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					Prostate Cancer                                                   This information is most useful in men with very large glands
Introduction                                                      or in men in whom one biopsy result has already been
Prostate cancer is the most common noncutaneous cancer            negative. In healthy men with a PSA level of 4-10 ng/mL,
among males. Lung and bronchial cancer account for 37% of         many recommend biopsy without the additional free-PSA
cancer-related death in males; prostate and colon cancers         test or consider a trial of antibiotic therapy for 4-6 weeks
account for another 10% each. The diagnosis and treatment         before repeating the PSA test. If antibiotic therapy quickly
of prostate cancer continue to evolve. With the development       lowers the PSA level to within the reference range, the cause
of prostate-specific antigen (PSA) screening, prostate cancer     of the prior elevation is less likely to be prostate cancer, and
is being diagnosed earlier in the disease course. Although        the PSA test should be repeated within a few months.
prostate cancer can be a slow-growing cancer, thousands of        Abnormal digital rectal examination findings
men die of the disease each year. Education is important to       Various factors are considered when a DRE is performed. A
help men understand the risk of progression and the various       nodule is important, but findings such as asymmetry,
treatment options. This article provides a current overview of    difference in texture, and bogginess are important clues to
the biology, pathology, diagnostic techniques, natural            the patient's condition and should be considered in
history, and screening of this disorder.                          conjunction with the PSA level. Change in texture over time
Incidental Findings                                               can offer important clues about the need for intervention.
In the modern era, most patients present because of               Cysts or stones cannot be accurately differentiated from
abnormalities in a screening PSA level or findings on digital     cancer based on DRE findings alone; therefore, maintain a
rectal examination (DRE) rather than because of symptoms          high index of suspicion if the DRE results are abnormal. In
(see Prostate-Specific Antigen). However, prostate cancer can     addition, if cancer is detected, the DRE findings form the
be an incidental pathologic finding when tissue is removed        basis of clinical staging of the primary tumor (ie, tumor [T]
during transurethral resection to manage obstructive              stage in the tumor node metastases [TNM] staging system).
prostatic symptoms (see Prostate Hyperplasia, Benign).            In current practice, the DRE results are normal but the PSA
Elevated prostate-specific antigen level                          readings are abnormal in most patients diagnosed with
PSA is a single-chain glycoprotein that has chymotrypsinlike      prostate cancer.
properties. PSA slowly hydrolyzes peptide bonds, thereby          Local Symptoms
liquifying semen. The upper limit of normal for PSA is 4          In the pre-PSA era, patients with prostate cancer commonly
ng/mL. Some advocate age-related cutoffs, such as 2.5 ng/mL       presented with local symptoms. Urinary retention developed
for the fifth decade of life, 3.5 ng/mL for the sixth decade of   in 20-25% of these patients, back or leg pain developed in 20-
life, and 4.5 ng/mL for the seventh decade of life. Others        40%, and hematuria developed in 10-15%. Currently, with
advocate race-specific reference ranges. Using recent data        PSA screening, patients report urinary frequency (38%),
from screening studies, some have advocated upper limits of       decreased urine stream (23%), urinary urgency (10%), and
normal of 2.5 ng/mL instead of 4 ng/mL.                           hematuria (1.4%). However, none of these symptoms is
Prostate-specific antigen velocity                                unique to prostate cancer and each could arise from various
PSA velocity is an important concept. A PSA velocity of lower     other ailments. Forty-seven percent of patients are
than 0.75 ng/mL/y has traditionally been used to prompt a         asymptomatic.
prostate biopsy. However, recent data suggest that, among         Metastatic Symptoms
men younger than 50 years, a PSA velocity of 0.6 ng/mL/y          Metastatic symptoms include weight loss and loss of
may be more appropriate.                                          appetite; bone pain, with or without pathologic fracture
Percent of free prostate-specific antigen                         (because prostate cancer, when metastatic, has a strong
The measurement of bound and free PSA is a recent                 predilection for bone); and lower extremity pain and edema
development that can help to differentiate mildly elevated        due to obstruction of venous and lymphatic tributaries by
PSA levels due to cancer from elevated levels due to benign       nodal metastasis. Uremic symptoms can occur from ureteral
prostatic hyperplasia. The lower the ratio of free-to-total       obstruction caused by local prostate growth or
PSA, the higher the likelihood of cancer. Free PSA is reported    retroperitoneal adenopathy secondary to nodal metastasis.
as a percentage. For example, among men with greater than         Frequency
25% free PSA, only 8% are found to have cancer at prostate        With the advent of PSA screening, a greater number of men
biopsy. In contrast, more than half of men with less than 10%     require education about prostate cancer and how it is
free PSA are found to have cancer at biopsy. While cutoffs        diagnosed, staged, and treated so they can select the most
may be used, the percentage of free PSA is usually used as an     appropriate treatment.
additional factor in making an informed recommendation for        According to figures from the American Cancer Society,
or against biopsy. Generally, these percentages are useful in     186,330 new cases will be diagnosed in 2008 and 26,000 men
patients who have a PSA level in the range of 4-10 ng/mL.         will die from prostate cancer (see Image 1). Prostate cancer is
rarely diagnosed in men younger than 40 years, and it is          cases. Recently, several reports have suggested a shared
uncommon in men younger than 50 years.                            familial risk (inherited or environmental) for prostate and
Prevalence rates of prostate cancer remain significantly          breast cancer. Men with a family history of prostate cancer
higher in African American men than in white men, while the       have a higher risk of developing prostate cancer and are also
prevalence in Hispanic men is similar to that of white men.       likely to present 6-7 years earlier.
Hispanic men and African American men present with more           Race
advanced disease, most likely related to external (eg, income,    African American men have a higher prevalence and more
education, insurance status) and cultural factors. In addition,   aggressive prostate cancer than white men, who, in turn,
African American men generally have higher levels of              have a higher prevalence than men of Asian origin. Studies
testosterone, which may contribute to the higher incidence        have found that young African American men have
of carcinoma.                                                     testosterone levels that are 15% higher than in young white
Between 1989 and 1992, incidence rates of prostate cancer         men. Furthermore, evidence indicates that 5-alpha reductase
increased dramatically, probably because of earlier diagnoses     may be more active in African Americans than in whites,
in asymptomatic men as a result of the increased use of           implying that hormonal differences may play a role. The
serum PSA testing. In fact, the incidence of organ-confined       independent contribution of race alone is difficult to qualify
disease at diagnosis has increased because both PSA testing       when the effects of health care access, income, education,
and standard DRE are performed.                                   and insurance status are also considered.
Prostate cancer incidence rates are continuing to decline;        Diet
rates in white men peaked in 1992, and they peaked in             A high-fat diet may lead to increased risks, while a diet rich in
African American men in 1993.                                     soy may be protective. These observations have been
During 1992-1996, mortality rates associated with prostate        proposed as reasons for the low prevalence of this cancer in
cancer declined significantly, approximately 2.5% per year        Asia. Rates of prostate cancer are much greater in Japanese
(seeImage 1). Although mortality rates are continuing to          American men than in native Japanese men, supporting the
decline among white and African American men, mortality           association of a high-fat diet with cancer. Cell culture studies
rates in African American men remain twice as high as in          have shown that omega-6 fatty acids are positive stimulants
white men, based on 2008 American Cancer Society                  of prostate cancer cell growth, while omega-3 fatty acids are
projections.                                                      negative stimuli. These fats may exert their effects by
Prostate cancer is also found during autopsies performed          alterations of sex hormones or growth factors or through
following other causes of death. The rate of this latent or       effects on 5-alpha reductase.
autopsy cancer is much greater than that of clinical cancer. In   Soy seems to decrease the growth of prostate cancer cells in
fact, it may be as high as 80% by age 80 years.                   mouse models; however, apart from epidemiologic factors,
The prevalence of clinical cancer varies by region, and these     no direct evidence supports a beneficial effect in humans.
differences may be due to some of the genetic, hormonal,          Vitamin E may have some protective effects because it is an
and dietary factors discussed in Etiology. High rates are         antioxidant. Decreased levels of vitamin A may be a risk
reported in northern Europe and North America,                    factor because this can promote cell differentiation and
intermediate rates are reported in southern Europe and            stimulate the immune system. Vitamin D deficiency was
Central and South America, and low rates are reported in          suggested as a risk factor, and studies show an inverse
Eastern Europe and Asia.                                          relationship between ultraviolet exposure and mortality rates
Interestingly, the prevalence of the latent or autopsy form of    for prostate cancer. However, a specific correlation between
the disease is similar worldwide. Together with migration         1,25-dihydroxyvitamin D levels and palpable disease, well-
studies, this suggests that environmental factors, such as        differentiated tumors, or mortality is inconclusive.
diet, may play a significant promoting role in the                Selenium may have a protective effect based on
development of a clinical cancer secondary to a latent            epidemiologic studies and is also believed to extend its effect
precursor.                                                        via its antioxidant properties. The Selenium and Vitamin E
Etiology                                                          Cancer Prevention Trial (SELECT) is an ongoing intergroup,
Genetics                                                          phase 3, randomized, controlled trial designed to test the
Gene alterations on chromosome 1, 17, and the X                   efficacy of selenium and vitamin E alone and in combination
chromosome have been found in some patients with a family         in the prevention of prostate cancer.
history of prostate cancer. The hereditary prostate cancer 1      For more information, see Prostate Cancer: Nutrition.
(HPC1) gene and the predisposing for cancer of the prostate       Hormones
(PCAP) gene are on chromosome 1, while the human                  Hormonal causes have also been postulated. Androgen
prostate cancer gene is on the X chromosome. In addition,         ablation causes a regression of prostate cancer. In addition,
genetic studies suggest that a strong familial predisposition     as indirect evidence of hormonal causes, eunuchs do not
may be responsible for as many as 5-10% of prostate cancer        develop adenocarcinoma of the prostate.
Hsing and Comstock performed a large study comparing               Approximately 4% of cases of prostate cancer have
patients with prostate cancer with controls and found no           transitional cell morphology and are thought to arise from
difference in levels of testosterone, dehydrotestosterone,         the urothelial lining of the prostatic urethra. Few cases have
                                                      1
prolactin, follicle-stimulating hormone, or estrone.               neuroendocrine morphology. When present, they are
The Prostate Cancer Prevention Trial studied the prevalence        believed to arise from the neuroendocrine stem cells
of prostate cancer between a control group and a group             normally present in the prostate or from aberrant
given a 5-alpha-reductase inhibitor (finasteride). While the 5-    differentiation programs during cell transformation.
alpha reductase inhibitor appeared to decrease the                 Of prostate cancer cases, 70% arise in the peripheral zone,
prevalence of tumors, those that did arise appeared                15-20% arise in the central zone, and 10-15% arise in the
histologically more aggressive. Only long-term follow-up of        transitional zone. Most prostate cancers are multifocal, with
these patients will determine whether this more aggressive         synchronous involvement of multiple zones of the prostate,
histology accurately reflects the underlying biology of these      which may be due to clonal and nonclonal tumors.
tumors or whether it is an artifact of the treatment.              Natural history
The American Society of Clinical Oncology (ASCO) Health            The natural history is still relatively unknown, and many
Services Committee (HSC), ASCO Cancer Prevention                   aspects of progression are poorly understood. Symptoms or
Committee, and the American Urological Association Practice        abnormal DRE findings in the pre-PSA era brought only 40-
Guidelines Committee jointly convened a Panel of experts           50% of patients with prostate cancer to medical attention,
who used the results from a systematic review of the               and these patients usually had locally advanced disease. The
literature to develop evidence-based recommendations on            advent of PSA testing has helped to identify patients with
the use of 5-alpha-reductase inhibitors for prostate cancer        less-advanced, organ-confined disease.
chemoprevention.                                                   In fact, the pendulum has shifted to the point that certain
The Expert Panel concluded that asymptomatic men with a            members of the urologic community feel that active
PSA level of less than 3 ng/mL who are regularly screened          surveillance, also known as expectant management, may
with PSA or are anticipating undergoing annual PSA screening       have a role. Twenty-year outcome data from Connecticut
for early detection of prostate cancer may benefit from a          confirm that mortality rates due to tumors with a Gleason
                                                                                                    3
discussion of both the benefits of 5-alpha-reductase               score of 2-4 was less than 7%. Urologists at Johns Hopkins
inhibitors for 7 years for the prevention of prostate cancer       University advocate active surveillance in patients with a PSA
and the potential risks (including the possibility of high-grade   density of less than 0.1 ng/mL, with no adverse pathologic
prostate cancer).                                                  findings on needle biopsy, and with tumors with a Gleason
Men who are taking 5-alpha-reductase inhibitors for benign         score of 6 that are smaller than 3 mm.
conditions, such as lower urinary tract (obstructive)              Evidence suggests that most prostate cancers are multifocal
symptoms (LUTS), may benefit from a similar discussion;            and heterogeneous. Cancers can start in the transitional zone
these patients should understand that the improvement of           or, more commonly, the peripheral zone. When these
LUTS relief should be weighed with the potential risks of          cancers are locally invasive, the transitional-zone tumors
high-grade prostate cancer from 5-alpha-reductase inhibitors       spread to the bladder neck, while the peripheral-zone tumors
(although most of the Panel members judged the risk of high-       extend into the ejaculatory ducts and seminal vesicles.
grade prostate cancer to be unlikely). A reduction of              Penetration through the prostatic capsule and along the
approximately 50% in PSA level by 12 months is expected in         perineural or vascular spaces occurs relatively late.
men taking a 5-alpha-reductase inhibitor; however, because         The mechanism for distant metastasis is poorly understood.
these changes in PSA may vary among men, and within                The cancer spreads to bone early, occasionally without
individual men over time, the Panel has no recommendations         significant lymphadenopathy. Currently, 2 predominant
for a specific cut point to trigger a biopsy for men taking a 5-   theories have been proposed for spread—the mechanical
alpha-reductase inhibitor. No specific cut point or change in      theory and the seed-and-soil theory.
PSA level has been prospectively validated in men taking a 5-      1. The mechanical theory involves direct spread through
                             2
alpha-reductase inhibitor.                                              the lymphatics and venous spaces into the lower lumbar
Pathophysiology and Natural History                                     spine.
Pathophysiology                                                    2. Advocates of the seed-and-soil theory believe that tissue
Prostate cancer develops when the rates of cell division and            factors that allow for preferential growth in certain
cell death are no longer equal, leading to uncontrolled tumor           tissues, such as the bone, must be present. Lung, liver,
growth. Following the initial transformation event, further             and adrenal metastases have also been documented.
mutations of a multitude of genes, including the genes for              Specific tissue growth factors and extracellular matrices
p53 and retinoblastoma, can lead to tumor progression and               are possible examples.
metastasis.     Most     (95%)     prostate    cancers    are      The doubling time in early-stage disease is as slow as 2-4
adenocarcinomas.                                                   years, but this changes as the tumor grows and becomes
more aggressive. Larger tumors usually have a higher               among patients with an estimated life expectancy exceeding
Gleason grade and a faster doubling time.                          15 years.
Natural history by stage                                           Screening
1. T1a - Progression over 10 years (uncommon)                      DRE and PSA evaluation are the 2 components necessary for
2. T1b - Tumor-related death rate of 10% in 10 years               a modern screening program. Transrectal ultrasonography
3. T2 - Ten-year metastasis-free survival rate of 81% with         (TRUS) has been associated with a high false-positive rate,
     grade 1, 58% with grade 2, and 26% with grade 3               making it unsuitable as a screening tool, although it is very
4. T3 - Lymph node metastasis at presentation in 50% and           useful for directing prostatic biopsies.
     approximately 25% rate of 10-year disease-free survival       The indications for screening are controversial. The American
The natural history of clinically localized disease varies, with   Cancer Society recommends that both PSA evaluation and
lower-grade tumors having a more indolent course, while            DRE should be offered annually, beginning at age 50 years, to
some high-grade lesions progress to metastatic disease with        men who have at least a 10-year life expectancy and to high-
relative rapidity. Several studies have examined the cancer-       risk younger men. Information should be provided to patients
specific and quality-of-life outcomes associated with a            regarding potential risks and benefits of intervention.
watchful-waiting approach to localized disease.                    Despite the apparent survival advantage of early diagnosis
1. Albertsen et al monitored patients who received no              conferred by PSA screening, a recent U.S. Preventive Services
                                                  3
     initial treatment for prostate cancer. As disease             Task Force statement recommends against screening for
     progression occurred, many received antiandrogens.            prostate cancer in men aged 75 years or older. The
     Men with poorly differentiated tumors lost 6-8 years of       statement also concludes that, currently, the balance of
     life, while those with moderately differentiated tumors       benefits versus drawbacks of prostate cancer screening in
     lost 4-5 years. Of all men monitored for 10 years, 40%        men younger than age 75 years cannot be assessed because
     died of causes other than prostate cancer. This study         of insufficient evidence.
                                                                                             7

     was performed prior to PSA screening.                         Advocates of screening believe that early detection is crucial
2. Graversen et al compared watchful waiting with radical          to finding organ-confined disease and to reducing the
                       4
     prostatectomy. They found no overall difference in            likelihood of mortality. When symptoms develop or when
     survival, but they did find that a high Gleason score was     DRE results become positive, most cases have already
     associated with poor survival in both groups.                 advanced beyond organ-confined disease. Those who do not
3. Chodak et al confirmed this finding by analyzing 6 studies      advocate screening worry that screening will detect cancers
     and finding a 34% survival rate associated with grade 3       that are not biologically significant (ie, in patients who
     tumors versus an 87% disease-specific survival rate           will die with prostate cancer rather than from it). Currently,
                                               5
     associated with grade 1 and 2 tumors. The metastasis-         age-specific PSA cutoffs are used to guide screening. The
     free survival rate also significantly dropped as the grade    trend is toward lowering the threshold level to 2.5 ng/mL,
     progressed from 1 to 3.                                       but this has not yet been widely accepted.
4. Johansson et al (2004) reported their recent update on a        Men who choose to undergo screening should begin at age
     population-based cohort study with a mean observation         50 years. Men in high-risk groups, such as African Americans
                          6
     period of 21 years. In this study, 223 patients with early-   and those with a strong familial predisposition (2 or more
     stage, initially untreated prostatic cancer were observed.    affected first-degree relatives), should begin screening at a
     Symptomatic patients with tumor progression received          younger age (40-45 y). These men are less likely to have the
     hormonal treatment (orchiectomy or estrogens). Thirty-        latent form of the disease and benefit from treatment. More
     nine (17%) developed metastatic disease, with most            data on the precise age to start prostate cancer screening are
     cancers having an indolent course during the first 10-15      needed for men at high risk.
     years. However, further follow-up at 15-20 years              Recent data from Canadian and Austrian studies suggest that
     revealed a substantial decrease in cumulative                 mortality rates are lower as a result of PSA screening.
     progression-free survival (from 45% to 36%), survival         Canadian data have shown that, from 1989-1996, the
     without metastases (from 76.9% to 51.2%), and prostate        mortality rate was lower in the PSA-screened cohort than in
     cancer–specific survival (from 78.7% to 54.4%). Prostate      the control group. Recent studies from Tyrol, Austria, also
     cancer mortality increased from 15 deaths per 1000            show a beneficial result for screening in reducing disease-
     person-years during the first 15 years to 44 deaths per       specific mortality. These beneficial effects are likely due to
     1000 person-years beyond 15 years of follow-up.               the fact that treatment rather than observation may enhance
Taken together, these data suggest that, although most             disease-specific survival. This was recently shown in a 2002
prostate cancers diagnosed at an early stage have an indolent      Scandinavian study, which reported that radical
course, local tumor progression and aggressive metastatic          prostatectomy was associated with significantly reduced
disease may develop in the long term. In addition, these           disease-specific mortality compared with watchful waiting.
findings would support early radical treatment, notably            No difference in overall survival was noted.
Currently, US data have shown a mortality rate decrease of             needle biopsy but not palpable or reliably visible by
1% per year since 1990, which coincides with the advent of             imaging
PSA screening. Other theories have been proposed to                8. T2 - Tumor confined within prostate
account for the decrease, and these include changing               9. T2a - Tumor involving less than half a lobe
treatment practices and artifacts in mortality rates secondary     10. T2b - Tumor involving less than or equal to 1 lobe
to the changing incidence.                                         11. T2c - Tumor involving both lobes
Abnormal rectal examination findings                               12. T3 - Tumor extending through the prostatic capsule; no
Findings from the DRE are crucial. An irregular firm prostate          invasion into the prostatic apex or into, but not beyond,
or nodule is typical, but many cancers are found in prostates          the prostatic capsule
that feel normal. Pay careful attention to the prostate            13. T3a - Extracapsular extension (unilateral or bilateral)
consistency, along with the seminal vesicles and adjacent          14. T3b - Tumor invading seminal vesicle(s)
organs, to detect spread of the disease to these structures.       15. T4 - Tumor fixed or invading adjacent structures other
1. Overdistended bladder due to outlet obstruction                     than seminal vesicles (eg, bladder neck, external
2. Neurologic findings secondary to cord compression:                  sphincter, rectum, levator muscles, pelvic wall)
     Other subtle findings, such as paresthesias or wasting,       16. NX - Regional lymph nodes (cannot be assessed)
     are uncommon.                                                 17. N0 - No regional lymph node metastasis
3. Lower extremity lymphedema                                      18. N1 - Metastasis in regional lymph node or nodes
4. Supraclavicular adenopathy                                      Regional lymph nodes are assessed via surgical removal or
5. Lower extremity deep venous thrombosis                          biopsy of the pelvic lymph nodes, including the obturator
6. Cancer cachexia                                                 chain. The surgical boundaries include the bifurcation of the
Transrectal ultrasonography                                        common iliac, the obturator nerve, and the node of Cloquet.
TRUS is used to examine the prostate for hypoechoic areas,         Distant metastasis
which are commonly associated with cancers but are not             1. PM1c - More than 1 site of metastasis present
specific enough for diagnostic purposes. At least 6 or, more       2. MX - Distant metastasis cannot be assessed
recently, 10 or more systematic biopsy specimens of                3. M0 - No distant metastasis
peripheral and, occasionally, transitional zones are taken         4. M1 - Distant metastasis
under ultrasonographic guidance. Samples should include            5. M1a - Nonregional lymph node(s)
most areas of the gland, irrespective of ultrasonographic          6. M1b - Bone(s)
abnormalities.                                                     7. M1c - Other site(s)
                                        Transrectal sonogram       Workup and Histologic Findings
                                        of      the     prostate
                                        showing a hypoechoic       Workup
                                        lesion in the peripheral   Determine the PSA level. Age-related PSA levels can be
                                        zone of the gland that     assessed, as can clinical evidence of prostatitis. If the
                                        is suggestive of cancer.
                                                                   physician believes that an elevated PSA level may be due to
Differential diagnoses
                                                                   infection, 4-6 weeks of antibiotics are provided, and then the
      Benign prostatic hypertrophy
                                                                   PSA level is rechecked.
      Calculi
                                                                   Perform a DRE. This is examiner-dependent, and serial
      Prostatic cysts
                                                                   examinations, over time, are best. Regard nodules or changes
      Prostatic tuberculosis
                                                                   in the texture or the level of asymmetry with a high index of
      Prostatitis                                                 suspicion. Physical examination findings alone cannot reliably
Staging                                                            differentiate a cyst or calculus from cancer foci; therefore, a
The 2002 TNM staging system is used to stage prostate              biopsy is warranted in these circumstances.
cancer, as follows:                                                Perform a biopsy to aid in diagnosis and determine the
1. T - Primary tumor                                               Gleason score. Antibiotics are administered, and an enema is
2. TX - Primary tumor cannot be assessed                           often provided before the procedure, followed by a short
3. T0 - No evidence of primary tumor                               course of antibiotics after the biopsy. Coagulation tests are
4. T1 - Clinically inapparent tumor not palpable or visible by     not routinely performed, but patients are instructed to stop
    imaging                                                        aspirin and nonsteroidal anti-inflammatory drugs 10 days
5. T1a - Tumor incidental histologic finding in less than or       prior to the biopsy. Many physicians use lidocaine prior to
    equal to 5% of tissue resected                                 the biopsy, while others do not. The number of biopsies that
6. T1b - Tumor incidental histologic finding in greater than       should be performed is debated. Sextant versus 12- versus
    5% of tissue resected                                          18-core biopsy protocols are published in the literature. The
7. T1c - Tumor identified by needle biopsy (because of             12- or 18-core protocols yield more specimens from the
    elevated PSA level); tumors found in 1 or both lobes by        lateral regions and usually sample the transition zone.
Several studies have demonstrated an increase in the cancer         is renewed interest in ProstaScint scans fused with MRI or CT
detection rate, while others have not.                              images. This modality involves a murine monoclonal antibody
In patients with a persistently elevated PSA level in the face      that reacts with prostate-specific membrane antigen to
of negative biopsy results, the literature supports repeating       identify cancer both in the prostate and in metastatic
the biopsy once or twice. Of cancer cases, 31% were                 deposits.
detected on repeat biopsy and 39% were detected if the PSA          Finally, conventional endorectal MRI is helpful for localizing
value was greater than 20 ng/mL. If all the biopsy results are      cancer within the prostate and seminal vesicles and for local
negative, a repeat round of biopsies has been suggested             staging. Dynamic contrast-enhanced MRI and MR
when the PSA increases by 25% from the level at which the           spectroscopic imaging are also complementary in local
last biopsies were performed.                                       staging, but their use is currently limited to a research
Further workup depends on the clinical staging. A higher            setting.
clinical stage of cancer determined by DRE findings, PSA level,     Preoperative workup includes the following:
and Gleason score (as determined by biopsy) correlates with         1. Chest radiography
an increased risk of extraprostatic spread, and these tests are     2. CBC count
considered key factors in determining the staging workup            3. CHEM-7
and predicting patient prognosis.                                   4. Prothrombin time and activated partial thromboplastin
The Partin tables are the best nomogram for predicting                   time
prostate cancer spread and prognosis. In addition, a series of      5. Electrocardiography
nomograms has been issued from the Memorial Sloan-                  Histologic findings
Kettering Cancer Center; these nomograms are used to                The most commonly used system of classifying histologic
predict biochemical-free survival after surgery and radiation.      characteristics of prostate cancer is the Gleason score, which
The most commonly used is the Kattan nomogram.                      is determined using the glandular architecture within the
Men with PSA levels less than 10 ng/mL and low- or                  tumor.
moderate-grade histology (Gleason score <7) with no findings        The predominant pattern and the second most common
or minimal findings on physical examination may proceed to          pattern are given grades from 1-5. The sum of these 2 grades
surgery or brachytherapy without further studies. Men with          is referred to as the Gleason score. Scoring based on the 2
PSA levels greater than 10 ng/mL, high-grade histology              most common patterns is an attempt to factor in the
(Gleason score >7), or physical findings that suggest stage T3      considerable heterogeneity within cases of prostate cancer.
disease should probably undergo a staging CT scanning and           In addition, this scoring method was found to be superior for
bone scan. CT scanning is the one modality with evidence-           predicting disease outcomes compared with using the
based guidelines. The CT scanning can be used to evaluate           individual grades alone.
extension into the bladder and lymph nodes to help stage the                                         Histologic scoring system
patient's cancer or to consider lymph node sampling prior to                                         showing the 2 most common
treatment. TRUS is no better than DRE, and positron emission                                         patterns seen on the biopsy
tomography scans have not been proven effective.                                                     specimen,      termed     the
MRI is superior to bone scan in evaluating bone metastasis                                           Gleason score.
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.
Anterior and posterior bone scans of a patient with prostate
cancer, with metastasis to the 12th rib and thoracic spine
represented by the increased uptake of isotope.                     Grades are based on the extent to which the epithelium
Neither CT scanning nor MRI can be used to determine if             assumes a normal glandular structure. A grade of 1 indicates
lymph nodes are reactive or contain malignant deposits              a near-normal pattern, and grade 5 indicates the absence of
unless the nodes are significantly enlarged and a                   any glandular pattern (less malignant to more malignant).
percutaneous biopsy can be performed.                               This scheme of grading histological features greatly depends
There is increasing interest in using metabolic activity to         on the skill and experience of the pathologist and is subject
detect cancer foci. Positron emission tomography (PET) uses         to some degree of individual variation.
glucose analogue 18 F-fluorodeoxyglucose (18 F-FDG) to              1. A score of 2-4 is considered low grade or well
detect cancer, but studies thus far have been disappointing              differentiated.
for prostate cancer detection.                                      2. A score of 5-7 is considered moderate grade or
C-choline PET scans fused with CT imaging show more                      moderately differentiated.
promise but are not yet the standard of care. Likewise, there       3. A score of 8-10 is considered high grade or poorly
                                                                         differentiated.
Although the change in glandular architecture represented by       over another remains controversial. The choice of definitive
the Gleason score is currently the most widely used and            therapy has been suggested to make a significant difference
correlative histological parameter, it is not the only             in long-term survival in less than 10% of patients. This means
histological change that can be observed in prostate cancers.      that most patients are either cured by any definitive therapy
Indeed, notable changes in cell and nuclear morphology,            or present with incurable disease that cannot be detected,
neuroendocrine differentiation, and vascularity can be             and, ultimately, any treatment modality fails to be curative.
observed and may have great prognostic significance.               A 2008 research summary by the Agency for Healthcare
Perineural invasion is an indicator of invasiveness and is         Research and Quality (AHRQ) concluded that no single
considered in terms of which side should possibly undergo a        therapy can be considered the preferred treatment for
nerve-sparing procedure and whether a patient might benefit        presumed organ-confined prostate cancer. The AHRQ based
more from high- or low-risk brachytherapy.                         this conclusion partly on the lack of data regarding efficacy
Prostatic intraepithelial neoplasia (PIN) represents the           and partly on the concept that differences in adverse effects,
putative precancerous end of the morphologic continuum of          convenience, and costs among the available therapies may
cellular proliferations within prostatic ducts, ductules, and      be important factors in the choice of treatment in an
acini.                                                             individual patient. The AHRQ noted that, although all
Two grades of PIN are identified. Low-grade PIN is mild            treatment options carry adverse effects, patient satisfaction
                                                                                         8
dysplasia. High-grade PIN encompasses moderate and severe          with therapy is high.
dysplasia. High-grade PIN is considered by most to be a            Molecular prognostic markers
precursor of invasive carcinoma. Men with high-grade PIN           Over the past few years, several molecular markers have
alone can be started on finasteride and monitored closely.         been shown to aid in the prognostication of patients
The continuum that culminates in high-grade PIN and early          undergoing treatment for localized and metastatic prostate
invasive cancer is characterized by basal cell layer or            cancers. Assessment of the molecular alterations or gene
basement membrane disruption, progressive loss of                  products ofTP53, RB, BCL2, cathepsin-D, CDH1, and PTEN,
secretory differentiation markers, increasing nuclear and          among many others, have been reported. Prospective trials
nucleolar abnormalities, increasing proliferative potential,       are needed to assess these markers more thoroughly before
and increasing variation in DNA content (aneuploidy).              their implementation in current management is
Clinical studies suggest that PIN predates a carcinoma by 10       recommended.
or more years. The clinical importance of recognizing PIN is       Reverse transcriptase-polymerase chain reaction
based on its strong association with carcinoma. Recent             Reverse transcriptase-polymerase chain reaction (RTPCR)
studies claim that men with high-grade PIN in a prostate           testing may be able to find very small amounts of PSA nucleic
biopsy specimen have a 35-50% chance of being diagnosed            acid in the blood stream, prostatic fossa, or bone marrow. In
with prostate cancer after a subsequent biopsy. Atypical           the future, this may be helpful in determining which patients
small acinar proliferation (ASAP) has also been associated         have residual tumor following surgery (RTPCR-positive
with higher cancer detection rates. The identification of PIN      prostate fossa) or a higher rate of tumor recurrence (RTPCR-
in prostate biopsy specimens warrants further searching for        positive lymph nodes at surgery or persistently positive bone
concurrent invasive carcinoma. In most men, this means             marrow samples months after treatment).
repeat biopsies if the PSA level changes significantly. The
same may also be true for ASAP findings after biopsy.
Relevant Anatomy
See Image 2. 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 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
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.
Future and Controversies
Whether one of the several different modalities used for
treating localized prostate cancer offers survival benefits

				
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