TNM classi \201 cation (Table 7.14). As with all can- cer, PC staging may be considered clinical (pre \201 xed with \200\230c \200\231) or patholog- ical (pre \201 xed with \200\230p \200\231). T stage is assessed by DRE (Fig. 7.6), imaging (TRUS, MRI), or exami- nation of radical pro statectomy (RP) specimens. Imaging resolution limits reliability in detection of multifocal and microscopic extraprostatic dis- ease. Only 60% of cancers are visible on TRUS and only 40% of pT3 tumors will be detected. Seminal vesicle biopsy may be carried out in cases con sidered at high risk of seminal vesicle involvement. Higher pathological stage (i.e. pT3 disease) found at radical prostatec- tomy may also be predicted by: - - Higher percentage (>66%) of positive biopsies. Cancer invading adipose in the biopsies (the re is no fat in the prostate). Presence of perineural cancer invasion within the prostate. Using standard MRI, prediction of extraprostatic extension and seminal vesicle involvement has 50 \200\22384% sensitivity and 22 \200\22395% speci \201 city. Recent prostatic biopsy may confuse the interpretation of MRI images, particu- larly the issue of hemorrhage or tu mor in \201 ltration of seminal vesicles. Endorectal MRI appears more accurate for T stagi ng than surface MRI or CT, but patients \201 nd it uncomfortable and it has not gained wi de ac- ceptance. The use of multiparametric MRI (dynamic gadolinium contrast enhancement (D CE-MRI), diffusion weighting, resonance spectroscopy) for high resolution diagnosis and T s taging is currently under evaluation. N stage is assessed by imaging (MRI) or histological examination. Pelvic lymphadenectomy is the gold standard assessment of N stage: this should be bilateral, even in cases where pro state biopsy shows unilateral cancer, since contralateral positive nodes are present in up to one-third of such cases. This has commonly involved obturator lymphadenectomy (OLND) dur ing the performance of RP. Since low-risk patients have <10% risk of metastatic disease, cu rrent EAU guidelines recommend these patients are spared OLND. In contrast, \200\230extend ed \200\231 pelvic lymphadenectomy (EPLND) is becoming standard practice for intermediate- and high-risk disease; a study of high-risk cases undergoing RP has demonstrated that <40% of patients would be correctly staged by OLND. EPLND also includes the external and iliac n odes up to the common iliac bifurcation; even the pre- sacral nodes were positive in 9%. Th ere is ongoing debate regarding the potential therapeutic value of EPLND, with some studies associating it with improved biochemical relapse-free survival (BRFS) and suggesting the n umber of positive nodes removed correlates with cancer-specific sur- vival (CSS), while oth ers have failed to show such bene \201 ts. MRI or CT scanning can image enlarged nodes; radiologists report nodes of >8mm in maximal d iameter. However, nodes larger than this often contain no cancer, while micrometastases may be present in normal- sized nodes. Sensitivity ranges from 0 \200\22370%, with a positive predictive value of only 50%. In practice, MRI pelvic imaging is restricted to intermediate - and high-risk patients (cT3 or PSA >10 or Gleason (cid:116)7). PROSTATE CANCER: STAGING AND IMAGING 307 Table 7.14 UICC (2009) TNM staging of adenocarcinoma of the prostate T0 No tumor (pT0 if no cancer found by histological examination) Tx T stage uncertain T1a Cancer non-palpable or visible by imaging, incidental \201 nding in (cid:100)5% of TURP s pecimen (found in up to 18% of TURPs); T1b Cancer non-palpable or visible by imaging, incidental \201 nding in >5% of TURP specimen T1c Cancer non-palpable or visible by imaging, present in needle biopsy taken because of elevat ed PSA T2a Palpable tumor, feels con \201 ned, in (cid:100) half of one \200\230lobe \200\231 T2b Palpable tumor, feels con \201 ned, in > half of one \200\230lobe \200\231 T2c Palpable tumor, feels con \201 ned, in both \200\230lobes \200\231 T3a Palpable tumor, locally advanced, through prostatic capsule into periprostatic fat, uni- or bilaterally, and mobile T3b Palpable tumor, locally advanced, growing into seminal vesicle(s) T4a Palpable tumor, feels locally advanced, and \201 xed onto adjacent structures or pelvic s ide wall Nx Regional lymph not assessed N0 No regional lymph node metastasis N1 Tumor involves regional (pelvic) lymph nodes (i.e below bifurcation of common iliac arterie s) Mx Distant metastases not assessed M0 No distant metastasis M1a Tumor involves non-regional lymph nodes M1b Tumor metastasis in bone M1c Tumor metastasis in other sites There is interest in 11C-choline PET/CT and lymphotropic nanoparticle- enhanced MRI for imp roving imaging N staging. A nomogram predicting the risk of lymph node invasion at extended pelvic lymphadenectomy is published.1 M stage is assessed by physical examination, imaging (MRI \200\230marrow screen \200\231 o r isotope bone scan, chest radiology) and biochemical investiga- tions (including creatinin e and alkaline phosphatase \200\224elevated in 70% of patients with bone metastases). MRI m arrow is more sensitive than iso- tope bone scintigraphy. In practice, bone imaging is not carried out unless there is biopsy Gleason score (cid:116) 4 + 3 = 7, PSA >20ng/mL or a cli nical indication. In these circumstances, the chance of detecting M+ disease is >5%. PSA >1 00ng/mL predicts metastatic disease in almost 100%. CHAPTER 7 Urological neoplasia 308 T1 Bladder Early (non-palpable) prostate cancer only detectable under the microscope; found at TURP or by needle biopsy Urethra T2 Early (palpable) prostate cancer \200\224still confined to the capsule T3 Locally advanced prostate cancer \200\224into peri prostate fat or seminal vesicles T4 Locally advanced prostate cancer \200\224invading the bladder, rectum, penile urethra, or p elvic side wall Fig. 7.6 The T stages of prostate cancer. PROSTATE CANCER: STAGING AND IMAGING 309 Partin \200\231s nomograms, based on >5000 radical prostatectomies, are widely used to help predict pathological T and N stage by combining clinical T stage, PSA, and biopsy Gleason score (Table 7.15).2 However, it is rec- ognized that N staging is underestimated because l ymphadenectomies were con \201 ned to the obturator fossa. There is no provision in the T staging for suspected local recurrence following RP since th e primary tumor has been removed. A nodule is occasionally palpable by DRE; imaging is usua lly unhelpful and not recom- mended unless there is a clinical indication or PSA is >7ng/mL . 11C-choline PET/CT imaging has been reported to detect local and lymph node recur- rence even when PSA <2.5ng/mL. 1 Briganti A, Larcher A, Abdollah F, et al. (2012) Updated nomogram predicting lymph node i nvasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol 61:480 \200\2237 2 Studer UE, Danuser H, Hochreiter W, et al. (1996) Summary of 10 years experience with an ileal low-pressure substitute combined with an afferent tubular isoperistaltic segment. Wor ld J Urol 14:29 \200\22339.