Prostate Cancer

At a Glance

Prostate cancer should be considered in any male patient older than 40 years of age with lower urinary tract symptoms (LUTS).

Prostate cancer develops from the prostate, a gland that is part of the male reproductive system, located below the bladder, in front of the rectum, and embracing the urethra. In the early stages, prostate cancer-related symptoms are nonspecific, and this is the main reason the disease remains undiscovered.

In more advanced stages, the cancer may press on the urethra, thus, diminishing urine flow and making urination more difficult. Patients may also experience urine hesitancy, nocturia, urgency, frequency, and a sensation of incomplete bladder emptying. These symptoms are generally defined as LUTS. However, since the LUTS are indistinguishable from those produced by benign prostatic hyperplasia (BPH) and prostatitis, these and other syndromes, especially urinary tract infections, should be included in the differential diagnosis. Pain in the back of the pelvis, spinal cord compression, bone pain, and anemia are also symptoms of advanced metastatic prostate cancer.

Compared with other cancer types, prostate cancer is the most common male cancer in the United States, except for non-melanoma skin cancer, and its incidence is higher in African American men than Caucasian or Hispanic ethnic groups. Age is the strongest risk factor for prostate cancer. This disease is rather rare before 40 years of age, but the chance of having prostate cancer rises rapidly after 50 years of age. Almost two out of three prostate cancers are found in men older than 65 years of age. Furthermore, many epidemiological studies have consistently noted the familial clustering of the disease, and, recently, some results have provided strong evidence that prostate cancer risk increases markedly with many affected relatives. This evidence suggests that, at least in most cases, there is an inherited or genetic factor to prostate cancer.

Although the prostate-specific antigen (PSA) assay is suggested in asymptomatic patients with a familiar history of prostate cancer or with risk factors other than the age, its use in population-based screening programs remains controversial.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A urinalysis should be performed on every patient with LUTS. The absence of nitrite, leukocyte esterase, and white blood cells on urinalysis essentially rules out a urinary tract infection. However, if a urinary tract infection is suspected, urine culture should be performed to characterize the infectious agent. In those patients without urinary tract infections, a digital rectal examination (DRE) and serum PSA assay are indicated.

PSA is a kallikrein-like serine protease produced almost exclusively by the epithelial cells of the prostate. It is measured in sera by means of immunometric assay. Levels greater than 10 ng/mL are highly suggestive of prostate cancer, whereas levels less than 2.5 ng/mL are highly suggestive of the absence of the disease. When serum PSA levels are between 2.5 and 10 ng/mL, the measurement of free PSA and the computation of the derived index free/total PSA, are recommended.

Free/Total PSA (f/tPSA)

The majority (60-90%) of serum immunoreactive PSA is covalently bound to endogenous prostate inhibitors, mainly alpha-1-antichymotrypsin, alpha-1-antitrypsin, and protease C inhibitor. A small fraction of unbound immunoreactive PSA is present in sera, and this fraction is called free PSA (fPSA). The free/total PSA ratio (f/tPSA ratio) is reduced in patients with prostate cancer. A value for this ratio below 10% in cases with tPSA between 2.5 and 10 ng/mL is suggestive of prostate cancer.

Transrectal Ultrasound Guided Biopsy (TRUS)

TRUS is recommended in the following conditions:

  1. if abnormal DRE raises the suspicion of prostate cancer independently from the results of tPSA test

  2. tPSA is greater than or equal to 10 ng/mL

  3. tPSA is less than or equal to 10 and greater than or equal to 2.5 ng/mL and percent f/t PSA is less than or equal to 10%

The other cases should be managed as follows:

  1. tPSA less than or equal to 10 and greater than or equal to 2.5 ng/mL and percent f/t PSA greater than 10% and less than or equal to 25%: strict follow-up (6-12 months) based on DRE and tPSA

  2. tPSA less than or equal to 10 and greater than or equal to 2.5 ng/mL and percent f/t PSA greater than 25%: annual follow-up based on DRE and tPSA

  3. tPSA less than or equal to 2.5 ng/mL: annual follow-up based on DRE and tPSA

Follow-up Patients with Negative (Noncancer) TRUS-guided Biopsy Results

TRUS-guided systematic prostatic biopsies are the standard procedure for prostate cancer detection. Despite that, prostate biopsies are not perfect tests. There is some evidence that, in a low percentage of patients, prostate biopsy misses cancer, especially when the tumor size is very small.

In patients with completely normal histology, two follow-up strategies are alternatively recommended: obtain a second set of biopsies, regardless of the serum PSA results, or obtain a second set of biopsies only if PSA levels continue to increase.

  • In patients with atypical glands suspicious for malignancy (Atypia) extended pattern, repeat biopsy (within 3 months) should be done. If no cancer is found, close follow-up monitoring with serum PSA and DRE is recommended every 6-12 months.

  • In patients with high-grade prostate intraepithelial neoplasia (PIN), immediate repeat biopsy is recommended using saturation biopsy or extended pattern, if initial sextant biopsy was used. However, if an extended strategy was used initially, repeat biopsy is probably not necessary within the first year. If the results of the repeat biopsy are benign, close follow-up with monitoring serum PSA and DRE is recommended every 6-12 months.

Follow-up of Patients with Prostate Cancer after Radical Prostatectomy

Because prostate cancer may recur in a substantial number of patients who receive treatment, close follow-up is recommended in all patients with the addition of adjunct therapy if appropriate.

Follow-up (also called active surveillance) includes watchful waiting and observation.

In patients without metastatic disease, serum PSA should be measured every 6-12 months for 5 years (then every year) together with annual DRE. In patients with metastatic prostate cancer, serum PSA and DRE should be performed every 3-6 months.

After radical prostatectomy, serum PSA is expected to be undetectable within 6 weeks following surgery. If PSA does not fall to undetectable or increases in two or more subsequent determinations, a bone scan or CT/MRI for metastasis is advised.

Follow-up Patients with Prostate Cancer after Radiation Therapy

The serum PSA level falls slowly after radiotherapy. Therefore, the optimal cut-off value for a favorable PSA nadir after radiotherapy is controversial. However, an increase in PSA by more than 23 ng/mL or above the nadir PSA is the standard definition for biochemical failure after radiation therapy.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Factors that Might Increase Serum PSA

Although high serum PSA levels are often observed in men with prostate cancer, PSA is not specific for prostate cancer. Elevation of serum PSA might be correlated with diseases of the prostate other than prostate cancer, particularly benign prostatic hyperplasia, which is the major medical condition that needs distinguished from prostate cancer. Medications, acute and subclinical prostatitis, urinary retention, and urinary tract infections can also cause temporary and occasionally permanent alteration is serum PSA values. Following treatment of these conditions, a waiting period of 4-6 weeks is generally advised before measuring PSA.

Physical manipulation of the male genitourinary tract, such as DRE or prostatic massage, can elevate PSA levels. For example, a two-fold increase in PSA has been reported following vigorous prostatic massage. If possible, PSA testing should be performed prior to the manipulation. If not, due to the relatively long half-life (2-3 days) of PSA in serum, PSA measurements should be taken after an extended period. Needle biopsies of the prostate are associated with large increases in serum PSA levels, which may persist for 1 month or longer; therefore, a waiting period of 4-6 weeks is advised. Some studies have shown significant increases in serum PSA levels following ejaculation. Therefore, it has been suggested that PSA measurement be deferred for at least 48 hours.

Factors that Might Decrease Serum PSA

Finasteride is a 5-alpha-reductase inhibitor used in prostate cancer treatment that decreases dihydrotestosterone production. It has been shown to cause a 50% decrease of total PSA levels in patients treated with this drug for 6-12 months. Also, several herbal supplements, such as Saw Palmetto (Serenoa repens), may contain phytoestrogenic compounds that can affect serum PSA levels. However, very little is known about the exact composition of these herbal supplements and their specific effects on serum PSA levels.

What Lab Results Are Absolutely Confirmatory?

Currently, there are no laboratory tests that absolutely confirm or rule out prostate cancer.

Additional Issues of Clinical Importance

To improve the clinical value of tPSA and f/tPSA in the early detection of prostate cancer, several serum PSA derived indices have been described. They include PSA density, PSA velocity, and age-specific reference ranges.

PSA Density

PSA density requires the measurement of prostate volume by TRUS, and it is calculated by dividing the serum PSA value (ng/mL) with the prostate volume (cm3). The use of PSA density to determine whether a patient requires prostatic biopsy is currently unclear and problematic.

PSA velocity

The rate of change in serum PSA over time (years) is called PSA velocity (PSAV). This parameter was first introduced in 1992, and its use is recommended in those cases with low serum PSA values (less than 2.5 ng/mL or between 2.5 and 4 ng/mL with f/tPSA less than or equal to 10%). A PSA velocity greater than 0.35 ng/mL/year, as well as a 20% increase per year, is suggestive of prostatic cancer and should prompt a prostatic biopsy. When very high PSA velocities are found, prostatitis is more likely than prostate cancer.

PSA velocity must be interpreted with caution. To avoid spurious results due to inter-laboratory variations, an elevated PSA velocity should only be considered significant when repeat assays are performed by the same laboratory.

Age-specific PSA Reference Ranges

Age-specific PSA reference ranges were introduced as a method to increase cancer detection in younger men and to decrease unnecessary biopsies in older men. However, the exact role of age-specific PSA cutoffs in the early detection of prostate cancer remains unclear and continues as a source of debate.

PCA3 Marker

In contrast to the serum markers discussed, the prostate specific mRNA marker, gene PCA3, is measured in urine sediment obtained after urological prostatic massage. Although PCA3 may have potential value for identifying prostate cancer in men with initially negative biopsies, despite an elevated PSA, the determination of PCA3 still remains experimental.

Errors in interpretation of test results for prostate cancer disease

Errors can occur, as for any laboratory test, by wrong procedures and mistakes in all phases (pre-, intra- and post-analytical) of the testing process. The primary mistake a clinician can make is to conclude that prostate cancer is absent if PSA is within the reference range in patients with a life expectancy longer than 10 years. It was found that 19% of patients with prostate cancer had PSA levels less than 4 ng/mL at the time of diagnosis. Equally as important, increased PSA levels should not be interpreted as a sign of cancer if prostatitis, benign hyperplasia, iatrogenic manipulations of the gland, or other causes of its increase in serum are excluded.

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