genitourinary disorders
Prostate Cancer
Diagnosis of Prostate Cancer
Screening by Prostate-specific antigen (PSA) levels (PSA) with or without a digital rectal examination (DRE) Diagnosis by needle biopsy of the prostate (most common) or biopsy of metastatic lesion Grading by histology Staging by CT/MRI and bone scanning, possibly newer modalities such as prostate-specific membrane antigen (PSMA)–based PET-CT or using other PET agents Sometimes stony-hard induration or nodules are palpable during DRE, but the examination is often normal; induration and nodularity suggest cancer but must be differentiated from granulomatous prostatitis, prostate calculi, and other prostate disorders. Extension of induration to the seminal vesicles and lateral fixation of the gland suggest locally advanced prostate cancer. Prostate cancers detected by DRE tend to be large, and>50% extend through the capsule. Diagnosis of prostate cancer requires histologic confirmation, most commonly by transrectal or transperineal ultrasound–guided needle biopsy, which can be done in an office with use of local anesthesia or in an operating room under sedation. Hypoechoic areas on ultrasound are more likely to represent cancer. Occasionally, prostate cancer is diagnosed incidentally in tissue removed during surgery for Benign Prostatic Hyperplasia (BPH) (BPH). Multiparametric MRI can risk-stratify patients for the need for a biopsy and identify suspect areas that should be targeted. It is now commonly used before initial biopsy or in men who are on active surveillance. Most cancers today are found by screening with serum PSA levels (and sometimes DRE). Screening recommendations can vary, but screening is commonly done annually in men>50 years old and is sometimes begun earlier for men at high risk (eg, those with a family history of prostate cancer, Black men). Screening is not usually recommended for men with a life expectancy<10 to 15 years. Abnormal findings are further investigated based on clinician and patient preferences. Multiparametric MRI can detect suspect lesions, and various urine and blood tests may help determine the need for prostate biopsy. It is still not certain whether screening decreases morbidity; decreases in mortality appear likely ( Diagnosis references ), but the number needed to screen is high. It remains unclear if any gains resulting from screening outweigh the decreases in quality of life resulting from treatment of asymptomatic cancers. Screening is recommended by some professional organizations and discouraged by others. A pooled analysis of ERSPC (European Randomized Study of Screening for Prostate Cancer) and PLCO (Prostate, Lung, Colorectal, and Ovarian) trial data suggests that screening in both trials demonstrated a reduction in prostate cancer mortality when controlling for differences in screening intensity despite the high rate of contamination in the control arm of PLCO ( The current USPSTF recommendation is that for men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)–based screening for prostate cancer should be an individual one after discussing the potential benefits and harms of screening with a clinician ( Diagnosis references ). Most patients with newly diagnosed prostate cancers have a normal DRE, and serum PSA measurement is not ideal as a screening test. Although PSA is elevated in 25 to 92% of patients with prostate cancer (depending on tumor volume), it also is moderately elevated in 30 to 50% of patients with A level of≥4 ng/mL (4 micrograms [mcg]/L) is often considered an indication for biopsy in men>50 years old. Although very high levels are significant (suggesting extracapsular extension of the tumor or metastases) and likelihood of cancer increases with increasing PSA levels, there is no cut-off below which there is no risk. In asymptomatic patients, positive predictive value for cancer is 67% for PSA>10 ng/mL (10 mcg/L) and 25% for PSA 4 to 10 ng/mL (4 to 10 mcg/L); recent evidence indicates a 15% prevalence of cancer in men≥55 years old with PSA<4 ng/mL (4 mcg/L) and a 10% incidence with PSA between 0.6 and 1.0 ng/mL (0.6 and 1.0 mcg/L). However, cancer present in men with lower levels tends to be smaller and of lower grade, although high-grade cancer (Gleason score 7 to 10) can be present at any level of PSA; perhaps 15% of cancers manifesting with PSA<4 ng/mL (4 mcg/L) are high grade. Although it appears that a cut-off of 4 ng/mL (4 mcg/L) will miss some potentially serious cancers, the cost and morbidity resulting from the increased number of biopsies necessary to find them are unclear. The decision whether to biopsy may be helped by other PSA-related factors, even in the absence of a family history of prostate cancer. For example, the rate of change in PSA (PSA velocity) should be<0.75 ng/mL/yr (0.75 mcg/L/yr; lower in younger patients). Biopsy is usually recommended for PSA velocities>0.75 ng/mL/yr (0.75 mcg/L/yr). Similarly, PSA density (PSA relative to prostate volume) can help guide need for biopsy; biopsy should be considered if values are≥0.15 (or sometimes≥0.10 ng/mL). Assays that determine the free-to-total PSA ratio and complex PSA are more tumor specific than standard total PSA measurements and may reduce the frequency of biopsies in patients without cancer. Prostate cancer is associated with less free PSA; no standard cut-off has been established, but generally, levels<10 to 20% warrant biopsy. Other isoforms of PSA and new markers for prostate cancer are being studied. None of these other uses of PSA answers all of the concerns about possibly triggering too many biopsies. Many new tests (eg, urinary prostate cancer antigen 3 [PCA-3], Prostate Health Index, 4Kscore, urinary SelectMDX, and others) are available commercially and may be useful in screening decisions. Clinicians should discuss the risks and benefits of PSA testing with patients. Some patients prefer to eradicate cancer at all costs—no matter how low the potential for progression and possible metastasis—and may prefer annual PSA testing. Others may value quality of life highly and can accept some uncertainty; they may prefer less frequent (or no) PSA testing. Men with newly diagnosed prostate cancer should be offered germline testing and genetic counseling if they have intraductal histology, metastatic or high-grade localized prostate cancer, a strong family history of prostate cancer, or a known family history ofBRCA1/2mutations/Lynch syndrome/hereditary breast and ovarian cancer. Grading, based on the resemblance of tumor architecture to normal glandular structure, helps define the aggressiveness of the tumor. Grading takes into account histologic heterogeneity in the tumor. The Gleason score is commonly used. The most prevalent pattern and the next most prevalent pattern are each assigned a grade of 1 to 5, and the two grades are added to produce a total score. Most experts consider a score≤6 to be well differentiated, 7 moderately differentiated, and 8 to 10 poorly differentiated. The lower the score, the less aggressive and invasive the tumor and the better the prognosis. For localized tumors, the Gleason score helps predict the likelihood of capsular penetration, seminal vesicle invasion, and spread to lymph nodes. Gleason grades 1 and 2 have now been eliminated; as a result, the lowest score possible (3 + 3) is 6. However, a Gleason score of 6 does not sound low on a scale previously ranging from 2 to 10. TheGleason Grade Groupis a newer score to help communicate this to patients, and also to simplify pathologic grading. This new scoring system was accepted by the World Health Organization (WHO) in 2016: Grade Group 1 = Gleason score 6 (3+3) Grade Group 2 = Gleason score 7 (3+4) Grade Group 3 = Gleason score 7 (4+3) Grade Group 4 = Gleason score 8 Grade Group 5 = Gleason score 9 and 10 Gleason Grade Group, clinical stage, and PSA level together (using tables or nomograms) predict pathologic stage and prognosis better than any of them alone. 20 ng/mL (20 mcg/L) with any Gleason score. Suspect lymph nodes can be further evaluated by using needle biopsy. An MRI may also help define the local extent of the tumor in patients with locally advanced prostate cancer (stage T3). The role of PSMA (prostate-specific membrane antigen) and fluciclovine F18 PET scanning for staging is evolving, but current guidelines ( Diagnosis references ) now suggest that PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can be effective first-line imaging studies (instead of conventional imaging studies) for intermediate or high-risk patients. Elevated serum acid phosphatase—especially the enzymatic assay—correlates well with the presence of metastases, particularly in lymph nodes. However, this enzyme may also be elevated in benign prostatic hyperplasia (BPH); it may also be slightly elevated after vigorous prostatic massage and in the presence of Multiple Myeloma , Risk of cancer spread can be estimated by tumor stage, Gleason score (Gleason Grade Group), and PSA level: Low risk: Stage≤T2a, Gleason score=6 (Gleason Grade Group 1), and PSA level≤10 ng/mL (10 mcg/L) Intermediate risk: Stage T2b-c, Gleason score=7 (Gleason Grade Group 2-3), or PSA level≥10 (10 mcg/L) and≤20 ng/mL (20 mcg/L) High risk: Stage≥T3, Gleason score≥8 (Gleason Grade Group 4-5), or PSA≥20 ng/mL (20 mcg/L) Both acid phosphatase and PSA levels decrease after treatment and increase with recurrence, but PSA is the most sensitive marker for monitoring cancer progression and response to treatment and has virtually replaced acid phosphatase for this purpose. 1.de Vos II, Meertens A, Hogenhout R, et al: A detailed evaluation of the effect of prostate-specific antigen-based screening on morbidity and mortality of prostate cancer: 21-year follow-up results of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer.Eur Urol84(4):426-434, 2023. doi: 10.1016/j.eururo.2023.03.016 2.European Randomized Study of Screening for Prostate Cancer.Accessed September 10, 2023. 3.Shoag JE, Mittal S, Hu JC: Reevaluating PSA testing rates in the PLCO trial.N Engl J Med374(18):1795-1796, 2016. doi: 10.1056/NEJMc1515131 4.U.S. Preventive Services Task Force: Prostate cancer: Screening. Final recommendation statement. Accessed September 6, 2023. 