Prostate Cancer Workup

Updated: May 22, 2020
  • Author: Gerald W Chodak, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Approach Considerations

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Digital rectal examination (DRE) and prostate-specific antigen (PSA) evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, but it has an established role in directing prostatic biopsies.

Needle biopsy of the prostate is indicated for tissue diagnosis in patients whose screening shows elevated PSA levels or abnormal DRE findings. Pathologic evaluation of the biopsy specimen permits calculation of the Gleason score, which is used to help determine prognosis.

Blood studies beyond PSA offer little useful information for men with newly diagnosed early stage prostate cancer. For men with advanced disease, a chemistry profile (including serum creatinine and liver function tests) is warranted. Acid and alkaline phosphatase measurements do not provide helpful information in most cases.

Urinalysis should be performed. If results are abnormal (ie, indicating the presence of hematuria or infection), further workup is warranted before planning cancer therapy.

Computed tomography (CT) scanning is rarely helpful except in men who are at high risk for lymph node metastases or who are going to be treated with radiation. Chest radiography is no longer a routinely advisable staging test for prostate cancer.

 In patients with a family history of high-risk germline mutations (eg, BRCA 1/2, Lynch mutation), a suspicious family history, or intraductal carcinoma on prostate biopsy, National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing, preferably with pre-test genetic counseling. If a genetic mutation is identified, the NCCN recommends post-test genetic counseling. [26]


Prostate Cancer Screening

DRE and PSA evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it has an established role in directing prostatic biopsies.

A systematic review and meta-analysis that included 7 studies with 9,241 patients who underwent both DRE and prostate biopsy found that DRE performed by primary care physicians has poor diagnostic accuracy in screening for prostate cancer. The sensitivity of DRE in that setting was estimated to be 0.51, with a specificity of 0.59 and a positive predictive value of 0.41. [27]

Screening for prostate cancer is a controversial topic. Screening offers the opportunity to find cancers at a more curable stage. However, given the variable natural history of prostate cancer—with some cases progressing aggressively but many being indolent and posing little threat of significant morbidity or mortality—and the absence of a reproducible method for identifying patients in whom the disease will progress rapidly in the absence of therapy, screening inevitably results in some degree of overtreatment.

Many clinicians have argued that early intervention for prostate cancer does not offer a measurable survival advantage. The Prostate Intervention Versus Observation Trial (PIVOT), which randomized men with localized prostate cancer to watchful waiting or radical prostatectomy, found no significant difference in either all-cause or prostate cancer mortality between the two groups through a median 10 years of follow-up. [28]

Longer-term follow-up data from PIVOT (from 12.0 to 19.5 years; median follow-up, 12.7 years) confirmed that compared with observation, surgery does not reduce the risk of death for men with low-risk early-stage prostate cancer. Moreover, surgery was associated with a higher incidence of adverse events necessitating treatment. [29]

A systematic review and meta-analysis of five randomized controlled trials that enrolled 721,718 men concluded that "at best, screening for prostate cancer leads to a small reduction in disease-specific mortality over 10 years but does not affect overall mortality." The authors found moderate-quality evidence that PSA screening probably results in one fewer death from prostate cancer per 1000 men screened (95% confidence index [CI], with an incidence rate ratio of 0.79 (95% Ci, 0.69 to 0.91). [30, 31]  

This study also analyzed complications from biopsies and subsequent treatment. The authors estimated that for every 1000 men screened who undergo biopsy, 94 will experience hematospermia and one will require hospitalization, most likely for sepsis. Comparison of screened with unscreened men showed that for every 1000 men screened who undergo treatment, 3 more men would require pads for urinary incontinence and 25 more men would experience erectile dysfunction. [30]

Screening recommendations

Guidelines on prostate cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • National Comprehensive Cancer Network (NCCN)
  • US Preventive Services Task Force (USPSTF)
  • American Urological Association (AUA)
  • American College of Physicians (ACP)

Although the guidelines vary in their specific recommendations, all emphasize that for an individual patient, whether to screen should be based on a discussion of the risks and benefits of screening, and when to screen depends on the patient's level of risk. 

American Cancer Society guidelines

The ACS recommends that men make an informed decision about whether to be screened for prostate cancer. The decision should be based on a discussion with their health care provider about the uncertainties, risks, and potential benefits of screening; men should not be screened unless they have received that information. [32, 2] Many critics have interpreted this to mean screening should not be done, which is incorrect.

The age at which to initiate discussion of screening depends on the patient's level of risk, as follows [32] :

  • Age 50 years –In men at average risk who have a life expectancy of at least 10 years
  • Age 45 years – In men at high risk (eg, African Americans and men who have had a first-degree relative diagnosed with prostate cancer before age 65)
  • Age 40 years – In men at especially high risk (ie, those with more than one first-degree relatives who had prostate cancer at an early age)

The ACS recommends that men who choose to be screened be tested with PSA measurement. DRE may also be done as a part of screening, but the ACS guideline notes that little evidence exists that the DRE adds significant benefit to the test unless the PSA level is in the borderline range. [32, 2]

The ACS advises that if the PSA level is less than 2.5 ng/mL, retesting may need to be done only every 2 years. Men whose PSA level is 2.5 ng/mL or higher should have annual testing. [32]

National Comprehensive Cancer Network guidelines

The NCCN recommends performing a baseline evaluation, with a history and physical examination that includes the following [33] :

  • Family history
  • Medications
  • History of prostate disease and screening, including prior PSA and/or isoforms, exams, and biopsies
  • Race
  • Family or personal history of BRC1/2 mutations

The clinician should then discuss of the risks and benefits of a baseline PSA test with the patient, and consider a baseline DRE to identify high-risk cancers associated with a seemingly normal PSA. In patients 45-75 years of age, subsequent evaluation is based on the results of those tests, as follows [33] :

  • PSA < 1 ng/mL, DRE normal (if done): Repeat testing at 2–4 year intervals
  • PSA 1-3 ng/mL, DRE normal (if done): Repeat testing at 1–2 year intervals
  • PSA > 3 ng/mL or very suspicous DRE result: Evaluate for biopsy

However, because African-American men and men with germline BRCA1/2 mutations are at greater risk for prostate cancer, the NCCN advises that it is reasonable to consider beginning shared decision-making about PSA screening at age 40 and to consider screening at annual intervals in those popuatlions.

Although very few men above the age of 75 years benefit from PSA testing, screening may be cautiously considered in selected cases of very healthy men with little or no comorbidity. If PSA is measured and is < 4 ng/mL, the DRE is normal (if done), and no other indications for biopsy are present, the NCCN recommends repeat testing in selected patients at 1–4 year intervals. If the PSA is > 4 ng/mL or DRE results are very suspicious, the patient should be evaluated for biopsy.

The NCCN notes that men 60 years of age and older whose serum PSA is less than 1.0 ng/mL have a very low risk of metastasis or death from prostate cancer and may not benefit from further testing. The same is true of men age 75 years with a PSA of less than 3.0 ng/mL.

Evaluation for biopsy includes the following:

  • Repeat PSA
  • Perform DRE, if not done performed during initial risk assessment
  • Workup for benign disease

US Preventive Services Task Force guidelines

Controversially, in 2012 the USPSTF recommended against any routine PSA-based screening of men for prostate cancer, concluding that the harms of screening may outweigh the benefits or that the benefit is either too small or nonexistent. [34, 35]  In an updated recommendation issued in May 2018, the USPSTF advised that in men aged 55 to 69 years, the decision of whether or not to undergo screening should be individualized. This is a grade C recommendation, meaning that there is at least moderate certainty that the net benefit is small. For men aged 70 years and older, the USPSTF recommends against PSA-based screening for prostate cancer. [3]

The USPSTF concluded that currently available data are insufficient to assess whether the benefits of prostate cancer screening are different for African-American men or men with a family history of prostate cancer, or whether starting screening in those high-risk groups before age 55 years offers benefits.

While acknowledging the higher risk of prostate cancer in those groups, the USPSTF also notes the significantly higher risk of major infections after prostate biopsy in black men than white men, and the potential for harm in men with relatives whose prostate cancer was overdiagnosed. The USPSTF suggests that men with a positive family history who are most likely to benefit from screening are those with a first-degree relative who had advanced prostate cancer at diagnosis, who developed metastatic prostate cancer, or who died of prostate cancer. [3]

American Urological Association guidelines

In May 2013, the AUA released new guidelines supporting routine use of the PSA test in healthy men 55 to 69 years of age who are at average risk for prostate cancer and asymptomatic. The AUA recommends that men consult their physician about the risks and benefits before undergoing PSA testing. This recommendation is in direct contrast to the 2012 USPSTF guidelines discussed above. [36]

The AUA guidelines do not recommend testing in the following groups [36] :

  • Men 40 years of age or younger
  • Men 40 to 54 years old who are at average risk
  • Men 70 years of age or older
  • Men with a life expectancy of less than 10 - 15 years

American College of Physicians guidelines

The ACP published guidelines on prostate cancer screening in 2013. [37] The ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer. The ACP advises that the decision to screen for prostate cancer with PSA testing should be based on the patient’s risk for prostate cancer, his general health and life expectancy, his preferences.

The ACP advises against screening for prostate cancer with PSA testing in the following cases:

  • Patients who do not express a clear preference for screening
  • Average-risk men under the age of 50 years
  • Men over the age of 69 years
  • Men with a life expectancy of less than 10-15 years

Screening trials

The results of two large-scale, randomized, controlled PSA screening trials were published in 2009. Although designed to compare screening to no screening, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was actually a trial comparing high-intensity PSA screening to less-intensive screening. This trial found no reduction in mortality with screening after 10 years. [38]

Conversely, the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial found that, over a median follow-up of 9 years, PSA-screening at an average of every 4 years resulted in a 20% reduction in the rate of death from prostate cancer. However, the risk of overdiagnosis was high. [39]

The ERSPC control group differed in terms of interval of screening amongst the 7 countries involved in the trial; 82% of patients underwent screening, although it is unclear how often. The longer screening interval, which might make it harder to show a screening effect, was offset by the lower PSA threshold used in this trial as compared with that of the PLCO Cancer Screening Trial.

The main flaw in this study was in the randomization strategy used by 3 of the 7 countries participating in the trial, whereby men identified from population registries were randomized before giving consent. Also, the screened group was more often treated at major medical centers, which could have affected the results. Nonetheless, this trial was twice as large as the PLCO Cancer Screening Trial, providing it with more power to detect a difference.

A Swedish study found that PSA screening reduced prostate cancer mortality almost by half over 14 years. In the ongoing prospective, randomized Göteborg trial, the risk of death from prostate cancer was 0.90% in the control group, versus 0.50% in the group that underwent PSA screening every 2 years. [40]

However, the risk of overdiagnosis was substantial. Overall, 293 men had to undergo screening and 12 had to be diagnosed and treated to prevent 1 prostate cancer death. (The number needed to treat was at least as high as in breast-cancer screening programs.) [40] Some of these men were part of the European trial and when they were excluded, the ESRPC study did not show a significant benefit.

Part of the reason for the variable results may be that the impact of treatment is unclear. A 2002 Scandinavian study randomized men to watchful waiting or radical prostatectomy and found a small, but statistically significant, reduction in prostate cancer mortality at 14 years. No difference in overall survival was noted, however. [41] The benefit was limited to men under 65 years. This study did not include men primarily diagnosed by screening.

In contrast, in the US PIVOT study (which, as noted above, showed no difference in mortality at 12 years), the patients were mostly from a screened population. The 2002 Scandinavian study and PIVOT did find a reduction in metastatic disease in treated patients. Also, in both studies, a portion of men did not comply with their assigned therapy, which could have affected the results.

Confounding these results is the observation from US data that prostate cancer mortality has decreased 1% per year since 1990, which coincides with the advent of PSA screening. Proponents of screening argue that this proves the benefit of screening. However, other theories have been proposed to account for the decrease, including changes in treatment practices and artifacts in mortality rates secondary to the changing incidence.

IMPACT study

Interim results of the international IMPACT (Identification of Men With a Genetic Predisposition to ProstAte Cancer) study demonstrated increased  prostate cancer risk in men with BRCA2 mutations. IMPACT recruited almost 3000 men from families known to harbor carriers of mutations of the BRCA1 and BRCA2 genes; participants received PSA screening for 3 years, and men whose PSA was greater than 3.0 ng/mL were offered prostate biopsy. The prostate cancer incidence rate per 1000 person-years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; P =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; P =  0.04) and BRCA2 carriers were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; P =  0.01).  The IMPACT authors concluded that systematic PSA screening is indicated for men with a BRCA2 mutation. [42]

IMPACT detected no statistically significant differences in age of onset or cancer characteristics between BRCA1 carriers and noncarriers. The authors consider that further follow-up is required to draw conclusions regarding the clinical management of BRCA1 carriers. [42]


Prostate-Specific Antigen

When PSA testing was first developed, the upper limit of normal for PSA was thought to be 4 ng/mL. However, subsequent studies have shown that no PSA level guarantees the absence of prostate cancer. As the PSA level increases, so does the risk of this disease. When the PSA is 1 ng/mL, cancer can be detected in about 8% of men if a biopsy is performed. With a PSA level of 4-10 ng/mL, the likelihood of finding prostate cancer is about 25%; with a level above 10 ng/mL, the likelihood is much higher. [32]

Although cancer may be present even when the PSA level is less than 1 ng/mL, experts do not recommend a biopsy unless the PSA is higher. Some use 2.5 ng/mL as the cutoff, while others wait until it is 3 ng/mL or greater.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) applied a PSA cutoff value of 3 ng/mL or higher as an indication for lateralized sextant biopsy. [43] For men with an initial PSA value of less than 3 ng/mL, the risk of developing aggressive prostate cancer and death has been found to significantly increase with PSA values in the 2-2.9 ng/mL range, although the overall risk of aggressive prostate cancer–related death remains limited. [44]

A review of data from the Surveillance, Epidemiology, and End Results (SEER) system of men with newly diagnosed prostate cancer from 2004 to 2006 by Shao et al found that most patients with a PSA threshold below 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Shao et al suggested that in the absence of the ability to distinguish indolent from aggressive cancers, lowering the biopsy threshold might increase the risk of overdiagnosis and overtreatment. [45]

A review by Preston and colleagues concluded that PSA levels in midlife correlate with future risk of lethal prostate cancer. The study population consisted of men who had PSA levels measured on enrollment in Physicians' Health Study, when they were 40-59 years old. In men with baseline PSA levels in the >90th percentile, versus those with levels at or below the median, the odds ratios for developing lethal prostate cancer (by age at baseline measurement) were as follows [46] :

  • Age 40-49 years: 8.7
  • Age 50-54 years: 12.6
  • Age 55-59 years: 6.9

A variety of approaches have been proposed for improving the accuracy of PSA for detecting prostate cancer. These include assessment of the velocity of PSA level increase and the percentage of free PSA.

See Prostate-Specific Antigen Testing for a complete discussion of this topic.

PSA velocity

PSA velocity is an important concept. To calculate velocity, at least 3 consecutive measurements on specimens drawn over at least 18-24 months should be used. Guidelines from the NCCN suggest that PSA velocity be considered in the context of the PSA level. [33] The following PSA velocities are suspicious for cancer:

  • PSA velocity of 0.35 ng/mL/y, when the PSA is ≤2.5 ng/mL
  • PSA velocity of 0.75 ng/mL/y, when the PSA is 4–10 ng/mL

However, a study by Vickers et al in 2011 called into question the concept of PSA velocity. In this study, PSA velocity cut points with a comparable specificity to PSA level cut points had a lower sensitivity, particularly for high-grade and clinically significant prostate cancer. The researchers concluded that “PSA velocity added little to the predictive accuracy of high PSA levels or positive DRE and would substantially increase the number of men recommended for a biopsy.” [47] This controversy has not been resolved.

Bound versus free PSA

The measurement of bound and free PSA can help to differentiate mildly elevated PSA levels due to cancer from elevated levels due to benign prostatic hyperplasia. Free PSA is calculated as a percentage of total PSA; the lower the percentage of free PSA, the higher the likelihood of cancer. For example, cancer is found at prostate biopsy in only 8% of men with greater than 25% free PSA, but in more than half of those with less than 10% free PSA.

The percentage of free PSA is generally used as an additional factor in making an informed recommendation for or against biopsy in patients with a PSA level of 4-10 ng/mL. Typically, a free PSA above 25% is considered normal. Some experts recommend biopsy when the free PSA is less than 18%; others advise a cutoff of 12%.

Free PSA percentage is most useful in men with very large glands and in patients in whom 1 biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many experts recommend biopsy without the additional free-PSA test. A common practice is to offer a course of antibiotics and anti-inflammatory drugs for a period of time and to then repeat the test to see if this treatment lowers the PSA level. However, no well-performed studies have established the value of this approach.

Fingerstick PSA testing

The Sangia Total PSA Test (OPKO Diagnostics) uses a fingerstick blood sample to measure PSA and provides results in 10 to 12 minutes, allowing its use at the point of care. In January 2019 the US Food and Drug Administration (FDA) approved the test for use with digital rectal examination (DRE) to screen for prostate cancer in men aged 50 years or older. [48]

In a trial in 434 men (median age 65 years), the test demonstrated a sensitivity of 85.4% and a specificity, 30.3%, at a total PSA cut-off value of 4 ng/mL. When combined with DRE, the test's sensitivity increased to 91% and the positive predicted value increased to approximately 70%.. Additionally, the test had a 95% correlation with an FDA-approved, laboratory-based PSA test. [48]  False negatives occur in about 36% of men who have a Gleason score of 6 or less and 18% of those with a Gleason score of 7 or higher. [48]

The test may have particular potential for use as part of active surveillance in patients with low-risk prostate cancer.  A possible risk, as with all PSA tests for prostate cancer screening, is that clinicians might fail to provide a discussion of the risks and benefits of PSA testing before performing the test. [48]




Prostate Biopsy

Needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated PSA levels or abnormal DRE findings. Transrectal ultrasonography (TRUS) is used to guide the biopsy, although MRI is being studied as an alternative. TRUS also permits measurement of the volume of the prostate. Hypoechoic areas on TRUS are commonly associated with cancers, but this finding is not specific enough for diagnostic purposes.

Ahmed et al reported that multi-parametric MRI (MP-MRI) may help men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. In their study of 576 men with suspected prostate cancer, MP-MRI had greater sensitivity than TRUS-biopsy for detecting clinically significant cancers (93% vs 48%) but lower specificity (41% vs 96%). If follow-up biopsy were performed only in men with suspicious MP-MRI scores, then 27% would potentially avoid primary biopsy. [49]

See Transrectal Ultrasonography of the Prostate for a discussion of TRUS and prostate biopsy, as well as Imaging in Prostate Carcinoma and Techniques of Local Anesthesia for Prostate Procedures and Biopsies.

The number of biopsy samples that should be taken is debated. The former standard consisted of 6 samples taken in a sextant pattern. In extended-pattern biopsies, the sextant samples are supplemented with 2 lateral samples from each lobe for a 10-biopsy scheme, or 6 lateral peripheral zone samples for a 12-biopsy scheme; 18-core biopsy protocols are also used, especially for larger glands.

In addition, samples may be taken from palpable nodules or ultrasonographically suspicious areas. Color Doppler TRUS is being used to help identify suspicious areas. [50]

In patients with a persistently elevated PSA level in the face of negative biopsy results, the literature supports repeating the biopsy once or twice. Repeat biopsies may also include cores from the transition zone, which is not usually the case in initial biopsies.

In a retrospective study of 178 patients with elevated PSA levels, negative results on previous random biopsies, and positive results on multiparametric MRI, Cornelis et al found that the injection of sulfur hexafluoride microbubbles as an ultrasonographic contrast medium improved the prostate cancer detection rate. Transrectal biopsies guided by contrast-enhanced ultrasonography had a positive overall detection rate of 30.9%, compared with 6.9% for 12-core nontargeted biopsies. [51]

Saturation biopsies, in which more than 20 cores are taken under general or spinal anesthesia, are sometimes used in men who are at high risk and have had multiple negative biopsies. No studies have proved that saturation biopsies offer important advantages and they do pose a higher risk of bleeding, infection, and urinary retention. Also, the number of tissue samples obtained is a two-edged sword; more samples increase the chance of finding cancer but also increase the chance of finding non–life-threatening disease.

Patients should receive prophylactic antibiotics at least 20 minutes before prostate biopsy, to reduce the risk of infection. No studies have proved, however, that more than 1 or 2 doses of antibiotic offer advantages over longer-term use following biopsy. Serious infections with resistant organisms are increasing.

Patient comfort is greatly improved by injecting a local anesthetic into the nerves near the seminal vesicles, under ultrasonographic guidance. An enema is usually given prior to the biopsy.

The National Comprehensive Cancer Network (NCCN) has established guidelines for follow-up of patients who have benign biopsy results but other indications of high risk for prostate cancer (eg, positive DRE or elevated PSA). [33] However, these recommendations are not based on level I studies, so their reliability is uncertain.

Epigenetic changes induced by DNA methylation may serve as field-effect biomarkers for the presence of neighboring prostate cancer in tissue samples, and thereby help differentiate true-negative from false-negative biopsies. In the Methylation Analysis to Locate Occult Cancer (MATLOC) study, an assay that measures methylation of the genes GSTP1, APC, and RASSF1 correctly confirmed negative biopsies in approximately 64% of men without prostate cancer and identified occult cancer in 68% of patients who had initial false-negative biopsies. [52]


The National Cancer Institute (NCI) has observed that prostatic biopsies can have complications, including fever, pain, hematospermia, hematuria, positive urine cultures, and (rarely) sepsis. Also, the screening process itself can lead to adverse psychological effects in men who have a prostate biopsy but do not have identified prostate cancer. [53]

These risks are multiplied because a significant percentage of men will have more than 1 biopsy before cancer is detected or they are considered free of the disease. In a cohort study of asymptomatic men who underwent transrectal ultrasonography–guided biopsy because of elevated PSA levels, Rosario et al found that although prostate biopsy was well tolerated by most men, a minority experienced significant symptoms—most often pain, but also infection and bleeding—which were associated with the development of a negative attitude toward repeat biopsies. [54]

Transperineal prostate biopsy

Although transrectal prostate biopsy has been the standard technique, transperineal biopsy is increasingly used. In the United Kingdom, the National Health Service is supporting an innovation program to completely replace transrectal with transperineal biopsy. Elsewhere in Europe, multiple medical centers have switched over, and some centers in the United States are adopting the approach. [55]

In the past, transperineal biopsies have required general or spinal anesthesia to allow patients to tolerate multiple needle passes through the perineal tissue. However, a new tool, the PrecisionPoint Transperineal Access System (Perineologic), reduces the number of needle passes, allowing transperineal biopsy to be performed with local anesthesia. The tool can be used with or without MRI fusion technology. It was approved by the US Food and Drug Administration in 2016. For routine clinical use, transperineal biopsies could be performed as an office procedure, with no need for prophylactic antibiotics. [55]

In a UK feasibility study of a transperineal-only biopsy strategy in 678 consecutive men with suspected or actual prostate cancer, which used the PrecisionPoint Transperineal Access System, complication rates were low:sepsis requiring hospital admission and intravenous antibiotics, urinary tract infection, and hematuria with clot retention each occurred in a single patient (0.16%).  Four patients (0.5%) had urinary retention, but none required surgery. No complications were classified as Clavien 3 or higher. Local anesthesia was used for the biopsy in 58% of patients; of those, 42%) underwent the procedure in the outpatient clinic.


Histologic Findings

Although the change in glandular architecture represented by the Gleason score is currently the most widely used histologic parameter, it is not the only histologic change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology, DNA ploidy, neuroendocrine differentiation, and vascularity can be observed and may have prognostic significance.

There is a continuum from normal prostatic epithelium to invasive carcinoma. Precursor lesions to carcinoma may include prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP). (See the images below.)

Micrograph of high-grade prostatic intraepithelial Micrograph of high-grade prostatic intraepithelial neoplasia
Prostate cancer. Adenocarcinoma around a small ner Prostate cancer. Adenocarcinoma around a small nerve (center). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Small focus of adenocarcinoma on Prostate cancer. Small focus of adenocarcinoma on needle biopsy on right side of slide (normal glands on left side). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Immunohistochemical stains showin Prostate cancer. Immunohistochemical stains showing normal basal cells (brown) in a benign gland with no basal cells in malignant glands (on right side with no brown staining). Malignant glands show increased expression of racemase (red cytoplasmic stain). Courtesy of Thomas M. Wheeler, MD.

The architecture of the gland remains normal but the epithelial layers become multi-layered and crowded. At a cellular level, the nucleus becomes large and nucleoli are visible. The term PIN is becoming less used in favor of atypical small acinar proliferation (ASAP), which is proliferation of usually small acini with features suggestive of but not diagnostic of cancer.

Clinical studies suggested that PIN predates a carcinoma by 10 or more years. This concept is less accepted in the modern era. PIN as a precursor of cancer has been replaced by ASAP. The identification of ASAP in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma, with up to 30% having cancer identified on subsequent biopsy specimens. Repeat biopsies are recommended in such cases within 1-2 months.

See Precancerous Lesions of the Prostate for a complete discussion of this topic.


Selection Criteria for Imaging Studies

Imaging studies can be a valuable part of pretreatment staging of prostate cancer, helping to differentiate clinically localized disease (ie, stage T1 or T2), which is generally amenable to local therapy, from more advanced disease that may require multimodal therapy. The currently accepted staging system allows for inclusion of these studies in the assessment of disease, although the medical literature suggests that no single study can be used to reproducibly detect non–organ-confined disease.

Defining the best candidates for radiologic assessment depends on a clear understanding of the accuracy of the proposed study and on the expected prevalence of the anticipated finding in the population at risk. Understanding the relative prevalence of the suspected abnormality (eg, non–organ-confined disease, regional nodal involvement) is important in the decision algorithm.

Retrospective surgical data (eg, from Partin and colleagues) suggest that patients who present with early stage disease (T2a or lower), those with PSA values of less than 10, and those with a Gleason score of 6 or less are at low risk for non–organ-confined disease. [56] The presence of PSA levels of greater than 10 ng/mL, high-grade histology (Gleason score ≥7), or physical findings that suggest stage T3 disease may warrant some imaging studies for staging.

Comparisons of the accuracy of each imaging modality fail to provide a uniform consensus regarding the optimum study. For T staging, MRI is more accurate than CT scanning. Unfortunately, a significantly high inaccuracy rate limits the value of both of these tests. For example, if the test suggests extracapsular disease but the false-positive rate is about 30%, many men may be incorrectly advised to avoid prostatectomy.

MRI and CT scanning have equivalent accuracy for N staging. Neither is worthwhile unless the risk of nodal metastases is at least 15% or higher.

For M staging, bone scintigraphy with technetium-99m (99m Tc) is typically used. It is rarely indicated unless the PSA is above 10 or 20 ng/mL, however, because the likelihood of finding metastases is otherwise very low. Obtaining a baseline bone scan for aid in evaluating future tests makes little sense. See Imaging in Prostate Carcinoma for more information.

Ongoing work with 11C-choline positron-emission tomography (PET) scans may lead to its use in the future. In a study of 31 patients undergoing restaging of prostate cancer, an 11C-choline dual positron PET/MR protocol detected significantly more recurrences (12 patients), particularly small local recurrences, than dual imaging with PET and computed tomography (PET/CT) scanning (8 patients). [57]

The radiation dose delivered by PET/MR was about 80% lower and the imaging time was longer (41 min) than that delivered by PET/CT (23 min), and it was well tolerated by patients. However, the investigators cautioned that further research on the clinical impact of PET/MR is needed. [57]

The American College of Radiology (ACR) has developed guidelines for the selection of imaging studies for pretreatment staging. [58] These guidelines rate the appropriateness of particular imaging modalities on the basis of such findings as T stage, Gleason score, PSA level, and percentage of positive biopsy cores.

ProstaScint scan

ProstaScint scans are a form of immunoscintigraphy that involves a murine monoclonal antibody that reacts with prostate-specific membrane antigen to identify cancer in the prostate and in metastatic deposits. ProstaScint scans frequently yield false-negative results, but the specificity of the study may be improved when combined with single-photon emission CT (SPECT) imaging or CT scanning. [59]

The ACR suggests that routine use of ProstaScint scanning as an initial staging procedure is not currently justified. Some evidence supports its use in patients with postoperative treatment failure, especially to guide decisions regarding radiation therapy, [58] but no long-term studies have demonstrated the therapeutic benefits of administering salvage radiation based on ProstaScint scan results.


Investigational Studies

Certain molecular markers are being evaluated to help characterize disease progression. These include the following:

  • E-cadherin
  • p53 and p21
  • DNA ploidy analysis
  • Human kallikrein 2
  • Microvessel density - Histologic marker of tumor angiogenesis

Reverse transcriptase-polymerase chain reaction (RTPCR) testing may be able to find very small amounts of PSA nucleic acid in the bloodstream. This technique has been investigated as a method for identifying treatment failure (eg, residual tumor following surgery), but rates of false-positive results have been too high to support its use for making treatment decisions.


TNM Staging System

The tumor node metastases (TNM) staging system of the American Joint Committee on Cancer (AJCC) is used to stage prostate cancer. The current revision of the AJCC system, which took effect in January 2018, also uses both the Gleason score and the grade group for staging. [60]  See Prostate Cancer Staging.

T (primary tumor)

Clinical (cT) stages of primary tumor are as follows:

  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • T1 - Clinically inapparent tumor not palpable or visible by imaging
  • T1a - Tumor incidental histologic finding in ≤5% of tissue resected
  • T1b - Tumor incidental histologic finding in >5% of tissue resected
  • T1c - Tumor identified by needle biopsy (because of elevated PSA level); tumors found in 1 or both lobes by needle biopsy but not palpable on digital rectal examination or reliably visible by imaging
  • T2 - Tumor confined within prostate (includes invasion into the prostatic apex or invasion into, but not beyond, the prostatic capsule)
  • T2a Tumor involves one-half or less of 1 lobe
  • T2b - Tumor involving more than half of a lobe but not more than 1 lobe
  • T2c - Tumor involving both lobes
  • T3 - Tumor extending through the prostatic capsule
  • T3a - Extracapsular extension (unilateral or bilateral)
  • T3b - Tumor invading seminal vesicle(s)
  • T4 - Tumor fixed to or invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, pelvic wall)

Pathologic (pT) stages of the primary tumor are as follows (there is no pT1 classification):

  • pT2–  Organ confined
  • pT3 –  Extraprostatic extension
  • pT3a – Extraprostatic extension or microscopic invasion of the bladder neck
  • pT3b – Seminal vesicle invasion
  • pT4 – Tumor is fixed or invades adjacent structures other than the seminal vesicles (eg, bladder, rectum)

N (nodes)

Clinical (cN) nodal stages are as follows:

  • NX - Regional lymph nodes were not assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in regional lymph node or nodes

Regional lymph nodes are assessed via surgical removal or biopsy of the pelvic lymph nodes, including the obturator chain.

Pathologic (pN) nodal stages are as follows:

  • pNX –  Regional nodes not sampled
  • pN0 – No positive regional nodes
  • pN1 – Metastases in regional nodes(s)

M (metastasis)

Metastatic stages are as follows:

  • M0 - No distant metastasis
  • M1 - Distant metastasis
  • M1a - Nonregional lymph node(s)
  • M1b - Bone(s)
  • M1c - Other site(s), with or without bone disease

Gleason Score

The Gleason grading system is used to help determine prognosis in prostate cancer. It is based on histologic evaluation of tumor biopsy specimens.

Grades are based on the extent to which the epithelium has a normal glandular structure. Grades progress from less malignant to more malignant; a grade of 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern. This scheme of grading histologic features greatly depends on the skill and experience of the pathologist and is subject to some degree of individual variation.

The predominant pattern and the second most common pattern are given grades from 1-5 (see the images below). The sum of these 2 grades is referred to as the Gleason score. Scoring based on the 2 most common patterns is an attempt to factor in the considerable heterogeneity within cases of prostate cancer. In addition, this scoring method has been found to be superior for predicting disease outcomes, compared with using the individual grades alone.

The standard approach for grading prostate cancer The standard approach for grading prostate cancer depends on a Gleason score, which is based on pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue. Prostate cancer patterns are assigned a number from 1-5; the score is created by adding the most common pattern and the highest-grade patterns. Courtesy of Wikimedia Commons.
Histologic scoring system showing the 2 most commo Histologic scoring system showing the 2 most common patterns seen on the biopsy specimen, termed the Gleason score.

Gleason score evaluations have changed considerably in recent years. Scores of 2-5 are rarely seen, while Gleason 7 is being reported more often.

The significance of the Gleason score is as follows:

  • A score of 2-6 indicates a low-grade or well-differentiated tumor

  • A score of 7 indicates a moderate-grade or moderately differentiated tumor

  • A score of 8-10 indicates a high-grade or poorly differentiated tumor


Prediction Models

Models have been developed that combine the clinical stage (as determined by DRE findings), Gleason score, and PSA level in an attempt to better predict which men have organ-confined cancer, as opposed to those who may have local extension. In addition, these models can be used to predict the time to biochemical failure and the time to the development of clinical metastatic disease in patients with rising PSA levels.

These models have been adapted to personal-computer and handheld-computer platforms and can be used with ease in clinical practice. One such program can be downloaded free of charge from the Prostate Nomogram section of the Memorial Sloan-Kettering Cancer Center Web site. The Partin tables, updated by experts at Johns Hopkins in January 2013, are another excellent nomogram for predicting prostate cancer spread and prognosis. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery. [61, 62]

The Cancer of the Prostate Risk Assessment (CAPRA) score is calculated from the PSA level, the Gleason score, the percentage of biopsy cores positive for cancer, the clinical tumor stage, and the patient age at diagnosis. In a large cohort of patients with clinically localized prostate cancer, the CAPRA score proved accurate for predicting metastases, cancer-specific mortality, and all-cause mortality. No patient with a CAPRA score of 0 reached either metastasis or mortality endpoints, but each single-point increase in the CAPRA score was associated with increasing risk. [63]

From the results of the Prostate Cancer Prevention Trial (PCPT), an online risk calculator was created. [64, 65] The information needed includes age, PSA score, ethnicity, family history, positive or negative DRE findings, and positive or negative prior biopsy findings. After those values are entered, the calculator predicts the chances for no, low-grade, and high-grade prostate cancer. The intent is to help guide treatment decision-making. See the PCPT prostate cancer risk calculator.

Whitmore-Jewett classification

The Whitmore-Jewett classification divides prostate cancer into 4 stages, A-D, as follows:

  • Stage A - Tumor is present, but not detectable clinically

  • Stage B - The tumor can be felt on physical examination but has not spread outside the prostatic capsule

  • Stage C - The tumor has extended through the capsule

  • Stage D- The tumor has spread to other organs

The Whitmore-Jewett classification is no longer widely used, as prostate cancer does not necessarily progress in a sequential manner. However, further stratification of stage D by Crawford and Blumenstein [66] has been thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:

  • Stage D1 - Involvement of pelvic lymph nodes

  • Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)

  • Stage D2 - Metastatic disease to bone and other organs

  • Stage D2.5 - Rising PSA after nadir level

  • Stage D3 - Castrate-resistant prostate cancer

  • Stage D3.5 - Sensitive to hormones

  • Stage D4 - Insensitive to hormones


Surgical Staging

In patients undergoing radical prostatectomy, pathologic assessment of extracapsular disease extension and regional nodal involvement is readily available. Routine node dissection is not worthwhile unless the likelihood of finding disease is more than 15%, which can be determined from the Partin tables.

An unresolved controversy is whether removing the prostate in patients with lymph node metastases provides a survival benefit over alternative therapy. Uncontrolled studies are difficult to interpret and no randomized studies are available. In addition, the standard limited node dissection will miss metastases, while the more extensive dissection has a higher complication rate.

One approach to this situation is to perform pelvic lymph node dissection selectively, limiting the procedure to men at increased risk and performing a more extensive dissection in those men. Dissected lymph nodes are sent for frozen sections; if these disclose no metastasis, the surgeon proceeds to prostatectomy.

Performing pelvic lymph node dissection in men scheduled for radiation therapy may be warranted. However, studies have shown a benefit to radiating the pelvic nodes along with the prostate, so lymph node dissection is rarely done unless a prostatectomy is planned.

Investigators from Johns Hopkins University have validated this data. Their analysis of the Hamburg nomogram for surgically treated patients revealed a similar low risk for certain groups of patients (2.5% vs 2.2%). More importantly, their analysis further stratified patients into low, intermediate, and high risk for nodal involvement. These categories correspond to the number of sextant biopsy specimens that are positive with at least Gleason 4+3 disease, as follows [67] :

  • Very low risk (2.5% chance) of nodal involvement - No evidence of Gleason 4+3 disease or greater

  • Intermediate risk (20% chance) of nodal involvement - Patients with 1-3 biopsy specimens positive for Gleason 4+3 disease or greater

  • High risk (44.4%) for nodal involvement - Patients with 4-6 cores positive for Gleason 4+3 disease or greater

Although the Hamburg nomogram and the clinical validation by the Hopkins group highlight patient cohorts that may benefit from surgical exploration of regional nodal disease, neither addresses the importance of this finding in relation to patient outcome. One may reasonably conclude that the risk of regional nodal disease is very low in patients with a Gleason score of 6 or less. This result is not unlike information summarized in the Partin tables.