Prostate Cancer Diagnosis and Staging Overview of Incidence and Mortality

Prostate cancer is the most common noncutaneous cancer among males. Although prostate cancer can be slow growing, the disease nonetheless accounts for 10% of cancer-related deaths in males, with thousands of men dying from prostate cancer each year.

With the development of prostate-specific antigen (PSA) screening, however, prostate cancer is being diagnosed earlier in the disease course than it was prior to PSA examination.

Currently, most cases of prostate cancer are found because of abnormalities in a screening PSA level or findings on DRE rather than because of symptoms (see Prostate-Specific Antigen). However, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive prostatic symptoms (see Prostate Hyperplasia, Benign).

The American Cancer Society estimated that 217,730 new cases of prostate cancer would be diagnosed in the United States in 2010 and that 32,050 men would die of the disease in that year.

For more information, see the following:

• Prostate Cancer
• Laparoscopic Pelvic Lymph Node Dissection in Prostate Cancer
• Prostate Cancer - Radical Perineal Prostatectomy
• Prostate Cancer - Radical Retropubic Prostatectomy
• Prostate Cancer - Brachytherapy (Radioactive Seed Implantation Therapy)
• Transrectal Ultrasonography of the Prostate
• Cryotherapy in Prostate Cancer
• Laparoscopic and Robotic Radical Prostatectomy
• Pelvic Lymph Node Dissection
• Prostate Cancer - External Beam Radiotherapy
• Postradiation Therapy Pathology of Prostate Cancer
• Precancerous Lesions of the Prostate
• Prostate Cancer and Nutrition
• Pathology of Hormonal Therapy on Prostate Cancer
• Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer
• Prostate-Specific Antigen
• Metastatic and Advanced Prostate Cancer

Age and race predilections

Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years.

Prevalence rates of prostate cancer remain significantly higher in African American men than in white men, while the prevalence in Hispanic men is similar to that of white men. Hispanic men and African American men tend to present with more advanced disease, a situation that is most likely related to external (eg, income, education, insurance status) and cultural factors. In addition, African American men generally have higher levels of testosterone, which may contribute to the higher incidence of carcinoma in that population.^{[1, 2]}

Patient information

Because of the advent of PSA screening, a greater number of men now require education about prostate cancer, including the risk of progression and how the disease is diagnosed, staged, and treated. A study by Hall et al found that 80% of primary care physicians discussed PSA screening with their male patients, with 64.1% encouraging the screening.^[3]

For patient education information, see eMedicine’s Prostate Health Center and Cancer and Tumors Center, as well as Prostate Cancer.

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. The position of the prostate in the male genitourinary tract is shown in the image below.

The blood supply to the base of the bladder and prostate is from the inferior vesical, which is derived from the internal iliac. The capsular branches of the inferior vesical artery help to identify the pelvic plexus arising from the S2-S4 and T10-T12 nerve roots.

The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

Ninety-five percent of prostate cancers are adenocarcinomas.

In approximately 4% of men with prostate cancer, the neoplasm has transitional cell morphology and is thought to arise from the urothelial lining of the prostatic urethra.

In rare cases, the tumor has a neuroendocrine morphology; in such instances the neoplasm is believed to have arisen from the neuroendocrine stem cells that are normally present in the prostate or from aberrant differentiation programs during cell transformation.

Seventy percent of prostate cancers arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transition zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Differential diagnoses of prostate cancer include the following:

• Benign prostatic hypertrophy
• Calculi
• Prostatic cysts
• Prostatic tuberculosis
• Prostatitis

The 2002 tumor node metastases [TNM] staging system^[4] is used to stage prostate cancer, as follows:

• T - Primary tumor
• 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 less than or equal to 5% of tissue resected
• T1b - Tumor incidental histologic finding in greater than 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 or reliably visible by imaging
• T2 - Tumor confined within prostate
• T2a - Tumor involving less than half a lobe
• T2b - Tumor involving less than or equal to 1 lobe
• T2c - Tumor involving both lobes
• T3 - Tumor extending through the prostatic capsule; no invasion into the prostatic apex or into, but not beyond, the prostatic capsule
• T3a - Extracapsular extension (unilateral or bilateral)
• T3b - Tumor invading seminal vesicle(s)
• T4 - Tumor fixed or invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, pelvic wall)
• NX - Regional lymph nodes (cannot be assessed)
• N0 - No regional lymph node metastasis
• N1 - Metastasis in regional lymph node or nodes

Regional lymph nodes are assessed via surgical removal or through biopsy of the pelvic lymph nodes, including the obturator chain. The surgical boundaries include the bifurcation of the common iliac, the obturator nerve, and the node of Cloquet.

Distant metastasis

Distant metastasis staging is as follows:

• PM1c - More than 1 site of metastasis present
• MX - Distant metastasis cannot be assessed
• M0 - No distant metastasis
• M1 - Distant metastasis
• M1a - Nonregional lymph node(s)
• M1b - Bone(s)
• M1c - Other site(s)

Digital rectal examination (DRE) and PSA evaluation are the 2 components necessary for a modern screening program.

The indications for screening are controversial. The American Cancer Society recommends that PSA evaluation and DRE be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy and to high-risk younger men. Information should be provided to patients regarding potential risks and benefits of intervention.

Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a US Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.^[5]

In a 2010 study, Tang et al concluded that in the 75- to 80-year age group, discontinuation of PSA screening may be safe in African American men with an initial PSA measurement of less than 6.0 ng/mL and in Caucasian men with an initial PSA measurement of less than 3.0 ng/mL. The investigators found that men in these groups are unlikely to develop high-risk prostate cancer or to die from prostate cancer.^[6]

Advocates of screening believe that early detection is crucial to finding organ-confined disease and to reducing the likelihood of mortality. When symptoms develop or when DRE results become positive, most cases have already advanced beyond organ-confined disease.

Those who do not advocate screening worry that screening will detect cancers that are not biologically significant (ie, in patients who will die with prostate cancer rather than from it).

Men who choose to undergo screening should begin at age 50 years. Men in high-risk groups, such as African Americans and persons with a strong familial predisposition (2 or more affected first-degree relatives), should begin screening at a younger age (40-45 y). These men are less likely to have the latent form of the disease and benefit from treatment. More data on the precise age to start prostate cancer screening are needed for men at high risk.

Data from Canadian and Austrian studies suggest that mortality rates are lower as a result of PSA screening. Canadian data have shown that, from 1989-1996, the mortality rate was lower in the PSA-screened cohort than in the control group.

Research from Tyrol, Austria, also indicates that screening can aid in reducing disease-specific mortality.

The Prostate, Lung, and Ovarian Cancer Screening Trial (PLCO) compared high-intensity PSA screening with standard screening. The trial found no improvement in mortality with screening.^[7] Conversely, the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial did show a decreased mortality in the PSA screened group; however, because it was a multicenter European study, it had flaws as well.^[8]

Similarly, a randomized trial of Swedish men allocated to screening every third year compared with no screening showed no difference in prostate cancer–specific survival.^[9] The issue remains unresolved.

These beneficial effects are likely due to the fact that treatment, rather than observation, may enhance disease-specific survival. This was indicated in a Scandinavian study, which reported that radical prostatectomy was associated with significantly reduced disease-specific mortality, compared with watchful waiting. No difference in overall survival was noted.^[10]

US data have shown a decrease of 1% per year since 1990 in the prostate-cancer mortality rate, which coincides with the advent of PSA screening. Other theories have been proposed to account for the decrease, and these include changing treatment practices and artifacts in mortality rates secondary to the changing incidence of prostate cancer.

Local symptoms

In the pre-PSA era, patients with prostate cancer commonly presented with local symptoms. Urinary retention developed in 20-25% of these patients, back or leg pain developed in 20-40%, and hematuria developed in 10-15%. Currently, with PSA screening, patients report urinary frequency (38%), decreased urine stream (23%), urinary urgency (10%), and hematuria (1.4%). However, none of these symptoms is unique to prostate cancer and each could arise from various other ailments. Forty-seven percent of patients are asymptomatic.

Metastatic symptoms

Metastatic symptoms include weight loss and loss of appetite; bone pain, with or without pathologic fracture (because prostate cancer, when metastatic, has a strong predilection for bone); and lower extremity pain and edema due to obstruction of venous and lymphatic tributaries by nodal metastasis. Uremic symptoms can occur from ureteral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.

Elevated prostate-specific antigen level

PSA is a single-chain glycoprotein that has chymotrypsinlike properties. The upper limit of normal for PSA is 4 ng/mL. Some advocate age-related cutoffs, such as 2.5 ng/mL for the fifth decade of life, 3.5 ng/mL for the sixth decade of life, and 4.5 ng/mL for the seventh decade of life. Others advocate race-specific reference ranges. Using data from screening studies, some have advocated upper limits of normal of 2.5 ng/mL instead of 4 ng/mL.

If the physician believes that an elevated PSA level may be due to infection, 4-6 weeks of antibiotics are provided, and then the PSA level is rechecked.

Prostate-specific antigen velocity

PSA velocity is an important concept. A PSA velocity of lower than 0.75 ng/mL/y has traditionally been used to prompt a prostate biopsy. However, data has suggested that, among men younger than 50 years, a PSA velocity of 0.6 ng/mL/y may be more appropriate.

Percentage of free prostate-specific antigen

The measurement of bound and free PSA can help to differentiate mildly elevated PSA levels caused by cancer from elevated levels resulting from benign prostatic hyperplasia. The lower the ratio of free-to-total PSA, the higher the likelihood of cancer. Free PSA is reported as a percentage. For example, among men with greater than 25% free PSA, only 8% are found to have cancer at prostate biopsy.

In contrast, more than half of men with less than 10% free PSA are found to have cancer at biopsy. While cutoffs may be used, the percentage of free PSA is usually employed as an additional factor in making an informed recommendation for or against biopsy. Generally, these percentages are useful in patients who have a PSA level in the range of 4-10 ng/mL.

This information is most useful in men with very large glands or in men in whom 1 biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many recommend biopsy without the additional free-PSA test or consider a trial of antibiotic therapy for 4-6 weeks before repeating the PSA test. (If antibiotic therapy quickly lowers the PSA level to within the reference range, the cause of the prior elevation is less likely to be prostate cancer, and the PSA test should be repeated within a few months.)

DREs are examiner dependent, and serial examinations are best.

Various factors are considered when a DRE is performed. A nodule is important, but findings such as asymmetry, difference in texture, and bogginess are important clues to the patient's condition and should be considered in conjunction with the PSA level. Change in texture over time can offer important clues about the need for intervention.

Pay careful attention to the prostate’s consistency, along with the seminal vesicles and adjacent organs. Such observation can be help to detect the disease’s spread to other structures, the results of which can be as follows:

• Overdistention of the bladder due to outlet obstruction
• Lower extremity lymphedema
• Supraclavicular adenopathy
• Lower extremity deep venous thrombosis
• Cancer cachexia
• Neurologic findings secondary to cord compression

With regard to the last item above, other subtle neurologic findings, such as paresthesias or wasting, are uncommon.

Cysts and stones cannot be accurately differentiated from cancer based on DRE findings alone; therefore, maintain a high index of suspicion if the DRE results are abnormal.

If cancer is detected, the DRE findings form the basis of clinical staging of the primary tumor stage in the TNM staging system.

In most patients who are diagnosed with prostate cancer, however, the DRE results are normal and the PSA readings are abnormal.

Physical examination findings alone cannot reliably differentiate a cyst or calculus from cancer foci; therefore, a biopsy is warranted in these circumstances, to aid in the diagnosis and to determine the Gleason score (see Histologic Findings).

Before the biopsy, antibiotics are administered and an enema is often provided, with a short course of antibiotics administered after the biopsy as well. Coagulation tests are not routinely performed, but patients are instructed to stop aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) 10 days prior to the biopsy. Many, but not all, physicians use lidocaine prior to the biopsy.

The number of biopsies that should be performed is debated. Sextant- versus 12- versus 18-core biopsy protocols are published in the literature. The 12- or 18-core protocols yield more specimens from the lateral regions and usually sample the transition zone. Several studies have demonstrated an increase in the cancer detection rate, but others have not.

In patients with a persistently elevated PSA level in the face of negative biopsy results, the literature supports repeating the biopsy once or twice. Of cancer cases, 31% were detected on repeat biopsy and 39% were detected if the PSA value was greater than 20 ng/mL. If all of the biopsy results are negative, a repeat round of biopsies has been suggested when the PSA increases by 25% from the level at which the last biopsies were performed.

Further workup depends on the clinical staging. A higher clinical stage of cancer determined by DRE findings, PSA level, and Gleason score (as determined by biopsy) correlates with an increased risk of extraprostatic spread, and these tests are considered key factors in determining the staging workup and predicting patient prognosis.

Bul et al studied the outcome of routinely obtained 1-year repeat biopsies and factors predicting reclassification to higher risk for men on active surveillance. Favorable results of repeat biopsies showing no or low-risk PCa were obtained in 594 patients (78.5%), which led to reclassification of risk in 163 (21.5%). Age, clinical stage, total number of biopsy cores, and PSA did not influence the outcome.^[11]

Gleason score

The most commonly used system of classifying the histologic characteristics of prostate cancer is the Gleason score, which is determined using the glandular architecture within the tumor.

The predominant pattern and the second-most common pattern (seen in the image below) are given grades of from 1-5. The Gleason score is the sum of these 2 grades. 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 was found to be superior for predicting disease outcomes compared with using the individual grades alone.

Grades are based on the extent to which the epithelium assumes a normal glandular structure. A grade of 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern (less malignant to more malignant). 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.

Gleason scores range as follows:

• Score of 2-4 - Considered low grade or well differentiated
• Score of 5-7 - Considered moderate grade or moderately differentiated
• Score of 8-10 - Considered high grade or poorly differentiated

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

Perineural invasion

Perineural invasion is an indicator of invasiveness and is considered in terms of which side should possibly undergo a nerve-sparing procedure and whether a patient might benefit more from high- or low-risk brachytherapy.

Prostatic intraepithelial neoplasia

Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations within prostatic ducts, ductules, and acini.

Two grades of PIN are identified. Low-grade PIN is mild dysplasia. High-grade PIN encompasses moderate and severe dysplasia. High-grade PIN is considered by most to be a precursor of invasive carcinoma. Men with high-grade PIN alone can be started on finasteride and monitored closely.

The continuum that culminates in high-grade PIN and early invasive cancer is characterized by basal cell layer or basement membrane disruption, progressive loss of secretory differentiation markers, increasing nuclear and nucleolar abnormalities, increasing proliferative potential, and increasing variation in deoxyribonucleic acid (DNA) content (aneuploidy).

Clinical studies suggest that PIN predates a carcinoma by 10 or more years.^[12] The clinical importance of recognizing PIN is based on its strong association with carcinoma. Studies claim that men with high-grade PIN in a prostate biopsy specimen have a 35-50% chance of being diagnosed with prostate cancer after a subsequent biopsy.^[13] Atypical small acinar proliferation (ASAP) has also been associated with higher cancer detection rates.

The identification of PIN in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma. In most men, this means repeat biopsies if the PSA level changes significantly. The same may also be true for ASAP findings after biopsy.

Evaluation of findings

Men with PSA levels less than 10 ng/mL and low- or moderate-grade histology (Gleason score < 7) with no findings or minimal findings on physical examination may proceed to surgery or brachytherapy without further studies.

Men with PSA levels of greater than 10 ng/mL, high-grade histology (Gleason score ≥7), or physical findings that suggest stage T3 disease should probably undergo a staging computed tomography (CT) scan and bone scan. CT scanning is the one modality with evidence-based guidelines. The CT scan can be used to evaluate extension into the bladder and lymph nodes to help stage the patient's cancer or to consider lymph node sampling prior to treatment.

Conventional endorectal magnetic resonance imaging (MRI) is helpful for localizing cancer within the prostate and seminal vesicles and for local staging. Dynamic contrast-enhanced MRI and MR spectroscopic imaging are also complementary in local staging, but their use is currently limited to a research setting.

MRI is superior to bone scanning in evaluating bone metastasis but is impractical for routine total-body surveys. Instead, it is used to determine the etiology of questionable lesions found on bone scans. MRI is promising for local staging but is not readily accessible, and no published guidelines are available. Bone-scan examples are seen below.

Despite of the wealth of literature regarding the lack of use for imaging studies in men with low risk disease, a SEER-Medicare analysis found almost a third of patients underwent cross sectional imaging.^[14]

Neither CT scanning nor MRI can be used to determine if lymph nodes are reactive or contain malignant deposits, unless the nodes are significantly enlarged and a percutaneous biopsy can be performed.

PET scanning

There is increasing interest in using metabolic activity to detect cancer foci. Positron emission tomography (PET) uses glucose analogue 18 F-fluorodeoxyglucose (18 F-FDG) to detect cancer, but studies thus far have been disappointing for prostate cancer detection.

C-choline PET scans fused with CT imaging show more promise but are not yet the standard of care.

ProstaScint scanning

Likewise, there is renewed interest in ProstaScint scans fused with MRI or CT images. This modality involves a murine monoclonal antibody that reacts with prostate-specific membrane antigen to identify cancer in the prostate and in metastatic deposits.

TRUS

Transrectal ultrasonography (TRUS) is used to examine the prostate for hypoechoic areas, which are commonly associated with cancers but are not specific enough for diagnostic purposes. An example of a hypoechoic lesion is seen below.