Editing Prostate Cancer: Diagnosis and evaluation (section)

==== PSA[https://pubmed.ncbi.nlm.nih.gov/12525533/] ====
* '''<span style="color:#ff0000">Serum PSA is the single test with the highest positive predictive value for prostate cancer</span>'''
**'''Although as many as 20-30% of males evaluated for an elevated PSA level may be diagnosed with prostate cancer after TRUS biopsy, as many as 70-80% will not be found to have cancer'''
*'''<span style="color:#ff0000">If newly elevated PSA (no prior PSA or current value inconsistent with previous trend), then repeat the PSA prior to a secondary biomarker, imaging, or biopsy.</span>'''
**'''In people with a newly elevated PSA, it will return to a normal level in 25-40% upon retesting.'''
**'''<span style="color:#ff0000">Half-life: 2-3 days</span>[https://pubmed.ncbi.nlm.nih.gov/9555548/][https://pubmed.ncbi.nlm.nih.gov/8973698/]'''
**'''A repeat PSA in a few months is recommended, though it can be shortened or lengthened depending on other clinical factors.'''

===== Causes of elevated PSA =====
# '''<span style="color:#ff0000">Prostate disease</span> (BPH, prostatitis, prostate cancer, etc.)'''
# '''<span style="color:#ff0000">Prostate manipulation</span> (prostate massage, biopsy, etc.)'''
* '''<span style="color:#ff0000">Prostate Disease</span>'''
**'''<span style="color:#ff0000">Prostate cancer</span>'''
***'''<span style="color:#ff0000">Prostate cancer cells produce less PSA than normal prostatic tissue</span>'''
***'''<span style="color:#ff0000">PSA becomes elevated in prostate cancer due to disruption of cellular architecture within the prostate gland</span>'''
**** '''<span style="color:#ff0000">Prostate cancer lacks basal cells</span>, resulting in the disruption of the basement membrane and normal lumen architecture'''
*** '''<span style="color:#ff0000">PSA levels are inversely correlated with risks of</span>''' 
****'''<span style="color:#ff0000">Pathologically organ-confined (pT2) disease</span>'''
***** '''<span style="color:#ff0000">PSA < 4.0 ng/mL: 80%</span>'''
***** '''<span style="color:#ff0000">PSA 4-10 ng/mL: 66%</span>'''
***** '''<span style="color:#ff0000">PSA > 10.0 ng/mL: <50%</span>'''
**** '''<span style="color:#ff0000">Pelvic lymph node involvement</span>'''
***** '''PSA >20 ng/ml: 20%'''
***** '''PSA >50 ng/mL: 75%'''
*'''<span style="color:#ff0000">Prostate manipulation</span>'''
**'''<span style="color:#ff0000">May influence PSA in a clinically meaningful way[https://pubmed.ncbi.nlm.nih.gov/23659877/]</span>'''
**#'''<span style="color:#ff0000">Urinary tract infections</span>'''
**#'''<span style="color:#ff0000">Instrumentation (e.g., prostate biopsy, cystoscopy, urinary retention, recent bladder catheterization)</span>'''
**##'''<span style="color:#ff0000">Biopsy</span>[https://pubmed.ncbi.nlm.nih.gov/7691013/][https://pubmed.ncbi.nlm.nih.gov/10376076/]'''
**##*'''Results in immediate elevation in the serum PSA level, with a median increase of 6-8 ng/mL'''
**##*'''Usually returns to a stable, baseline level within 2-3 weeks'''
**##'''<span style="color:#ff0000">Cystoscopy</span>[https://pubmed.ncbi.nlm.nih.gov/7691013/][https://pubmed.ncbi.nlm.nih.gov/10376076/]'''
**##*Studies have found that cystoscopy results in small (0.05-0.15 ng/mL) increase in PSA and have suggested that serum PSA determination after either a flexible or a rigid cystoscopy is accurate and reliable
**##'''<span style="color:#ff0000">TURP</span>[https://pubmed.ncbi.nlm.nih.gov/7691013/][https://pubmed.ncbi.nlm.nih.gov/10376076/]'''
**##*'''Results in immediate elevation in the serum PSA level, with a median increase of 6-13 ng/mL[https://pubmed.ncbi.nlm.nih.gov/7691013/]'''
**##*'''Usually returns to a stable, baseline level within 2-3 weeks[https://pubmed.ncbi.nlm.nih.gov/7691013/]'''
**##'''<span style="color:#ff0000">Recent bladder catheterization</span>'''
**##*One study found very little effect on PSA level at day 1 and 3 after catheterization and suggested that routine evaluation PSA in patients with recent catheterization.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393098/]
**'''<span style="color:#ff0000">Unlikely to influence PSA in a clinically meaningful way[https://pubmed.ncbi.nlm.nih.gov/23659877/]'''
**#'''<span style="color:#ff0000">DRE</span>''' 
**#*'''Can lead to slight increases in serum PSA level; however, the resultant change in PSA values falls within the error of the assay and''' '''<span style="color:#ff0000">rarely causes false-positive test results</span>'''
**#'''<span style="color:#ff0000">Bicycle riding</span>'''
**#*With long-distance (> 55km) bicycle rides, PSA levels increasing by ≈10%
**#'''<span style="color:#ff0000">Ejaculation</span>'''
**#*'''Studies examining the effect of ejaculation on serum PSA have reported conflicting results.'''
**#**Most controlled studies evaluating ejaculation suggest it either does not significantly impact or modestly increases (~10%) PSA. 
**#*'''<span style="color:#ff0000">A repeat PSA test after 48 hours of sexual abstinence may be helpful for interpreting serum PSA levels that are minimally elevated or newly elevated.</span>'''
**#'''<span style="color:#ff0000">TRUS</span>[https://pubmed.ncbi.nlm.nih.gov/10376076/]'''
**#*'''Results in small (0.3 ng/mL) increase in PSA'''
**#*'''Serum PSA determination after TRUS without biopsy is accurate and reliable'''
**'''Most of the rise in total PSA after prostate manipulation is contributed by the free (non-bound) component.'''
*** '''In general, complexed PSA is the most stable component and relatively little rise occurs following prostate manipulation.'''

===== Clinical factors that influence PSA =====
* '''<span style="color:#ff0000">In the absence of prostate cancer, PSA levels vary with (4):</span>'''
*# '''<span style="color:#ff0000">Age</span>'''
*# '''<span style="color:#ff0000">Race</span>'''
*#* '''African-American males without prostate cancer have higher PSA values than Caucasians'''
*# '''<span style="color:#ff0000">Prostate volume</span>'''
*#* '''PSA increases 4%/mL prostate volume'''
*#** '''BPH surgery can lead to reductions in the serum PSA level'''
*#** '''Annual rate of change in PSA is higher in men with BPH compared to men without BPH'''
*# '''<span style="color:#ff0000">BMI</span>'''
*#* '''<span style="color:#ff0000">Increasing BMI independently associated with decreasing serum PSA</span>'''

===== PSA-derivatives =====
*'''Concept is to adjust for known factors that can influence PSA (age, volume, race (BMI can also influence PSA)) and improve specificity'''
**'''Patients with prostate cancer may have a “normal” PSA (i.e. false-negative) and patients without prostate cancer may have "elevated" PSA (i.e. false-positive); PSA is neither sensitive nor specific, particularly between 4.0-10.0 ng/dL.'''
======<span style="color:#ff0000">Volume-adjusted PSA</span>======
*'''Concept is to reduce confounding from BPH'''
*'''Includes PSA divided by prostate volume (PSA density, PSAD), complexed PSAD (cPSA divided by prostate volume), and PSA transition zone density (PSA divided by transition zone volume, PSAT)'''
**'''<span style="color:#ff0000">A PSAD of ≥0.15 has been proposed for recommending prostate biopsy in men with PSA levels between 4-10 ng/mL and normal DRE</span>'''
**'''PSAT has been developed to adjust for the transition zone volume, the major determinant of serum PSA in men without prostate cancer'''
*'''Prostate volume typically determined by US''' 
====== <span style="color:#ff0000">Age-/race- adjusted PSA</span>======
*'''Race: African-American men without prostate cancer have higher PSA values than Caucasian men'''
*'''Age: PSA normally increases with age'''
**'''The mature prostate is between 20-25 g and remains relatively constant until ≈age 50, when the gland enlarges in many men; the average prostate volume in a 60-70 year old is ≈48 g'''
======<span style="color:#ff0000">PSA velocity</span>======
*'''Short-term fluctuations in PSA can occur between measurements in the presence or absence of prostate cancer, primarily as a result of physiologic variation. However, the rate of change in PSA (PSAV)—PSA corrected for the elapsed time between measurements is associated with the risk for prostate cancer'''
*'''<span style="color:#ff0000">PSAV > 0.75 ng/mL/year has been shown to be a specific marker for the presence of prostate cancer in men with PSA levels between 4-10 ng/mL</span>'''
*'''There are conflicting studies on whether PSAV provides more information than total PSA in predicting disease aggressiveness'''
======<span style="color:#ff0000">Free-PSA (fPSA)</span>======
* '''<span style="color:#ff0000">%fPSA varies directly with age and volume, and indirectly with total PSA. Does not vary by race.</span>'''
*'''<span style="color:#ff0000">Low %fPSA is associated with increased risk of prostate cancer'''
**'''PSA produced by malignant cells escapes proteolytic processing more frequently, resulting in a <span style="color:#ff0000">greater fraction of serum PSA complexed</span> to α1-antichymotrypson and a lower %fPSA compared to men without cancer'''
**'''<span style="color:#ff00ff">Catalona et al. (1998)</span>'''
***Population:
****Prospective cohort study of 773 men aged 50-75 enrolled primarily through screening centers with PSA 4-10 and palpably benign gland that underwent diagnostic biopsy
*****49% had cancer, 51% had benign disease
*** Primary outcome:
****%fPSA that maintained 95% sensitivity for PC detection
***Results:
****%fPSA was inversely associated with risk of cancer
****AUC 0.72 %fPSA vs. 0.53 total PSA
****%fPSA cut-off:
*****≤25: sensitivity: 95%, specificity 20%
***** ≤22: sensitivity 90%, specificity 29%
****INSERT FIGURE
***Catalona, William J., et al. "Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial." ''Jama'' 279.19 (1998): 1542-1547.
**'''%fPSA as a test is FDA-approved in men with a total PSA 4-10ng/mL and negative DRE'''
***'''%fPSA is most useful in the setting of PSA levels < 10ng/ml because the PPV of tPSA > 10- 20ng/ml has been shown to be ≈80%; it’s utility in PSA <4.0ng/ml is unknown'''
*** '''No %fPSA threshold has been established, proposed cut points generally range from 15-25%'''
***'''Debate remains surrounding the utility of %fPSA as a prognostic biomarker'''
*'''Complexed-PSA (as opposed to the free-PSA)'''
**'''Overall, at a high sensitivity, cPSA provides higher specificity than tPSA and comparable specificity to %fPSA in prostate cancer detection. A potential advantage of cPSA is the requirement for one assay''' 
*'''<span style="color:#ff0000">5ARIs lower total PSA levels by ≈50% after 12 months of treatment</span>'''
** '''With the use of 5ARIs, fPSA decreases in a similar fashion to tPSA, and the %fPSA is not altered significantly'''
**'''Finasteride 1 mg (Propecia) used for male pattern hair loss (androgenic alopecia) results in the same decline in serum PSA levels as the 5-mg dosage used for the treatment of BPH'''
**'''In the PCPT trial, PSA had statistically significantly better sensitivity and AUC for detecting prostate cancer in the finasteride arm[https://www.ncbi.nlm.nih.gov/pubmed/16912265]'''