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. 3 1 0 Table 7.15 Combination of prostate-speci \201 c antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. (Adapted with permission from Elsevier.1) C H A P T E R 7 Gleason score PSA range (ng/mt) U r o l o g i c a l Pathologic stage 2 \200\2234 5 \200\2236 3+4=7 4+3=7 8 \200\22310 Clinical stage T1c (nonpalpable, PSA elevated) 0 \200\22325 Organ con \201 ned 95 (89 \200\22399) 90 (88 \200\22393) 79 (74 \200\22385) 71 (62 \200\22379) 66 (54 \200\22376) Extraprostatic extension 5(1 \200\22311) 9(7 \200\22312) 17(13 \200\22323) 25 (18 \200\22323) 28 (20 \200\22338) n e o p l a s i a Seminal vesicle (+) \200\223 0 (0 \200\2231) 2 (1 \200\2235) 2 (1 \200\2235) 4(1 \200\22310) Lymph node (+) \200\223 \200\223 1 (0 \200\2232) 1 (0 \200\2234) 1(0 \200\2234) 2.6 \200\2234.0 Organ con \201 ned 92 (82 \200\22398) 84 (81 \200\22386) 68 (62 \200\22374) 58 (48 \200\22367) 52 (41 \200\22363) Extraprostatic extension 8(2 \200\22318) 15 (13 \200\22318) 27 (22 \200\22333) 37 (29 \200\22346) 40 (31 \200\22350) Seminal vesicle (+) \200\223 1 (0 \200\2231) 4(2 \200\2237) 4(1 \200\2237) 6(3 \200\22312) Lymph node (+) \200\223 \200\223 1 (0 \200\2232) 1 (0 \200\2233) 1(0 \200\2234) 4.1 \200\2236.0 Organ con \201 ned 90 (78 \200\22398) 80 (78 \200\22383) 63 (58 \200\22383) 52 (43 \200\22360) 46 (36 \200\22356) Extraprostatic extension 10(2 \200\22322) 19(16 \200\22321) 32 (27 \200\22336) 42 (35 \200\22350) 45 (36 \200\22354) Seminal vesicle (+) \200\223 1 (0 \200\2231) 3 (2 \200\2235) 3 (1 \200\2236) 5 (3 \200\2239) Lymph node (+) \200\223 0 (0 \200\2231) 2 (1 \200\2233) 3 (1 \200\2235) 3 (1 \200\2236) 6.1 \200\22310.0 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 87 (73 \200\22397) 13(3 \200\22327) \200\223 \200\223 80 (61 \200\22395) 20 (5 \200\22339 ) \200\223 \200\223 75 (72 \200\22377) 23 (21 \200\2232 5) 2 (2 \200\2233) 0 (0 \200\2231) 62 (58 \200\22364) 3 3 (30 \200\22336) 4 (3 \200\2235) 2 (1 \200\2233) 54 (49 \200\22359) 36 (32 \200\22340) 8(6 \200\22311) 2 (1 \200\2233) 37 (32 \200\22342) 43 (38 \200\22348) 12(9 \200\22317) 8(5 \200\22311) 43 (35 \200\22351) 47(40 \200\22354) \200\231 8 (4 \200\22312) 2(1 \200\2234) 27 (21 \200 \22334) 51 (44 \200\22359) 11 (6 \200\22317) 10(5 \200\22317) 37 (28 \200\22346) 48 (39 \200\22357) 13 (8 \200\22319) 3 (1 \200\2235) 22 (16 \200\22330) 50 (42 \200\22359) 17(10 \200\22325) 11 (5 \200\22318) >10.0 P R O S T A T E Clinical stage T2a (palpable <1/2 of one lobe) 0 \200\2232.5 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 91 (79 \200\22398) 9 (2 \200\22321) \200\223 \200\223 85 (69 \200\22396) 15 (4 \200\22331 ) \200\223 \200\223 81 (77 \200\22385) 17(13 \200\22321) 1 (0 \200\2232) 0 (0 \200\2231) 71 (66 \200\22375) 27( 23 \200\22331) 2 (1 \200\2233) 0 (0 \200\2231) 64 (56 \200\22371) 29 (23 \200\22336) 5 (1 \200\2239) 2 (0 \200\2235) 50 (43 \200\22357) 41 (35 \200\22348) 7 (3 \200\22312) 2(0 \200\2234) 53 (43 \200\22363) 40 (30 \200\22349) 4 (1 \200\2239) 3 (0 \200\2238) 39 (30 \200\22348) 52 (43 \200\22361) 6 (2 \200\22312) 2 (0 \200\2236) 47 (35 \200\22359) 42 (32 \200\22353) 7(2 \200\22316) 3 (0 \200\2239) 33 (24 \200\22344) 53 (44 \200\22363) 10(4 \200\22318) 3 (0 \200\2238) C A N C E R 2.6 \200\2234.0 : S T A G N G I A N D 4.1 \200\2236.0 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 81 (63 \200\22395) 19(5 \200\22337) \200\223 \200\223 66 (62 \200\22370) 32 (28 \200\22336) 1 (1 \200\2232) 1 (0 \200\2232) 44 (39 \200\22350) 46 (40 \200\22352) 5 (3 \200\2238) 4(2 \200\2237) 33 (25 \200\22341) 56 (48 \200\22364) 5 (2 \200\2238) 6(3 \200\22311) 28 (20 \200\22337) 58 (49 \200\22366) 8(4 \200\22313) 6(2 \200\22312) I M A G N G I (Continued) 3 1 1 3 1 2 C H A P T E R 7 Table 7.15 Combination of prostate-speci \201 c antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. (Continued) Gleason score PSA range (ng/mt) U r o l o g i c a l Pathologic stage 2 \200\2234 5 \200\2236 3+4=7 4+3=7 8 \200\22310 6.1 \200\22310.0 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 76 (56 \200\22394) 24 (6 \200\22344) \200\223 \200\223 65 (43 \200\22389) 35 (11 \200\223 57) \200\223 \200\223 58 (54 \200\22361) 37 (34 \200\22341) 4 (3 \200\2235) 1 (0 \200\2232) 42 (38 \200\22346) 47 (43 \200\22352) 6 (4 \200\2238) 4(3 \200\2237) 35 (30 \200\22340) 49 (43 \200\22354) 13 (9 \200\22318) 3 (2 \200\2236) 20(17 \200\22324) 4 9 (43 \200\22355) 16(11 \200\22322) 14 (9 \200\22321) 25 (19 \200\22332) 58 (51 \200\22366) 11 (6 \200\22317) 5 (2 \200\2238) 14 (10 \200\2238) 5 5 (46 \200\22364) 13 (7 \200\22320) 18 (10 \200\22327) 21 (15 \200\22328) 57 (48 \200\22365) 17(11 \200\22326) 5 (2 \200\22310) 11 (7 \200\22315) 52 (41 \200\22362) 19(12 \200\22329) 17(9 \200\22329) n e o p l a s i a >10.0 Clinical stage T2b (palpable > of one lobe, not both lobes) 0 \200\2232.5 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 88 (73 \200\22397) 12(3 \200\22327) \200\223 \200\223 75 (69 \200\22381) 22(17 \200\22328) 2 (0 \200\2233) 1 (0 \200\2232) 54 (46 \200\22363) 35 (28 \200\22343) 6 (2 \200\22312) 4 (0 \200\22310) 43 (33 \200\22354) 45 (35 \200\22356) 5(1 \200\22311) 6 (0 \200\22314) 37 (26 \200\22349) 46 (35 \200\22358) 9 (2 \200\22320) 6(0 \200\22316) 2.6 \200\2234.0 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 80 (61 \200\22395) 20 (5 \200\22339) \200\223 \200\223 63 (57 \200\22369) 34 (28 \200\22340) 2(1 \200\2234) 1 (0 \200\2232) 41 (33 \200\22348) 47 (40 \200\22355) 9(4 \200\22315) 3 (0 \200\2238) 30 (22 \200\22339) 57 (47 \200\22367) 7 (3 \200\22314) 4(0 \200\22312) 25 (17 \200\22334) 57 (46 \200\22368) 12(5 \200\22322) 5 (0 \200\22314) 4.1 \200\2236.0 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Ex traprostatic extension Seminal vesicle (+) Lymph node (+) 75 (55 \200\22393) 25 (7 \200\22345) \200\223 \200\223 69 (47 \200\22391) 31 (9 \200\2235 3) \200\223 \200\223 57 (35 \200\22386) 43 (14 \200\22365) \200\223 \200\223 57 (52 \200\22363) 39 (33 \200\22344) 2 (1 \200\2233) 2 (1 \200\2233) 49 (43 \200\22354) 44 (39 \200\22349) 5 (3 \200\2238) 2 (1 \200\2233) 33 (28 \200\22338) 52 (46 \200\22356) 8(5 \200\22311) 8 (5 \200\22312) 35 (29 \200\22340) 51 (44 \200\22357) 7(4 \200\22311) 7 (4 \200\22313) 26 (22 \200\22331) 5 2 (46 \200\22358) 16(10 \200\22322) 6 (4 \200\22310) 14 (11 \200\22317) 47 (40 \200\22353) 17(12 \200\22324) 22(15 \200\22330) 25 (18 \200\22332) 60 (50 \200\22368) 5 (3 \200\2239) 10(5 \200\22318) 19(14 \200\22325) 60 (52 \200\22368) 13 (7 \200\22320) 8 (5 \200\22314) 9 (6 \200\22313) 50 (40 \200\22360) 13 (8 \200\22321) 27 (16 \200\22339) 21 (14 \200\22329) 59 (49 \200\22369) 9(4 \200\22316) 10(4 \200\22320) 15 (10 \200\22321) 5 7 (48 \200\22367) 19(11 \200\22329) 8(4 \200\22316) 7 (4 \200\22310) 46 (36 \200\22359) 19 (12 \200\22329) 27 (14 \200\22340) P R O S T A T E 6.1 \200\22310.0 C A N C E R >10.0 : S T A G N G I Clinical stage T2c (palpable on both lobes) 0 \200\2232.5 Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 86 (71 \200\22397) 14 (3 \200\22329) \200\223 \200\223 73 (63 \200\22381) 24(17 \200\22333) 1(0 \200\2234) 1(0 \200\2234) 51 (38 \200\22363) 36 (26 \200\22348) 5 (1 \200\22313) 6 (0 \200\22318) 39 (26 \200\22354) 45 (32 \200\22359) 5 (1 \200\22312) 9 (0 \200\22326) 34 (21 \200\22348) 47 (33 \200\22361) 8(2 \200\22319) 10(0 \200\22327) A N D I M A G N G I (Continued) (Continued) 3 1 3 3 1 4 C H A P T E R 7 Table 7.15 Combination of prostate-speci \201 c antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. (Continued) Gleason score PSA range (ng/mt) 2 \200\2234 5 \200\2236 3+4=7 4+3=7 8 \200\22310 Pathologic stage U r o l o g i c a l 2.6 \200\2234.0 Organ con \201 ned 78 (58 \200\22394) 61 (50 \200\22370) 38 (27 \200\22350) 27(18 \200\22340) 23 (14 \200\22334) Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprosta tic extension Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extensi on Seminal vesicle (+) Lymph node (+) Organ con \201 ned Extraprostatic extension Seminal vesicle (+) Lymph node (+) 22 (6 \200\22342) \200\223 \200\223 73 (52 \200\22393) 27 (7 \200\22348) \200\223 \200 \223 67 (45 \200\22391) 33 (9 \200\22355) \200\223 \200\223 54 (32 \200\22385) 46(15 \200 \22368) \200\223 \200\223 36 (27 \200\22345) 2 (1 \200\2235) 1(0 \200\2234) 55 (44 \200\22364) 40 (32 \200\22350) 2(1 \200\2234) 3(1 \200\2237) 46 (36 \200\22356) 46 (37 \200\22355) 5 (2 \200\2239) 3 (1 \200 \2236) 30 (21 \200\22338) 51 (42 \200\22360) 6 (2 \200\22312) 13 (6 \200\22322) 48 (37 \200\22359) 8 (2 \200\22317) 5 (0 \200\22315) 31 (23 \200\2234) 50 (40 \200\22360) 6 (2 \200\22311) 12(5 \200\22323) 24(17 \200\22332) 52 (42 \200\22361) 13 (6 \200\22323) 10(5 \200\22318) 11(7 \200\22317) 42 (30 \200\22355) 13 (6 \200\22324) 33 (18 \200\22349) 57 (44 \200\22370) 6 (2 \200\22316) 7 (0 \200\22321) 21 (14 \200\22331) 57 (43 \200\22368) 4 (1 \200\22310) 16 (6 \200\22332) 16(10 \200\22324) 58 (46 \200\22369) 11 (4 \200\22321) 1 3 (6 \200\22325) 7(4 \200\22312) 43 (29 \200\22359) 10 (3 \200\22320) 38 (20 \200\22358) 57 (44 \200\22370) 10(3 \200\22322) 8 (0 \200\22322) 18(11 \200\22328) 57 (43 \200\22370) 7 (2 \200\22315) 16(5 \200\22333) 13 (8 \200\22320) 56 (43 \200\22369) 16 (6 \200\22329) 13 ( 5 \200\22326) 6(3 \200\22310) 41 (27 \200\22357) 15 (5 \200\22328) 38 (20 \200\22359) n e o p l a s i a 4.1 \200\2236.0 6.1 \200\22310.0 >10.0 Key PSA = prostate-speci \201 c antigen. PROSTATE CANCER: CLINICAL PRESENTATION 315 Prostate cancer: clinical presentation Since the introduction of serum PSA testing in the l ate 1980 \200\231s, the major- ity of new patients have non-metastatic disease at presentat ion. Shown here are possible presentations, grouped by disease stage. Localized prostate cancer (T1 \200\2232) - Asymptomatic; detected in association with elevated or rising serum PSA or incidental abnor mal DRE. LUTS BOO). Haematospermia. Haematuria (probably in most cases due to coexisting be nign hyperplasia). Perineal or voiding discomfort (probably due to coexisting prostatitis). (in most cases due to coexisting benign hyperplasia causing Locally advanced cancer, non-metastatic (T3 \200\2234 NOMO) - Asymptomatic; detected in association with elevated or rising serum PSA or incidental abnor mal digital rectal examination (DRE). LUTS Haematospermia. Haematuria. Perineal or voiding discomfort. Symptoms of renal failure/anuria due to ureteric obstruction. Malignant priapis m (rare). Rectal obstruction (rare). - - - - - . Metastatic disease (N+, M+) - Asymptomatic ( \200\230occult disease \200\231); detected in association with elevated or r ising serum PSA or incidental abnormal DRE. Swelling of lower limb(s) due to lymphatic obst ruction. Anorexia, weight loss. Bone pain, pathological fracture. Neurological symptoms/sig ns in lower limbs (spinal cord compression). Anemia. Dyspnoea, jaundice, bleeding tendency (coagulopathy). - - - - A note about DRE Since most prostate cancers arise in the peripheral, posterior part of the prostate, they should be palpable on DRE. An abnormal DRE is de \201 ned by asymmetry, a nodule, or a \201 xed craggy mass. Approximately 50% of ab- normal DREs are associated wi th PC, the remainder being caused by be- nign hyperplasia, prostatic calculi, chronic prost atitis, or post-RT change. Only 40% of cancers diagnosed by DRE will be organ-con \201 ned . The fact that an abnormal DRE in the presence of a \200\230normal \200\231 PSA (<4.0ng/m L) carries a 30% chance of predicting PC underlines its important role in clinical practice . CHAPTER 7 Urological neoplasia 316 Prostate cancer: screening Screening is de \201 ned as \200\231The systematic application of a test or inquiry to identify individuals at suf \201 cient risk of a speci \201 c di sorder to warrant fur- ther investigation or direct preventive action, amongst persons who have not sought medical attention on account of symptoms of that disorder \200\231 (UK Nati onal Screening Committee, 2001). The obvious candidate test to be applied to PC screening is PSA. By early detection and tre atment, population screening of men aged 50 to 70 \200\22375y using PSA 9 DRE may reduce th e signi \201 cant mortality and morbidity caused by PC. Proponents of screening say these acceptable and relatively inexpensive evaluations will detect clinically signi \201 cant, but curable (localized) disease. The lead time, estimated at 9 \200\22312y, between the scr eened diagnosis and the clinical diagnosis due to symptoms should enable more organ-con \201 ned cancers to be diagnosed and cured. However, because of the low speci \201 city of PSA (40%) and the high prevalence of latent PC, those against screening argue that many me n would suffer unnecessary anxiety, biopsy, overdiagnosis, and overtreatment. Added to this , the treatments have morbidity and add cost to the already overbur- dened health care syst ems of most developed countries. Mathematical models suggest fewer men screened in their si xth decade would be over- diagnosed compared to those in their seventh or eighth decade; yo unger men have potentially more to gain in terms of life expectancy. From an academic point of view, PC fails to ful \201 l many of the 10 screen- ing criteria set out by Wilson and Jungner, including the possession of a highly sensitive and speci \201 c test and a clear understanding of the disease \200\231s natural history. UK population screening studies have diagnosed PC in 2 \200\2233% of men tested, the vast m ajority diagnosed with localized disease. A large non- randomized study over a 6y period fr om Tyrol, Austria, demonstrated an 80% reduction in the diagnosis of metastatic disease and a 30% reduction in the expected mortality due to PC. The results of pivotal European and North American randomized tri- als were published in 20 09: the European Randomized trial of Screening for Prostate Cancer (ERSPC) and the US PLCO trial.1,2 Cancer-speci \201 c survival (CSS) was the key outcome measure in both trials. W hile the ERSPC, mean follow-up 8y, showed a 20% CSS advantage in the screened group over th e control group, no difference between groups was observed in the PLCO. Even with the CSS a dvantage, ERSPC concluded that the number (of men) needed to treat to save one life (NNT) w as 48 men so highlighting concerns regarding overtreatment. Interestingly, the Swedish subs et of the ERSPC, with 14y mean follow-up, reported a 40% CSS advantage to the screened grou p, the NNT reduced to 12.2 This suggests that the bene \201 ts of screening continue to ac crue in the longer term. Despite this, a 2011 Cochrane meta-analysis of randomized trials c oncluded that there is no CSS advantage to PSA screening. The ERSPC was updated with mean f ollow-up of 11y; adjusting for non-compliance, CSS is reduced by 29% in the screened arm an d the number (of cancers) needed to detect to save one life (NND) had fallen to 33.3 ERSPC also reported a 30% reduction of metastasis in the screened group at 11y follow-up. PROSTATE CANCER: SCREENING 317 A large UK multicentre study, ProTECT, aims to address both the screening question and rand omizes treatment of screen-detected disease. Starting in 2001 and with 260 000 men now recr uited, results are not expected until 2013. Currently, there is little support for a PC scr eening program in the UK; unchanged since 2002, the Department of Health recommends that as ymptomatic men requesting screening should be counseled prior to being offered a PSA test ( see b p. 322). 1 Schr der FH, Hugosson J, Roobol MJ, et al. (2009) Screening and prostate-cancer mortalit y in a randomized European study. N Engl J Med 360:1320 \200\2238. 2 Andriole GL, Grubb RL 3rd, Buys SS, et al. (2009) Mortality results from a randomized pro state- cancer screening trial. N Engl J Med 360:1310 \200\2239. 3 Hugosson J et al. (2010) Mortality results from the G teborg randomized population-based prostate-cancer screening trial. Lancet Oncol 11: 725 \200\223732. 4 Schr der FH, Hugosson J, Roobol MJ, et al. (2012) Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 366:981 \200\22390. CHAPTER 7 Urological neoplasia 318 Prostate cancer: prostate-speci \201 c antigen (PSA) See b p. 43 for an introduction to th e serum PSA test. Until the devel- opment of commercial serum PSA assays in the late 1980s, the only serum marker for PC was acid phosphatase. This was highly speci \201 c for PC me t- astatic to bone, but lacked sensitivity in detecting less advanced disease and was norma l in >20% patients with bone metastases. Prior to the PSA era, most men with newly diagnose d PC had advanced incurable disease. PSA has revolutionized the diagnosis and management of PC, although its use in screening remains controversial. The predictive values of PSA and DRE for diagnosing PC in biopsies are shown in Table 7.16. Two sophisti- cated PC predictor s, which also consider family history, LUTS, race, and previous negative biopsy, are availa ble online at: M http://www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp?t=prost atean dsub=disclaimerandv=prostateandm=andx=Prostate%20Cancer and M http://www.prostatecancer-ris kcalculator.com/via.html Table 7.16 The predictive value of PSA and DRE for TRUS-biopsy diagnosis of prostate cancer PSA (ng/mL) 0.1 \200\2231.0 1.1 \200\2232.5 2.6 \200\2234.0 4 \200\22310 >10 DRE normal 10% 17% 23% 26% >50% DRE abnormal 15% 30% 40% 50% >75% In addition to its use as a serum marker for the diagnosis of PC, PSA elevations may help i n staging, counseling, and monitoring PC patients. PSA is used, along with clinical (DRE) T stage and Gleason score, to predict pathological tumor staging and outcome after radical t reatments using statistically derived nomograms and arti \201 cial neural networks. Here a re some examples: - PSA generally increases with advancing stage and tumor volume, although a small proportion of poorly differentiated tumors fail to express PSA. A single 0.5% risk of metastatic disea se by age 85. Any prompt concern regarding the presence of PC and consideration of biopsy. Over 50% of patients have extraprostatic disease if PSA >10ng/mL. Less than 5% of patients have obturator lymph node metastases and only 1% have bone metastases shown by isotope scin tigraphy if PSA <20ng/mL. Sixty-six percent of patients have lymphatic involvement and 90% have seminal vesicle involvement if PSA >50ng/mL. PSA following radical prostatectomy for g land-con \201 ned disease. PSA (cid:100)1.0ng/mL at age 60 carries 0.2% risk of PC death or PSA rise from its nadir when on 5ARI treatment for BPH should should be undetectable (<0.1ng/mL in many laboratories) PROSTATE CANCER: PROSTATE-SPECIFIC ANTIGEN (PSA) 319 PSA metastatic disease by a mean time of 8y. PSA disease within 4 months of starting androg en ablation therapy; the PSA rises in a mean time of 18 months after starting hormone thera py, signaling progressing disease. rise after radical prostatectomy precedes the development of falls to within the normal range in 80% of patients with metastatic PSA is prostate-speci \201 c, but not prostate cancer-speci \201 c. Other causes of eleva ted serum PSA are shown in Table 7.17, the most common of which is BPH. Table 7.17 Conditions, excluding prostate cancer, which cause elevated PSA Cause of elevated PSA Minor elevation <1.0ng/mL Intermediate elevation 1.0 \200\22320ng/mL Major Elevation 20 \200\223100ng/mL Benign hyperplasia (cid:151) (cid:151) Urinary tract infection (cid:151) (cid:151) Acute prostatitis (cid:151) (cid:151) Chronic prostatitis (cid:151) (cid:151) Retention/catheterization (cid:151) Biopsy, TURP (cid:151) (cid:151) Ejaculation, DRE (cid:151) In the presence of infection or instrumentation, PSA should be requested at least 28 days a fter the event to avoid a false-positive result, which may cause unnecessary anxiety. Ideal ly, PSA should not be requested within 2 days of ejaculation or DRE, but in practice, it ca uses little difference (<1ng/mL) to the result. CHAPTER 7 Urological neoplasia 320 Prostate cancer \200\224PSA derivatives and kinetics: free-to-total, density, velocity, and doubling time Measurement of the free-to-total (F:T) PSA ratio increases the speci \201 c ity of total PSA because the ratio is lower in men with PC than in men with benign hyperpla sia. This may be helpful in deciding whether to rebiopsy a patient with previous benign bio psies. While overall a man with a normal DRE and a PSA of 4 \200\22310ng/mL has a 25% risk of PC (Table 7.15), this risk rises to 60% if the F:T ratio is 10% and falls to 10% if his ratio is >25%. The F:T ratio may also be useful in the total PSA range 2.5 \200\2234ng/mL. Chronic prostatitis may also cause a reduced F:T ratio. An important limitation of this inv estigation is the instability of free PSA. The serum must be assayed within 3h or frozen at \200\22320 C, otherwise the free component reduces and a low ratio will be reported, per haps leading to unnecessary biopsy. Assays measuring the more stable complexed PSA concentration and the \200\230Prostate Heal th Index \200\231 ([phi=[ \200\2232]proPSA/fPSA)x(cid:151)tPSA] Beckmann Coulter combined a ssay) are developed, but their place in clinical practice has not been de \201 ned, despit e studies claiming greater accuracy than total PSA. Consideration may be given to the prostate volume, since large benign prostates are the mos t common cause of mildly elevated PSA. Serum PSA/prostate volume = PSA density. Various cut -off densities have been proposed to raise the speci \201 city of total PSA in the predict ion of PC diagnosis by biopsy, e.g. >0.15. If the diagnosis of PC is made, PSAD >0.19 predi cts pT3 and high-grade disease in 50% of cases. Short-term variations in serum PSA occur, the cause of which may be technical or physiologi cal. Over longer term, the PSA tends to rise slowly (<0.3ng/mL/y) due to BPH, faster due to PC. The rate of rise per year is the PSA velocity. Despite current controversy over its us e in untreated men, a landmark study introduced the concept of PSA velocity in 1992. It dem onstrated 95% of PSA increases >0.75ng/mL/y in PSA range 4 \200\22310ng/ mL (over a minimum of three measurements 6 months apart) were associ- ated with a diagnosis of PC several yea rs later. Only 5% of men without cancer exhibited such a velocity.1 A PSA velocity >20% per year should also prompt the recommendation of a biopsy, although a slower velocity does no t exclude the presence of cancer. It has been suggested that a PSA velocity of >2ng/mL/y in the year prior to radical curative treatment of PC is associated with a poorer cancer outc ome. PSA doubling time (PSADT): is the time it takes for the PSA to double. It is calculated wit h the formula: PSADT = log2 \227 dT/(logB \200\223 logA), A and B are the initial (A) and \201 nal (B) PSA measurements and dT is the time differ- ence between the calendar dates of the two PSA measurements. PSADT may be the best indicator of the likely presence of PC or the rate of dis- ease progression. Several serial measurements reduce confounding physi- ological variability. Not always easy to calculate, PSADT can be obtained online at: M www .pcngcincinnati.org/psa/index.htm. PROSTATE CANCER \200\224PSA DERIVATIVES AND KINETICS 321 PSADT is used to drive clinical management following treatment of PC. Reports from Johns Ho pkins con \201 rm that PSADT correlates with cancer- speci \201 c survival (CSS) followin g RP: 379 patients experiencing BCR where followed up for a median of 10y. Signi \201 cant risk factors included PSADT (cid:100)3 months, GS >7, and time to BCR (cid:100)3y. For exa mple, patients with a PSADT <3 months had a median survival of 6y; this reduced to only 3y if their GS was >7. Conversely, patients with none of these risk factors had a 100% CSS.2 W hen 21% of these patients had died of PC and 6% had died other causes, it was appreciated t hat only 15% of the PC deaths were associated with PSADT (cid:100)3 month while the majorit y (60%) of deaths were associated with PSADT of 3 \200\2239 months. PSADT >15 months had gr eater risk of death from competing causes.3 Other examples of PSADT in clinical practice in clude: <5y raises suspicion of the presence of PC; <3y often drives recommendation to treat a patient on active surveillance; (cid:100)6 months should drive recommendation of hormone therapy following radical treatment. 1 Carter HB, Pearson JD, Metter EF, et al. (1992) Longitudinal evaluation of prostate-speci \201 c antigen levels in men with and without prostate disease. JAMA 267:2215 \200\22320. 2 Freedland S, Humphreys EB, Mangold LA, et al. (2005) Risk of prostate cancer-speci \201 c mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433 \200 \2239. 3 Freedland S, Humphreys EB, Mangold LA, et al. (2007) Death in patients with recurrent pro s- tate cancer after radical prostatectomy: prostate-speci \201 c antigen doubling time su bgroups and their associated contributions to all-cause mortality. J Clin Oncol 25:1765 \200\22371. CHAPTER 7 Urological neoplasia 322 Prostate cancer: counseling before PSA testing Counseling is mandatory before offering a PS A and DRE to asymptomatic men, particularly to highlight the potential disadvantages of hav ing an ab- normal result. These must be weighed up against the potential bene \201 t of ha ving clinically signi \201 cant PC diagnosed at an earlier stage than it would have been w ithout these evaluations. There is currently no clear evidence of bene \201 t by screening for PC (see b p. 316). This forms the basis of the UK Department of Health NHS Prostate Ca ncer Risk Management Program (2002), whereby only men requesting the investigations and who have been appropriately counseled should be tested. Such counsel- ling is less fundamental when investigating a symptomatic patient because the diagnosis of PC could alter his clini cal management. However, all pa- tients should be informed when PSA testing is being consid ered. The following points should be used in counseling asymptomatic men: Cancer will be identi \201 ed in <5% of men screened. The bene \201 ts of PC screening remain controversial. Sen sitivity is 80%: a false-negative result is possible; there is no level of detectable PSA a t which PC can be excluded. Speci \201 city is 40 \200\22350%: a fals-positive result is p ossible; age-related benign hyperplasia and UTI are the most common causes. Prostatic biops y is uncomfortable (despite local anesthetic) and carries a risk of septicaemia or signi \201 cant bleeding, each 0.5%. Prostatic biopsy may miss a cancer. Repeat biopsy may be rec ommended (presence of persisting clinical suspicion or rising PSA). Treatment may not be ne cessary. Treatment may not be curative. Treatment-related morbidity could lead to a diminis hed quality of life. - PIN, ASAP, - This page intentionally left blank CHAPTER 7 Urological neoplasia 324 Prostate cancer: other diagnostic markers Given the limitations of PSA discussed on b pp. 3 18 \200\223321, there is con- siderable ongoing effort to identify better diagnostic marker s in both se- rum and \201 rst-voided urine following a DRE. These are mostly the RNA or protein products of genes commonly over- or underexpressed in PC tissue. Prostate cancer antigen 3 (PCA3) The \201 rst of these, already commercially available, i s the PCA3 test. This gene is overexpressed in 95% of PC, though its function is unclear. R NA transcripts are ampli \201 ed and detected from urine sediment. Speci \201 city for PC diagnosis is improved compared with serum PSA alone (around 70%) in men who have already u ndergone one negative biopsy, though sensitivity of 50 \200\22360% (i.e. at least 40% false -negative results) remains an issue when advising patients whether or not to undergo repeat biopsy re- gardless of PSA changes. Studies exploring potential improved sensitivity by co mbining detection of PCA3 with other molecular markers, e.g. the TMPRSS2-ERG fusion transcr ipt (see b p. 302) are ongoing. Engrailed 2 (EN2) protein EN2 is a transcription factor expressed in PC cell lines and secr eted into the urine by PC in men. First pass urine DRE is collected and EN2 pro- tein measu red by ELISA. A study of 82 men with PC and 102 controls demonstrated the presence of EN2 i n urine was highly predictive of PC, sensitivity of 66% and speci \201 city 88.2%. There w as no correlation with PSA levels. A large multicenter study to further evaluate the diagno stic potential of EN2 is justi \201 ed.1 Microseminoprotein-beta (MSMB) MSMB regulates apoptosis; using genome-wide association stud ies, the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing PC. MSMB expres- sion in benign and malignant prostate tiss ue was examined using immu- nohistochemistry. Urinary MSMB concentrations were determined b y ELISA and correlated with urinary PSA, the presence or absence of PC, rs10993994 genotype , and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with PC. Urinary MSMB was better than urinary PSA at differentiating men with PC at all Gleason grad es.2 Further studies are ongoing. A-methylacyl CoA racemase (AMACR) immunohistochemical overex- pression is 97% sensitive and 100% speci \201 c for PC diagnosis in needle biopsies. It is used routinely by histopatho logists. Efforts are ongoing to develop AMACR assay for testing on body \202 uids. Promotor hypermethylation of reducing enzyme glutathione-S-trans- ferase P1 (GSTP1) is the commonest epigenetic abnormality in PC, inac- tivating its transcription in 90% PCs and 70% of PIN lesions. Methylated GSTP1 DNA is detectable in both urine and serum. PROSTATE CANCER: OTHER DIAGNOSTIC MARKERS 325 Finally, human kallikrein 2 (hK2) is a member of the same protease fam- ily as PSA (which i s also known as hK3), bearing 78% sequence homology. hK2 is expressed almost exclusively by prostatic epithelium, in lesser quan- tity than PSA. It is relatively overexpressed in PIN and higher Gleason score cancers. The ratio of hK2:PSA mRNA in urinary sediments may help to distinguish aggressive or advanced cancers. 1 Morgan R, Boxall A, Bhatt A, et al. (2011) Engrailed-2 (EN2): a tumor speci \201 c urina ry biomarker for the early diagnosis of prostate cancer. Clin Cancer Res 17:1090 \200\2238. 2 Whittaker H. et al. (2010) The rs10993994 Risk Allele for Prostate Cancer Results in Clin ically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine. M http:/ /www. plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013363 M www.plosone.org/art icle/info% 3Adoi%2F10.1371%2Fjournal.pone.0013363. CHAPTER 7 Urological neoplasia 326