Prostate cancer is usually adenocarcinoma. Symptoms are rare until urethral obstruction occurs. Diagnosis is suggested by digital rectal examination or prostate-specific antigen measurement and confirmed by biopsy. Prognosis for most patients with prostate cancer, especially when it is localized or regional, is very good; more men die with prostate cancer than of it. Treatment is with prostatectomy, radiation therapy, palliative measures (eg, hormonal therapy, radiation therapy, chemotherapy), or, for many elderly and even carefully selected younger patients, active surveillance.
Adenocarcinoma of the prostate is the most common nondermatologic cancer in men > 50 in the US. In the US, about 217,750 new cases and about 32,000 deaths (2010 estimates) occur each year. Incidence increases with each decade of life; autopsy studies show prostate cancer in 15 to 60% of men age 60 to 90 yr, with incidence increasing with age. The lifetime risk of being diagnosed with prostate cancer is 1 in 6. Median age at diagnosis is 72, and > 75% of prostate cancers are diagnosed in men > 65. Risk is highest for black men.
Sarcoma of the prostate is rare, occurring primarily in children. Undifferentiated prostate cancer, squamous cell carcinoma, and ductal transitional carcinoma also occur infrequently. Prostatic intraepithelial neoplasia is considered a possible premalignant histologic change.
Hormonal influences contribute to the course of adenocarcinoma but almost certainly not to other types of prostate cancer.
Symptoms and Signs
Prostate cancer usually progresses slowly and rarely causes symptoms until advanced. In advanced disease, hematuria and symptoms of bladder outlet obstruction (eg, straining, hesitancy, weak or intermittent urine stream, a sense of incomplete emptying, terminal dribbling) may appear. Bone pain may result from osteoblastic metastases to bone (commonly pelvis, ribs, vertebral bodies).
Sometimes stony, hard induration or nodules are palpable during digital rectal examination (DRE), but the examination is often normal; induration and nodularity suggest cancer but must be differentiated from granulomatous prostatitis, prostate calculi, and other prostate disorders. Extension of induration to the seminal vesicles and lateral fixation of the gland suggest locally advanced prostate cancer. Prostate cancers detected by DRE tend to be large, and > 50% extend through the capsule.
Most cancers today are found by screening with serum prostate-specific antigen (PSA) levels (and sometimes DRE), commonly done annually in men > 50 yr. Sometimes, annual screening is begun earlier for men at high risk (eg, those with a family history of prostate cancer and blacks). Abnormal findings require histologic confirmation, most commonly by transrectal ultrasound (TRUS)–guided transrectal needle biopsy, which can be done in an office with use of local anesthesia. Hypoechoic areas are more likely to represent cancer. Occasionally, prostate cancer is diagnosed incidentally in tissue removed during surgery for benign prostatic hyperplasia (BPH).
It is still not certain whether screening decreases morbidity or mortality or whether any gains resulting from screening outweigh the decreases in quality of life from treatment of asymptomatic cancers. Most clinicians recommend annual screening. However, most patients with newly diagnosed prostate cancers have a normal DRE, and serum PSA is not ideal as a screening test. Although PSA is elevated in 25 to 92% of patients with prostate cancer (depending on tumor volume), it also is moderately elevated in 30 to 50% of patients with BPH (depending on prostate size and degree of obstruction), in some smokers, and for several weeks after prostatitis. A level of ≥ 4 ng/mL has traditionally been considered an indication for biopsy in men > 50 yr (in younger patients, levels > 2.5 ng/mL probably warrant biopsy because BPH, the most common cause of PSA elevation, is rare in younger men). Although very high levels are significant (suggesting extracapsular extension of the tumor or metastases) and likelihood of cancer increases with increasing PSA levels, there is no cut-off below which there is no risk.
In asymptomatic patients, positive predictive value for cancer is 67% for PSA > 10 ng/mL and 25% for PSA 4 to 10 ng/mL; recent evidence indicates a 15% prevalence of cancer in men ≥ 55 yr with PSA < 4 ng/mL and a 10% incidence with PSA between 0.6 and 1.0 ng/mL. Cancer present in men with lower levels tends to be smaller (often < 1 mL) and of lower grade, although high-grade cancer (Gleason score 7 to 10) can be present at any level of PSA; perhaps 15% of cancers manifesting with PSA < 4 ng/mL are high grade. Although it appears that a cut-off of 4 ng/mL will miss some potentially serious cancers, the cost and morbidity resulting from the increased number of biopsies necessary to find them is unclear.
The decision whether to biopsy may be helped by other PSA-related factors, even in the absence of a family history of prostate cancer. For example, the rate of change in PSA (PSA velocity) should be < 0.75 ng/mL/yr (lower in younger patients). Biopsy is indicated for PSA velocities higher than this.
Assays that determine the free-to-total PSA ratio and complex PSA are more tumor-specific than standard total PSA measurements and may reduce the frequency of biopsies in patients without cancer. Prostate cancer is associated with less free PSA; no standard cut-off has been established, but generally, levels < 10 to 20% warrant biopsy. Other isoforms of PSA and new markers for prostate cancer are being studied. None of these other uses of PSA answers all of the concerns about possibly triggering too many biopsies.
Clinicians should discuss the risks and benefits of PSA testing with patients. Some patients prefer to eradicate cancer at all costs no matter how low the potential for progression and possible metastases is and may prefer annual PSA testing. Others may value quality of life highly and can accept some uncertainty; they may prefer less frequent (or no) PSA testing.
Grading and staging
Grading, based on the resemblance of tumor architecture to normal glandular structure, helps define the aggressiveness of the tumor. Grading takes into account histologic heterogeneity in the tumor. The Gleason score is commonly used. The most prevalent pattern and the next most prevalent pattern are each assigned a grade of 1 to 5, and the two grades are added to produce a total score. Most experts consider a score ≤ 6 to be well differentiated, 7 moderately differentiated, and 8 to 10 poorly differentiated. The lower the score, the less aggressive and invasive is the tumor and the better is the prognosis. For localized tumors, the Gleason score helps predict the likelihood of capsular penetration, seminal vesicle invasion, and spread to lymph nodes. Gleason score, clinical stage, and PSA level together (using tables or nomograms) predict pathologic stage and prognosis better than any of them alone.
Prostate cancer is staged to define extent of the tumor (see Table 1: Genitourinary Cancer: Genitourinary Cancer Staging ). TRUS may provide information for staging, particularly about capsular penetration and seminal vesicle invasion. Patients with clinical stage T1c to T2a tumors, low Gleason score (≤ 7), and PSA < 10 ng/mL usually get no additional staging tests before proceeding to treatment. Radionuclide bone scans are rarely helpful for finding bone metastases (they are frequently abnormal because of the trauma of arthritic changes) until the PSA is > 20 ng/mL. CT (or MRI) of the abdomen and pelvis is commonly done to assess pelvic and retroperitoneal lymph nodes if the Gleason score is 8 to 10 and the PSA is > 10 ng/mL, or if the PSA is > 20 ng/mL with any Gleason score. Suspect lymph nodes can be further evaluated by using needle biopsy. An MRI with endorectal coil may also help define the local extent of the tumor in patients with locally advanced prostate cancer (stage T3). The role of In-111 capromab pendetide scanning for staging is evolving but is certainly not needed for early, localized disease. Elevated serum acid phosphatase—especially the enzymatic assay—correlates well with the presence of metastases, particularly in lymph nodes. However, this enzyme may also be elevated in BPH (and is slightly elevated after vigorous prostatic massage), multiple myeloma, Gaucher's disease, and hemolytic anemia. It is rarely used today to guide treatment or to follow patients after treatment, especially because its value when done as a radioimmune assay (the way it is usually done) has not been established. Reverse transcriptase–PCR assays for circulating prostate cancer cells are being studied as staging and prognostic tools.
Risk of cancer spread is considered low if
T2b tumor, Gleason score 7, or PSA > 10 ng/mL are considered intermediate risk by most experts. T2c tumor, Gleason score ≥ 8, or PSA > 20 ng/mL (or 2 intermediate risk factors) are generally high risk.
Both acid phosphatase and PSA levels decrease after treatment and increase with recurrence, but PSA is the most sensitive marker for monitoring cancer progression and response to treatment and has virtually replaced acid phosphatase for this purpose.
Prognosis for most patients with prostate cancer, especially when it is localized or regional, is very good. Life expectancy for elderly men with prostate cancer may differ little from age-matched men without prostate cancer, depending on their age and comorbidities. For many patients, long-term local control, or even cure, is possible. Potential for cure, even when cancer is clinically localized, depends on the tumor's grade and stage. Without early treatment, patients with high-grade, poorly differentiated cancer have a poor prognosis. Undifferentiated prostate cancer, squamous cell carcinoma, and ductal transitional carcinoma respond poorly to conventional therapies. Metastatic cancer has no cure. Median life expectancy with metastatic disease is 1 to 3 yr, although some patients live for many years.
Treatment is guided by PSA level, grade and stage of tumor, patient age, coexisting disorders, and life expectancy. The goal of therapy can be
Most patients, regardless of age, prefer definitive therapy if cancer is potentially curable. However, therapy is palliative rather than definitive if cancer has spread outside the prostate, because cure is unlikely.
Active surveillance is appropriate for many asymptomatic patients > 70 with low-risk, or possibly even intermediate-risk, localized prostate cancer or if life-limiting disorders coexist; in these patients, risk of death due to other causes is greater than that due to prostate cancer. This approach requires periodic DRE, PSA measurement, and monitoring of symptoms. In healthy younger men with low-risk cancer, active surveillance also requires periodic repeat biopsies. If the cancer progresses, treatment is required. About 30% of patients undergoing active surveillance eventually require therapy. In elderly men, active surveillance results in the same overall survival rate as prostatectomy; however, patients who had surgery have a significantly lower risk of distant metastases and disease-specific mortality.
Definitive therapy is aimed at curing prostate cancer. Radical prostatectomy and the minimally invasive techniques of cryotherapy and brachytherapy are used.
Radical prostatectomy (removal of prostate with seminal vesicles and regional lymph nodes) is probably best for patients < 70 with a tumor confined to the prostate. Prostatectomy is appropriate for some elderly patients, based on life expectancy, coexisting disorders, and ability to tolerate surgery and anesthesia. Prostatectomy is done through an incision in the lower abdomen. More recently, a robot-assisted laparoscopic approach has been developed that minimizes blood loss and hospital stay but has not been shown to alter outcomes. Complications include urinary incontinence (in about 5 to 10%), bladder neck contracture or urethral stricture (in about 7 to 20%), erectile dysfunction (in about 30 to 100%—heavily dependent on age and current function), and rectal injury (in 1 to 2%). Nerve-sparing radical prostatectomy reduces the likelihood of erectile dysfunction but cannot always be done, depending on tumor stage and location.
Cryotherapy (destruction of prostate cancer cells by freezing with cryoprobes, followed by thawing) is less well established; long-term outcomes are unknown. Adverse effects include bladder outlet obstruction, urinary incontinence, erectile dysfunction, and rectal pain or injury.
Standard external beam radiation therapy usually delivers 70 Gy in 7 wk, but this technique has been supplanted by conformal 3-dimensional radiation therapy and by intensity modulated radiation therapy (IMRT), which safely deliver doses approaching 80 Gy to the prostate; data indicate that the rate of local control is higher, especially for high-risk patients. Some decrease in erectile function occurs in at least 40%. Other adverse effects include radiation proctitis, cystitis, diarrhea, fatigue, and possibly urethral strictures, particularly in patients with a prior history of transurethral resection of the prostate. Results with radiation therapy and prostatectomy may be comparable, especially for patients with low pretreatment PSA levels.
Brachytherapy involves the implantation of radioactive seeds into the prostate through the perineum. These seeds emit a burst of radiation over a finite period (usually 3 to 6 mo) and are then inert. Research protocols are examining whether high-quality implants used as monotherapy or implants plus external beam radiation therapy are superior for intermediate-risk patients. Brachytherapy also decreases erectile function, although onset may be delayed and patients may be more responsive to phosphodiesterase type 5 inhibitors than patients whose neurovascular bundles are resected or injured during surgery. Urinary frequency, urgency, and, less often, retention are common but usually subside over time. Other adverse effects include increased bowel movements; rectal urgency, bleeding, or ulceration; and prostatorectal fistulas.
For short-term palliation, ≥ 1 drugs may be used, including antiandrogens, chemotherapy drugs (eg, mitoxantrone, estramustine, taxanes), corticosteroids, and ketoconazole; docetaxel plus prednisone is a common combination. Local radiation therapy is usually palliative for patients with symptomatic bone metastases.
Patients with a locally advanced tumor or metastases may benefit from androgen deprivation by castration, either surgically with bilateral orchiectomy or medically with luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide, goserelin, and buserelin, with or without radiation therapy. Reduction in serum testosterone with LHRH agonists equals that with bilateral orchiectomy. All of these treatments cause loss of libido and erectile dysfunction and may cause hot flashes. LHRH agonists may cause PSA levels to increase temporarily. Some patients benefit from adding antiandrogens (eg, flutamide, bicalutamide, nilutamide, cyproterone acetate [not available in US]) for total androgen blockade. Maximal androgen blockade usually refers to LHRH agonists plus antiandrogens, but its benefits appear minimally better than those of an LHRH agonist (or orchiectomy) alone. Another approach is intermittent androgen blockade, which purports to delay emergence of androgen-independent prostate cancer. Total androgen ablation is given until PSA levels are reduced (usually to undetectable levels), then stopped. Treatment is started again when PSA levels rise above a certain threshold, although the ideal threshold is not yet defined. The optimal schedules for treatment and time off treatment have not been determined and vary widely among practitioners. Androgen deprivation may impair quality of life significantly (eg, self-image, attitude toward the cancer and its treatment, energy levels) and cause osteoporosis, anemia, and loss of muscle mass with long-term treatment. Exogenous estrogens are rarely used because they have a risk of cardiovascular and thromboembolic complications. There is no standard therapy for hormone-refractory prostate cancer.
Angiogenesis inhibitors (eg, thalidomide, endostatin), matrix metalloproteinase inhibitors, and cytotoxic and biologic drugs (eg, genetically designed vaccines, antisense therapy, monoclonal antibodies) are being studied and may provide palliation and prolong survival, but their superiority over corticosteroids alone has not been proved. Sipuleucel-T, an autologous cellular immunotherapy drug, is now available for some men with advanced prostate cancer.
For high-grade tumors that extend beyond the prostatic capsule, several treatment protocols exist. Chemotherapy, with or without hormonal therapy, is used before surgery in some protocols and along with radiation therapy in others. Chemotherapy regimens vary by center and trial.
Last full review/revision December 2007 by David A. Swanson, MD