Diagnosis of prostate cancer

Transcription

1 Diagnosis of prostate cancer Epidemiology Prostate cancer (PC) is the most common cancer in men and the 2 nd cause of cancer death in the developed world. Incidence with age, reaching 80% at age 80 (at autopsy), but clinical cancer is much lower. Risk factors Age. Hormonal influence. Dietary factors: animal fats the risk; foods rich in vitamins E and D, selenium, zinc, isoflavones, carotenoids, and lycopene (fruit, vegetables, and cereals) the risk. Occupational factors: exposure to cadmium oxide. Genetic factors: if a 1 st degree family member is affected, the risk is doubled; if two 1 st degree family m embers are affected, the risk increases 5 to 11 fold. 9% of patients have a true familial PC, defined as 3 family members affected or 2 diagnosed before the age of 55. Racial factors: twice as common in black men as in whites or Asians. Histology Acinar adenocarcinoma (95%): - Location: 80 85% of prostate cancers (PC) appear in the peripheral zone, 10 15% in the transitional zone, and 5 10% in the central zone. - Gleason score: because PC is a heterogeneous tumor that can be multifocal with different growth patterns in the same sample, and because any given patient s prognosis falls between two predominant patterns, Gleason assigned each tumor a degree for the primary pattern (predominant) and another for the secondary pattern. A tertiary pattern may exist, but it does not enter into the sum of the two predominant degrees, except in prostatic biopsies. Surgical specimen: the degrees of the primary and secondary patterns are added together. For a pattern to be considered secondary, it must occupy at least 5%. Transrectal biopsy: the primary degree is added to the worst pattern, although it oc cupies <5%. The degrees range from 1 (well differentiated) to 5 (anaplastic). The Gleason score or sum of the two degrees (between 2 and 10) has the following prognostic values: 2 4: good prognosis 5 6: intermediate prognosis 7: a sum of 4+3 is closer to the poor prognosis group while 3+4 is closer to the in 8 10: poor prognosis. termediate prognosis group. - High grade prostatic intraepithelial neoplasm (PIN): the only recognized precursor lesion of PC. It is no longer an indication for re biopsy, unless it was extensive in the 1 st biopsy ( risk of association with concomitant PC). - Atypical small acinar proliferation (ASAP): when there are changes without all the defining characteristics of adenocarcinom a or when the number of acinar cells is insufficient for a diagnosis of PC. If ASAP is found, re biopsy is indicat ed (45 60% positive). Variants of adenocarcinoma: ductal or endometrioid, mucinous, glomeruloid, pseudohyperplastic, xanthomatoid, atrophic. Transitional cell carcinoma of prostatic urethra or prostatic ducts: considered to be a urethral tumor and treate d as such. May be multicentric. If identified, the remaining urinary tract must be studied. It is hormone resistant. Others: neuroendocrine carcinoma, small cell carcinoma, signet ring cell carcinoma, sarcomatoid, lymphoepitheliomatoid, cribriform, squamous, rhabdomyosarcoma, metastatic.

2 Pattern of spread Local spread: slow growth. Extends locally through capsule invasion until reaching the periprostatic space, seminal vesicles, or the base of the bladder. Distant spread: lymphadenopathies primarily affect the obturator and hypogastric nodes. Bone metastases are often osteoblastic and appear mostly in the spine, proximal femur, pelvis, ribs, and skull. Visceral metastases are much rarer. Mass screening and early diagnosis Concepts: mass screening involves the search for cancer in asymptomatic patients in a research context whereas opportunistic screening or early diagnosis is the search for cancer in individual cases as initiated by the physician or the patient. In both cases, the aim is to reduce mortality and increase survival (in years) and quality of life. It has not yet been proven that PSA prostate cancer screening leads to mortality. Recommendations: PSA and DRE should be offered to asymptomatic patients between years of age only after emphasizing to the patient that the benefit has not been proven. DRE: to identify indurated nodules or diffuse increases in the consistency of one or more lobes or fixation to neighboring structures. Its sensitivity is between 70 80%, with a specificity of 93.5%. Suspicious DRE findings always call for a biopsy, regardless of PSA value. Prostate specific antigen (PSA): a serine protease produced almost exclusively by prostate epithelial cells. It is organ specific, but not cancer specific. - Cut off values: in general, values up to 4 ng/ml are considered normal while values >10 ng/ml are considered pathological. For PSA between 0 0.5, the cancer risk is 6.6%; for PSA between 0.6 1, the risk is 10.1%; for PSA between 1.1 2, the risk is 17%; for PSA between 2.1 3, the risk is 23.9%; and for PSA between 3.1 4, the risk is 26.9%. In young patients, a PSA >2 3 ng/ml should be considered pathological. However, lowering the cut off values too much leads to detection and overtreatment of clinically insignificant cancers. - Free PSA/total PSA ratio: the most widespread form of increasing the specificity of PSA to distinguish BPH from PC when total PSA is <10 ng/ml. For free/total ratios <0.1, the biopsies are positive in 56% of cases, while for ratios >0.25, only 8% are positive. Biopsies are generally recommended for ratios < PSA velocity (PSAv) and PSA doubling time (PSADT): PSAv measures the annual in PSA in ng/ml while PSADT measures the exponentia l of PSA. Both measurements have prognostic value after PC treatment, but their diagnostic value is limited. - False positives: prostate manipulation (urethral catheter, prostate massage, biopsy) leads to inflammation of the gland and high PSA. It is recommended to wait 20 days after any manipulation or infection to obtain a reliable PSA reading. - False negatives: in localized stages, PSA values may be normal. - After rad ical prostatectomy: the PSA should be <0.04 ng/ml. Progression is defined as 2 consecutive PSA values 0.2 ng/ml after radical prostatectomy. PSA >3 years after surgery, PSADT 11 m, PSAv <0.75 ng/ml/year, Gleason score 6, and a stage pt3a or N0 indicate local recurrence with high probability. PSA <1 year after surgery, PSADT 4 6 m, PSAv >0.75 ng/ml/year, Gleason score 8, and a stage pt3b or N1 indicate distant spread. - After radiation therapy: previously, progression was defined as 3 consecutive PSA increases, but in 2006, ASTRO redefined biochemical progression as a PSA increase 2 ng/ml above the PSAnadir (lowest PSA value reached after radiation therapy). - After hormone therapy: cancer is considered castration resistant when: 3 consecutive increases above the PSAnadir resulting in 2 increases 50% above the nadir, with PSA >2 ng/ml. Testosterone <50 ng/dl. Attempted withdrawal of antiandrogen for at least 4 weeks. PSA progression despite hormonal manipulations.

3 Diagnostic confirmation: prostate biopsy Indications: suspicious DRE, PSA >10 mg/ml, or PSA between 4 10 ng/ml (2 10 ng/ml in young patients) with a free/total PSA ratio <0.2. In elderly men with a large PSA and suspicious DRE, histological confirmation is not required (the result does not change treatment). Patient preparation: - Elimination of antiplatelet drugs or anticoagulation reversal. - Enema 250 ml the night before and another the mo rning of the biopsy. - Prophylaxis with a quinolone oa. Alternatively with Tobramycin or Ceftriaxone im. Generic name Brand name Dose Ciprofloxacin CIPRO tablet 500 mg 1 tablet/12 h 3 5 d Levofloxacin TAVANIC tablet 500 mg 1 tablet/24 h 3 5 d Tobramicina T OBRAMYCIN sol 80 mg/2ml 160 mg im 30 min before Ceftriaxona ROCEFALIN vial 1g/3,5 ml 1 g im 30 min before Procedure: - Local anesthesia: ultrasound guided periprostatic infiltration with 5 ml of 2% Lidocaine in each prostatic seminal angle is better than anesthetic gel. - Transrectal ultrasound: to measure prostate volume, detect hypoechoic lesions (although 36% of PC are isoechoic), detect capsular or seminal vesicle invasion (blurring of the prostatic seminal angles), etc. - Ultrasound guided puncture: the most posterior and lateral areas possible on the periphery of the gland should be punctured cylinders are acceptable (depending on prostatic volume), plus additional samples in suspi cious areas. Sem inal vesicles may be biopsied if PSA is >15 20 ng/ml since a positive result rules out radical treatment. Complications: the most frequent is hematospermia, followed by urethral bleeding or hematuria and rectal bleeding. Sepsis occurs in 1% of cases. Interpretation of the biopsy: the number of positive cylinders from each lobe and their % of involvement are relevant (they are correlated to tumor volume, extraprostatic invasion, and recurrence after radical treatment), as is the Gleason score (degree of the predominant pattern + worst degree); capsular, perineural, or seminal vesicle invasion; and the presence of PIN or ASAP. Re biopsy: indicated if PSA increases, there are changes in the DRE, or if ASAP is detected in the 1 st biopsy. PIN is no longer an indication for re biopsy unless it is very extensive (appears in many cylinders). If after several negative biopsies PC is still suspected, MRI can be performed (for the possibility of anteriorly located PC), followed by MRI or ultrasound directed biopsy of the suspicious area. Staging (TNM classification of the UICC, 2009) Histological types: applies only to adenocarcinomas and squamous cell carcinomas, not to sarcomas or transitional cell carcinomas. TCC of the prostatic urethra or ducts is classified as a urethral tumor (see chapter on Urethral Tumors). Latest TNM updates from 2009 (Fig 1): unlike the 6 th edition of the TNM (2002), microscopic invasion of the bladder neck has been included in T3a instead of T4, and PSA and Gleason scores are taken into account for grouping tumors into stages. Clinical staging: - T category: to determine the local clinical stage, a DRE, PSA, transrectal ultrasound, and biopsy are required. Endorectal MRI is better than DRE and transrectal ultrasound for determining extracapsular invasion and seminal involvement, but the results are difficult to interpret and radiologist dependent. - N & M categories: no need to stage lymph node involvement or distant spread in asymptomatic patients with PSA <20 ng/ml, Gleason <7, and clinical stage T2a. In the rest: Abdomino pelvic CT: assessment of lymph node and liver metastasis.

4 Open or laparoscopic lymphadenectomy: better than CT for assessing lymph node involvement. Should include not only obturator lymph nodes, but all pelvic lymph nodes, although the morbidity is greater. Bone scintigraphy: very sensitive, but not specific. Does not detect osteolytic lesions. Conventional radiology is needed in questionable lesions to distinguish between typi cal blast lesions and less frequent osteolytic lesions. PSA >100 ng/ml predicts with 100% likelihood the presence of bone metastasis. Chest x ray: mandatory due to the possibility of lung metastasis (6%). Pathological staging: requires microscopic examination of the surgical specimen. pt, pn, and pm categories correspond to the clinical categories T, N, and M. Primary tumor Regional Lymph nodes Distant Metas tasis Stage I Stage IIa Stage IIb Tx T0 T1 T1a T1b T1c T2 T2a T2b T2c T3 T3a T3b T4 Nx N0 N1 M0 M1a M1b M1c TNM classification (UICC, 2009) Primary tumor cannot be assessed No evidence of primary tumor Clinically unapparent tumor not palpable or visible by imaging Tumor is an incidental histological finding in 5% or less of resected tissue Tumor is an incidental histological finding in more than 5% of resected tissue Tumor identified by needle biopsy (e.g. because of elevated PSA level) Tumor confined within the prostate Tumor involves one half of one lobe or less Tumor involves more than half of one lobe, but not both lobes Tumor involves both lobes Tumor extends throughout the prostatic capsule Extracapsular extension (unilateral or bilateral) Tumor invades seminal vesicle(s) Tumor is fixed or invades adjacent structures other than seminal vesicles: external sphinter, rectum, levator ani and/or pelvic wall Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis No distant metastasis Non regional lymph node(s) Bone(s) Other site(s) Stages T1a cn0m 0: PSA <10 and Gleason 6 T2aN0M0: PSA <10 and Gleason 6 T1 2aN0M 0: PSA X and Gleason X T1a cn0m 0: PSA and Gleason 6 T1a cn0m0: PSA <20 and Gleason 7 T2a bn0m 0: PSA <20 and Gleason 7 T2bN0M 0: PSA X and Gleason X T2cN0M 0 : any PSA and any Gleason T1 2N0M0: any PSA 20 and any Gle ason T1 2N0M 0 : any PSA and any Gleason 8 Stage III T3a bn0m0: any PSA and any Gleason Stage IV T4N0M 0: any PSA and any Gleason T1 4N1M0: any PSA and any Gleason T1 4N0 1M1: any PSA and any Gleason

5 Fig 1. Estadificación del cáncer de próstata (TNM UICC, 2009).

6 Nomograms and calculators Partin tables (2007): based on PSA, clinical stage, and Gleason score, they predict pathological staging (probability of organ confined cancer, extraprostatic extension, seminal invasion, and lymph node involvement). In clinical practice they help guide treatment decisions. The prediction can be obtained by consulting the tables or entering data on the PSA, clinical stage, and Gleason score into the website: Prostatic nomograms from the Memorial Sloan Kettering Cancer Center (MSKCC): - Pre treatment: to predict the probability of curing the disease after primary PC treatment (radical prostatectomy, brachytherapy, or external RT). - After radical prostatectomy: to predict the probability of biochemical recurrence if radical prostatectomy was the only treatment. - Salvage radiotherapy after radical prostatectomy: to predict the probability that recur rence after radical prostatectomy can be successfully treated with radiotherapy. - Hormone refractory prostate cancer: to predict the probability of survival at 1 and 2 years in patients with advanced metastatic, hormone refractory PC. Calculators elaborated by the Memorial Sloan Kettering Cancer Center (MSKCC): - PSA doubling time (PSADT) and PSA velocity (PSAv) in ng/ml/year: calculation based on various data and PSA values. - Prostate volume and PSA density: calculation based on 3 prostatic diameters and PSA. The prostatic nomograms and calculators of the MSKCC can be found at: ww w.mskcc.org/applications/nomograms/prostate/index.aspx Partin Tables. Clinical Stage T1c (non palpable, PSA elevated) N=4419 PSA range Pathologic Stage Biopsy Gleason Score (ng/ml) =7 4+3= Organ confined (N=226) 93 (91 95) 82 (76 87) 73 (64 80) 77 (65 85) Extraprostatic extension (N=19) 6 (5 8) 14 (10 18) 20 (14 28) 16 (11 24) Seminal vesicle (+) (N=1) 0 (0 1) 2 (0 5) 2 (0 5) 3 (0 8) Lymph node (+) (N=3) 0 (0 1) 2 (0 6) 4 (1 12) 3 (1 12) Organ confined (N=619) 88 (86 90) 72 (67 76) 61 (54 68) 66 (57 74) Extraprostatic extension (N=92) 11 (10 13) 23 (19 27) 33 (27 39) 26 (19 34) Seminal vesicle (+) (N=8) 1 (0 1) 4 (2 7) 5 (2 8) 7 (3 13) Lymph node (+) (N=1) 0 (0 0) 1 (0 1) 1 (0 3) 1 (0 3) Organ confined (N=1266) 83 (81 85) 63 (59 67) 51 (45 56) 55 (46 64) Extraprostatic extension (N=297) 16 (14 17) 30 (26 33) 40 (34 45) 32 (25 40) Seminal vesicle (+) (N=37) 1 (1 1) 6 (4 8) 7 (4 10) 10 (6 15) Lymph node (+) (N=12) 0 (0 0) 2 (1 3) 3 (1 6) 3 (1 6) Organ confined (N=989) 81 (79 83) 59 (54 64) 47 (41 53) 51 (41 59) Extraprostatic extension (N=281) 18 (16 19) 32 (27 36) 42 (36 47) 34 (26 42) Seminal vesicle (+) (N=36) 1 (1 2) 8 (6 11) 8 (5 12) 12 (8 19) Lymph node (+) (N=5) 0 (0 0) 1 (1 3) 3 (1 5) 3 (1 5) >10.0 Organ confined (N=324) 70 (66 74) 42 (37 48) 30 (25 36) 34 (26 42) Extraprostatic extension (N=165) 27 (23 30) 40 (35 45) 48 (40 55) 39 (31 48) Seminal vesicle (+) (N=25) 2 (2 3) 12 (8 16) 11 (7 17) 17 (10 25) Lymph node (+) (N=13) 1 (0 1) 6 (3 9) 10 (5 17) 9 (4 17)

7 Partin Tables. Clinical Stage T2a (palpable <½ of one lobe) N=998 PSA range Pathologic Stage Biopsy Gleason Score (ng/ml) =7 4+3= Organ confined (N=156) 88 (84 90) 70 (63 77) 58 (48 67) 63 (51 74) Extraprostatic extension (N=18) 12 (9 15) 24 (18 30) 32 (24 41) 26 (18 36) Seminal vesicle (+) (N=2) 0 (0 1) 2 (0 6) 3 (0 7) 4 (0 10) Lymph node (+) (N=1) 0 (0 1) 3 (1 9) 7 (1 17) 6 (1 16) Organ confined (N=124) 79 (75 82) 57 (51 63) 45 (38 52) 50 (40 59) Extraprostatic extension (N=49) 20 (17 24) 37 (31 42) 48 (40 55) 40 (30 50) Seminal vesicle (+) (N=5) 1 (0 1) 5 (3 9) 5 (3 10) 8 (4 15) Lymph node (+) (N=0) 0 (0 0) 1 (0 2) 2 (0 5) 2 (0 4) Organ confined (N=171) 71 (67 75) 47 (41 52) 34 (28 41) 39 (31 48) Extraprostatic extension (N=101) 27 (23 31) 44 (39 49) 54 (47 60) 46 (37 54) Seminal vesicle (+) (N=10) 1 (1 2) 7 (4 10) 7 (4 11) 11 (6 17) Lymph node (+) (N=3) 0 (0 1) 2 (1 4) 5 (2 8) 4 (2 9) Organ confined (N=142) 68 (64 72) 43 (38 48) 31 (26 37) 36 (27 44) Extraprostatic extension (N=99) 29 (26 33) 46 (41 51) 56 (49 62) 47 (37 56) Seminal vesicle (+) (N=12) 2 (1 3) 9 (6 13) 9 (5 14) 13 (8 20) Lymph node (+) (N=6) 0 (1 0) 2 (1 4) 4 (2 8) 4 (1 8) >10.0 Organ confined (N=36) 54 (49 60) 28 (23 33) 18 (14 23) 21 (15 28) Extraprostatic extension (N=47) 41 (35 46) 52 (46 59) 57 (48 66) 49 (39 59) Seminal vesicle (+) (N=9) 3 (2 5) 12 (7 18) 11 (6 17) 17 (9 25) Lymph node (+) (N=7) 1 (0 3) 7 (3 14) 13 (6 24) 12 (5 22) Partin Tables. Clinical Stage T2b (palpable > ½ of lobe) or T2c (palpable both lobes) N=313 PSA range Pathologic Stage Biopsy Gleason Score (ng/ml) =7 4+3= Organ confined N=16 84 (78 89) 59 (47 70) 44 (31 58) 49 (32 65) Extraprostatic extension (N=10) 14 (9 19) 24 (16 33) 29 (19 42) 24 (14 36) Seminal vesicle (+) (N=0) 1 (0 3) 6 (0 14) 6 (0 14) 8 (0 21) Lymph node (+) (N=0) 1 (0 3) 10 (2 25) 19 (4 40) 17 (3 42) Organ confined (N=28) 74 (68 80) 47 (39 56) 36 (27 45) 39 (28 50) Extraprostatic extension (N=15) 23 (18 29) 37 (28 45) 46 (36 55) 37 (27 48) Seminal vesicle (+) (N=3) 2 (1 5) 13 (7 21) 13 (7 22) 19 (9 32) Lymph node (+) (N=2) 0 (0 1) 3 (0 7) 5 (0 14) 4 (0 13) Organ confined (N=46) 66 (59 72) 36 (29 43) 25 (19 32) 27 (19 37) Extraprostatic extension (M=40) 30 (24 36) 41 (33 47) 47 (38 55) 38 (28 48) Seminal vesicle (+) (N=7) 4 (2 6) 16 (10 23) 15 (9 23) 22 (13 33) Lymph node (+) (N=4) 1 (0 2) 7 (3 12) 13 (6 21) 11 (4 23) Organ confined (N=53) 62 (55 68) 32 (26 38) 22 (17 29) 24 (17 33) Extraprostatic extension (N=28) 32 (26 38) 41 (33 49) 47 (38 56) 38 (29 48) Seminal vesicle (+) (N=15) 5 (3 8) 20 (13 28) 19 (11 28) 27 (16 39) Lymph node (+) (N=5) 1 (0 2) 6 (3 11) 11 (5 19) 10 (3 20) >10.0 Organ confined (N=8) 46 (39 53) 18 (13 24) 11 (7 15) 12 (7 18) Extraprostatic extension (N=15) 41 (34 50) 40 (31 51) 40 (30 52) 33 (22 46) Seminal vesicle (+) (N=10) 7 (4 12) 23 (15 33) 19 (10 29) 28 (16 42) Lymph node (+) (N=8) 5 (2 8) 18 (9 30) 29 (15 44) 26 (12 44)