Benign Prostatic Hyperplasia (BPH)
Incidence & Epidemiology BPH is the most common benign tumor in men, and its incidence is age-related. The prevalence of histologic BPH in autopsy studies rises from approximately 20% in men aged 41–50, to 50% in men aged 51–60, and to over 90% in men older than 80. Although clinical evidence of disease occurs less commonly, symptoms of prostatic obstruction are also age-related. At age 55, approximately 25% of men report obstructive voiding symptoms. At age 75, 50% of men complain of a decrease in the force and caliber of their urinary stream. Risk factors for the development of BPH are poorly understood. Some studies have suggested a genetic predisposition, and some have noted racial differences. Approximately 50% of men under the age of 60 who undergo surgery for BPH may have a heritable form of the disease. This form is most likely an autosomal dominant trait, and first-degree male relatives of such patients carry an increased relative risk of approximately 4-fold. Etiology The etiology of BPH is not completely understood, but it seems to be multifactorial and endocrine controlled. The prostate is composed of both stromal and epithelial elements, and each, either alone or in combination, can give rise to hyperplastic nodules and the symptoms associated with BPH. Each element may be targeted in medical management schemes. Observations and clinical studies in men have clearly demonstrated that BPH is under endocrine control. Castration results in the regression of established BPH and improvement in urinary symptoms. Additional investigations have demonstrated a positive correlation between levels of free testosterone and estrogen and the volume of BPH. The latter may suggest that the association between aging and BPH might result from the increased estrogen levels of aging causing induction of the androgen receptor, which thereby sensitizes the prostate to free testosterone. However, no studies to date have been able to demonstrate elevated estrogen receptor levels in human BPH. Pathology As discussed above, BPH develops in the transition zone. It is truly a hyperplastic process resulting from an increase in cell number. Microscopic evaluation reveals a nodular growth pattern that is composed of varying amounts of stroma and epithelium. Stroma is composed of varying amounts of collagen and smooth muscle. The differential representation of the histologic components of BPH explains, in part, the potential responsiveness to medical therapy. Thus alpha-blocker therapy may result in excellent responses in patients with BPH that has a significant component of smooth muscle, while those with BPH predominantly composed of epithelium might respond better to 5 As BPH nodules in the transition zone enlarge, they compress the outer zones of the prostate, resulting in the formation of a so-called surgical capsule. This boundary separates the transition zone from the peripheral zone and serves as a cleavage plane for open enucleation of the prostate during open simple prostatectomies performed for BPH. Pathophysiology One can relate the symptoms of BPH to either the obstructive component of the prostate or the secondary response of the bladder to the outlet resistance. The obstructive component can be subdivided into the mechanical and the dynamic obstruction. As prostatic enlargement occurs, mechanical obstruction may result from intrusion into the urethral lumen or bladder neck, leading to a higher bladder outlet resistance. Prior to the zonal classification of the prostate, urologists often referred to the "3 lobes" of the prostate, namely, the median and the two lateral lobes. Prostatic size on digital rectal examination (DRE) correlates poorly with symptoms, in part because the median lobe is not readily palpable. The dynamic component of prostatic obstruction explains the variable nature of the symptoms experienced by patients. The prostatic stroma, composed of smooth muscle and collagen, is rich in adrenergic nerve supply. The level of autonomic stimulation thus sets a tone to the prostatic urethra. Use of alpha-blocker therapy decreases this tone, resulting in a decrease in outlet resistance. The irritative voiding complaints (see below) of BPH result from the secondary response of the bladder to the increased outlet resistance. Bladder outlet obstruction leads to detrusor muscle hypertrophy and hyperplasia as well as collagen deposition. Although the latter is most likely responsible for a decrease in bladder compliance, detrusor instability is also a factor. On gross inspection, thickened detrusor muscle bundles are seen as trabeculation on cystoscopic examination. If left unchecked, mucosal herniation between detrusor muscle bundles ensues, causing diverticula formation (so-called false diverticula composed of only mucosa and serosa). Clinical Findings Symptoms As discussed above, the symptoms of BPH can be divided into obstructive and irritative complaints. Obstructive symptoms include hesitancy, decreased force and caliber of stream, sensation of incomplete bladder emptying, double voiding (urinating a second time within 2 h of the previous void), straining to urinate, and post-void dribbling. Irritative symptoms include urgency, frequency, and nocturia. The self-administered questionnaire developed by the American Urological Association (AUA) is both valid and reliable in identifying the need to treat patients and in monitoring their response to therapy. The AUA Symptom Score questionnaire (Table 22–1) is perhaps the single most important tool used in the evaluation of patients with BPH and is recommended for all patients before the initiation of therapy. This assessment focuses on 7 items that ask patients to quantify the severity of their obstructive or irritative complaints on a scale of 0–5. Thus, the score can range from 0 to 35. A symptom score of 0–7 is considered mild, 8–19 is considered moderate, and 20–35 is considered severe. The relative distribution of scores for BPH patients and control subjects is, respectively, 20% and 83% in those with mild scores, 57% and 15% in those with moderate scores, and 23% and 2% in those with severe scores (McConnell et al, 1994). A detailed history focusing on the urinary tract excludes other possible causes of symptoms that may not result from the prostate, such as urinary tract infection, neurogenic bladder, urethral stricture, or prostate cancer. Signs A physical examination, DRE, and focused neurologic examination are performed on all patients. The size and consistency of the prostate is noted, even though prostate size, as determined by DRE, does not correlate with severity of symptoms or degree of obstruction. BPH usually results in a smooth, firm, elastic enlargement of the prostate. Induration, if detected, must alert the physician to the possibility of cancer and the need for further evaluation (ie, prostate-specific antigen [PSA], transrectal ultrasound, and biopsy). Laboratory Findings A urinalysis to exclude infection or hematuria and serum creatinine measurement to assess renal function are required. Renal insufficiency may be observed in 10% of patients with prostatism and warrants upper-tract imaging. Patients with renal insufficiency are at an increased risk of developing postoperative complications following surgical intervention for BPH. Serum PSA is considered optional, but most physicians will include it in the initial evaluation. PSA, compared with DRE alone, certainly increases the ability to detect CaP, but because there is much overlap between levels seen in BPH and CaP, its use remains controversial (see Screening for CaP). Imaging Upper-tract imaging (intravenous pyelogram or renal ultrasound) is recommended only in the presence of concomitant urinary tract disease or complications from BPH (eg, hematuria, urinary tract infection, renal insufficiency, history of stone disease). Cystoscopy Cystoscopy is not recommended to determine the need for treatment but may assist in choosing the surgical approach in patients opting for invasive therapy. Additional Tests Cystometrograms and urodynamic profiles are reserved for patients with suspected neurologic disease or those who have failed prostate surgery. Measurement of flow rate, determination of post-void residual urine, and pressure-flow studies are considered optional. Differential Diagnosis Other obstructive conditions of the lower urinary tract, such as urethral stricture, bladder neck contracture, bladder stone, or CaP, must be entertained when evaluating men with presumptive BPH. A history of previous urethral instrumentation, urethritis, or trauma should be elucidated to exclude urethral stricture or bladder neck contracture. Hematuria and pain are commonly associated with bladder stones. CaP may be detected by abnormalities on the DRE or an elevated PSA (see below). A urinary tract infection, which can mimic the irritative symptoms of BPH, can be readily identified by urinalysis and culture; however, a urinary tract infection can also be a complication of BPH. Although irritative voiding complaints are also associated with carcinoma of the bladder, especially carcinoma in situ, the urinalysis usually shows evidence of hematuria. Likewise, patients with neurogenic bladder disorders may have many of the signs and symptoms of BPH, but a history of neurologic disease, stroke, diabetes mellitus, or back injury may be present as well. In addition, examination may show diminished perineal or lower extremity sensation or alterations in rectal sphincter tone or the bulbocavernosus reflex. Simultaneous alterations in bowel function (constipation) might also alert one to the possibility of a neurologic origin. Treatment After patients have been evaluated, they should be informed of the various therapeutic options for BPH. It is advisable for patients to consult with their physicians to make an educated decision on the basis of the relative efficacy and side effects of the treatment options. Specific treatment recommendations can be offered for certain groups of patients. For those with mild symptoms (symptom score 0–7), watchful waiting only is advised. On the other end of the therapeutic spectrum, absolute surgical indications include refractory urinary retention (failing at least one attempt at catheter removal), recurrent urinary tract infection from BPH, recurrent gross hematuria from BPH, bladder stones from BPH, renal insufficiency from BPH, or large bladder diverticula (McConnell et al, 1994). Watchful Waiting Very few studies on the natural history of BPH have been reported. The risk of progression or complications is uncertain. However, in men with symptomatic BPH, it is clear that progression is not inevitable and that some men undergo spontaneous improvement or resolution of their symptoms. Retrospective studies on the natural history of BPH are inherently subject to bias, related to patient selection and the type and extent of follow-up. Very few prospective studies addressing the natural history of BPH have been reported. Recently, a large randomized study compared finasteride with placebo in men with moderately to severely symptomatic BPH and enlarged prostates on DRE (McConnell et al, 1998). Patients in the placebo arm of the study had a 7% risk of developing urinary retention over 4 years. As mentioned above, watchful waiting is the appropriate management of men with mild symptom scores (0–7). Men with moderate or severe symptoms can also be managed in this fashion if they so choose. Neither the optimal interval for follow-up nor specific endpoints for intervention have been defined. Medical Therapy Alpha Blockers The human prostate and bladder base contains alpha-1-adrenoreceptors, and the prostate shows a contractile response to corresponding agonists. The contractile properties of the prostate and bladder neck seem to be mediated primarily by the subtype Phenoxybenzamine and prazosin have comparable efficacy with respect to symptomatic relief, but the higher side-effect profile of phenoxybenzamine, associated with its lack of alpha-receptor specificity, precludes its use in BPH patients. Dose titration is necessary with prazosin, with typical therapy started at 1 mg at bedtime for 3 nights, then increased to 1 mg twice a day, which is titrated up to 2 mg twice a day if necessary. At higher doses, little additional symptomatic improvement is observed and side-effect profiles worsen. Typical side effects include orthostatic hypotension, dizziness, tiredness, retrograde ejaculation, rhinitis, and headache. Long-acting alpha blockers make once-a-day dosing possible, but dose titration is still necessary. Terazosin is initiated at 1 mg daily for 3 days and increased to 2 mg daily for 11 days and then to 5 mg per day. Dosage can be escalated to 10 mg daily if necessary. Therapy with doxazosin is started at 1 mg daily for 7 days and increased to 2 mg daily for 7 days, and then to 4 mg daily. Dosage can be escalated to 8 mg daily if necessary. Side effects are similar to those described for prazosin. The most recent advance in alpha-blocker therapy is related to the identification of subtypes of alpha-1-receptors. Selective blockade of the Several randomized, double-blind, placebo-controlled trials, individually comparing terazosin, doxazosin, or tamsulosin with placebo, have demonstrated the safety and efficacy of all of these agents. Comparative trials of various alpha blockers are ongoing. 5 Finasteride is a 5 Several randomized, double-blind, placebo-controlled trials have compared finasteride with placebo. Efficacy, safety, and durability are well established. However, symptomatic improvement is seen only in men with enlarged prostates (> 40 cm3). Side effects include decreased libido, decreased ejaculate volume, and impotence. Serum PSA is reduced by approximately 50% in patients being treated with finasteride, but individual values may vary, thus complicating cancer detection. A recent report suggests that finasteride therapy may decrease the incidence of urinary retention and the need for surgical intervention in men with enlarged prostates and moderate to severe symptoms (McConnell et al, 1998). However, optimal identification of appropriate patients for prophylactic therapy remains to be determined. Combination Therapy The first randomized, double-blind, placebo-controlled study investigating combination alpha-blocker and 5 Phytotherapy Phytotherapy refers to the use of plants or plant extracts for medicinal purposes. The use of phytotherapy in BPH has been popular in Europe for years, and its use in the United States is growing as a result of patient-driven enthusiasm. Several plant extracts have been popularized, including the saw palmetto berry, the bark of Pygeum africanum, the roots of Echinacea purpurea and Hypoxis rooperi, pollen extract, and the leaves of the trembling poplar. The mechanisms of action of these phytotherapies are unknown, and the efficacy and safety of these agents have not been tested in multicenter, randomized, double-blind, placebo-controlled studies. Conventional Surgical Therapy Transurethral Resection of the Prostate (TURP) Ninety-five percent of simple prostatectomies can be done endoscopically. Most of these procedures involve the use of a spinal anesthetic and require a 1- to 2-day hospital stay. Symptom score and flow rate improvement with TURP is superior to that of any minimally invasive therapy. The length of hospital stay of patients undergoing TURP, however, is greater. Much controversy revolves around possible higher rates of morbidity and mortality associated with TURP in comparison with those of open surgery, but the higher rates observed in one study were probably related to more significant comorbidities in the TURP patients than in the patients undergoing open surgery. Several other studies could not confirm the difference in mortality when results were controlled for age and comorbidities. Risks of TURP include retrograde ejaculation (75%), impotence (5–10%), and incontinence (< 1%). Complications include bleeding, urethral stricture or bladder neck contracture, perforation of the prostate capsule with extravasation, and if severe, TUR syndrome resulting from a hypervolemic, hyponatremic state due to absorption of the hypotonic irrigating solution. Clinical manifestations of the TUR syndrome include nausea, vomiting, confusion, hypertension, bradycardia, and visual disturbances. The risk of the TUR syndrome increases with resection times over 90 min. Treatment includes diuresis and, in severe cases, hypertonic saline administration. Transurethral Incision of the Prostate Men with moderate to severe symptoms and a small prostate often have posterior commissure hyperplasia (elevated bladder neck). These patients will often benefit from an incision of the prostate. This procedure is more rapid and less morbid than TURP. Outcomes in well-selected patients are comparable, although a lower rate of retrograde ejaculation with transurethral incision has been reported (25%). The technique involves two incisions using the Collins knife at the 5 and 7 o'clock positions. The incisions are started just distal to the ureteral orifices and are extended outward to the verumontanum. Open Simple Prostatectomy When the prostate is too large to be removed endoscopically, an open enucleation is necessary. What constitutes "too large" is subjective and will vary depending upon the surgeon's experience with TURP. Glands over 100 g are usually considered for open enucleation. Open prostatectomy may also be initiated when concomitant bladder diverticulum or a bladder stone is present or if dorsal lithotomy positioning is not possible. Open prostatectomies can be done with either a suprapubic or retropubic approach. A simple suprapubic prostatectomy is performed transvesically and is the operation of choice in dealing with concomitant bladder pathology. After the bladder is opened, a semicircular incision is made in the bladder mucosa, distal to the trigone. The dissection plane is initiated sharply, and then blunt dissection with the finger is performed to remove the adenoma. The apical dissection should be done sharply to avoid injury to the distal sphincteric mechanism. After the adenoma is removed, hemostasis is attained with suture ligatures, and both a urethral and a suprapubic catheter are inserted before closure. In a simple retropubic prostatectomy, the bladder is not entered. Rather, a transverse incision is made in the surgical capsule of the prostate, and the adenoma is enucleated as described above. Only a urethral catheter is needed at the end of the procedure. Minimally Invasive Therapy Laser Therapy Many different techniques of laser surgery for the prostate have been described. Two main energy sources of lasers have been utilized—Nd:YAG and holmium:YAG. Several different coagulation necrosis techniques have been described. Transurethral laser-induced prostatectomy (TULIP) is done with transrectal ultrasound guidance. The TULIP device is placed in the urethra, and transrectal ultrasound is used to direct the device as it is slowly pulled from the bladder neck to the apex. The depth of treatment is monitored with ultrasound. Most urologists prefer to use visually directed laser techniques. Visual coagulative necrosis techniques have been popularized by Kabalin. Under cystoscopic control, the laser fiber is pulled through the prostate at several designated areas, depending upon the size and configuration of the prostate. Four quadrant and sextant approaches have been described for lateral lobes, with additional treatments directed at enlarged median lobes. Coagulative techniques do not create an immediate visual defect in the prostatic urethra, but rather tissue is sloughed over the course of several weeks and up to 3 months following the procedure. Visual contact ablative techniques are more time-consuming procedures because the fiber is placed in direct contact with the prostate tissue, which is vaporized. An immediate defect is obtained in the prostatic urethra, similar to that seen during TURP. Interstitial laser therapy places fibers directly into the prostate, usually under cystoscopic control. At each puncture, the laser is fired, resulting in submucosal coagulative necrosis. This technique may result in fewer irritative voiding symptoms, because the urethral mucosa is spared and prostate tissue is resorbed by the body rather than sloughed. Advantages of laser surgery include (1) minimal blood loss, (2) rare instances of TUR syndrome, (3) ability to treat patients receiving anticoagulation therapy, and (4) ability to be done as an outpatient procedure. Disadvantages include (1) lack of availability of tissue for pathologic examination, (2) longer postoperative catheterization time, (3) more irritative voiding complaints, and (4) high cost of laser fibers and generators. Large-scale, multicenter, randomized studies with long-term follow-up are needed to compare laser prostate surgery with TURP and other forms of minimally invasive surgery. Transurethral Electrovaporization of the Prostate Transurethral electrovaporization uses the standard resectoscope but replaces a conventional loop with a variation of a grooved rollerball. High current densities cause heat vaporization of tissue, resulting in a cavity in the prostatic urethra. Because the device requires slower sweeping speeds over the prostatic urethra, and the depth of vaporization is approximately one-third of a standard loop, the procedure usually takes longer than a standard TURP. Long-term comparative data are needed. Hyperthermia Microwave hyperthermia is most commonly delivered with a transurethral catheter. Some devices cool the urethral mucosa to decrease the risk of injury. However, if temperatures do not exceed 45 C, cooling is unnecessary. Improvement in symptom score and flow rate is obtained, but as with laser surgery, large-scale, randomized studies with long-term follow-up are needed to assess durability and cost-effectiveness. Transurethral Needle Ablation of the Prostate Transurethral needle ablation uses a specially designed urethral catheter that is passed into the urethra. Interstitial radiofrequency needles are then deployed from the tip of the catheter, piercing the mucosa of the prostatic urethra. The use of radio frequencies to heat the tissue results in a coagulative necrosis. This technique is not adequate treatment for bladder neck and median lobe enlargement. Subjective and objective improvement in voiding occurs, but as mentioned above, comparative long-term randomized studies are lacking. High-Intensity Focused Ultrasound High-intensity focused ultrasound is another means of performing thermal tissue ablation. A specially designed, dual-function ultrasound probe is placed in the rectum. This probe allows transrectal imaging of the prostate and also delivers short bursts of high-intensity focused ultrasound energy, which heats the prostate tissue and results in coagulative necrosis. Bladder neck and median lobe enlargement are not adequately treated with this technique. Although ongoing clinical trials demonstrate some improvement in symptom score and flow rate, the durability of response is unknown. Intraurethral Stents Intraurethral stents are devices that are endoscopically placed in the prostatic fossa and are designed to keep the prostatic urethra patent. They are usually covered by urothelium within 4–6 months after insertion. These devices are typically used for patients with limited life expectancy who are not deemed to be appropriate candidates for surgery or anesthesia. With the advent of other minimally invasive techniques requiring minimal anesthesia (conscious sedation or prostatic blocks), their application has become more limited. Transurethral Balloon Dilation of the Prostate Balloon dilation of the prostate is performed with specially designed catheters that enable dilation of the prostatic fossa alone or the prostatic fossa and bladder neck. The technique is most effective in small prostates (< 40 cm3). Although it may result in improvement in symptom score and flow rates, the effects are transient and the technique is rarely used today. |
-reductase inhibitors. Patients with significant components of collagen in the stroma may not respond to either form of medical therapy. Unfortunately, one cannot reliably predict responsiveness to a specific therapy (see below).Carcinoma of the Prostate (CaP)
Incidence & Epidemiology Prostate cancer is the most common cancer diagnosed and is the second leading cause of cancer death in American men. Of all cancers, the prevalence of CaP increases the most rapidly with age. However, unlike most cancers, which have a peak age of incidence, the incidence of CaP continues to increase with advancing age. The lifetime risk of a 50-year-old man for latent CaP (detected as an incidental finding at autopsy, not related to the cause of death) is 40%; for clinically apparent CaP, 9.5%; and for death from CaP, 2.9%. Thus, many prostate cancers are indolent and inconsequential to the patient while others are virulent, and if detected too late or left untreated, they result in a patient's death. This broad spectrum of biological activity can make decision making for individual patients difficult. Several risk factors for prostate cancer have been identified. As discussed above, increasing age heightens the risk for CaP. Which of the factors associated with the aging process are responsible for this observation is unknown. The probability of CaP developing in a man under the age of 40 is 1 in 10,000; for men 40–59 it is 1 in 103, and for men 60–79 it is 1 in 8. African Americans are at a higher risk for CaP than whites. In addition, African American men tend to present at a later stage of disease than whites. Controversial data have been reported suggesting that mortality from this disease may also be higher for African Americans. A positive family history of CaP also increases the relative risk for CaP. The age of disease onset in the family member with the diagnosis of CaP affects a patient's relative risk. If the age of onset is 70, the relative risk is increased 4-fold; if the age of onset is 60, the relative risk is increased 5-fold; and if the age of onset is 50, the relative risk is increased 7-fold. High dietary fat intake increases the relative risk for CaP by almost a factor of 2. Another exposure that may increase the risk for CaP involves cadmium, which is found in cigarette smoke, alkaline batteries, and in the welding industry. Previous vasectomy has been suggested as a factor that heightens the risk for CaP, but these data are controversial. Etiology The specific molecular mechanisms involved in the development and progression of CaP are an area of intense interest in the laboratory. The gene responsible for familial CaP resides on chromosome 1. Several regions of the human genome have been identified as possible areas that harbor tumor suppressor genes that may be involved in CaP. The regions most commonly identified are chromosomes 8p, 10q, 13q, 16q, 17p, and 18q. Pathology Over 95% of the cancers of the prostate are adenocarcinomas. Of the other 5%, 90% are transitional cell carcinomas, and the remaining cancers are neuroendocrine ("small cell") carcinomas or sarcomas. This discussion will address only adenocarcinomas. The cytologic characteristics of CaP include hyperchromatic, enlarged nuclei with prominent nucleoli. Cytoplasm is often abundant; thus, nuclear-to-cytoplasmic ratios are not often helpful in making a diagnosis of CaP, unlike their usefulness in diagnosing many other neoplasms. Cytoplasm is often slightly blue-tinged or basophilic, which may assist in the diagnosis. The diagnosis of CaP is truly an architectural one. The basal cell layer is absent in CaP, although it is present in normal glands, BPH glands, and the precursor lesions of CaP. If the diagnosis of CaP is in question, high-molecular-weight keratin immunohistochemical staining is useful, as it preferentially stains basal cells. Absence of staining is thus consistent with CaP. Prostatic intraepithelial neoplasia (PIN) is the precursor to invasive CaP. The critical distinguishing feature of invasive CaP is that the basal cell layer of the glandular architecture is absent. While PIN has the cytologic characteristics of CaP, the basal cell layer is present. PIN is usually classified into two categories, high grade (HGPIN) and low grade (LGPIN). The clinical importance of this distinction is that, when detected on prostate needle biopsy, HGPIN is usually associated with invasive CaP in approximately 50–80% of cases, whereas LGPIN is associated with invasive CaP only about 20% of the time. Thus, if a patient has needle biopsies showing only HGPIN, a repeat biopsy is critical to exclude the possibility of having missed an invasive cancer. Sixty to 70 percent of cases of CaP originate in the peripheral zone, while 10–20% originate in the transition zone and 5–10% in the central zone. Radical prostatectomy series often demonstrate multifocal cancers within the prostate, with some variation in tumor grade. Grading & Staging The Gleason grading system is the most commonly employed grading system in the United States. It is truly a system that relies upon the low-power appearance of the glandular architecture under the microscope. In assigning a grade to a given tumor, pathologists assign a primary grade to the pattern of cancer that is most commonly observed and a secondary grade to the second most commonly observed pattern in the specimen. Grades range from 1 to 5. If the entire specimen has only one pattern present, then both the primary and secondary grade are reported as the same grade. The Gleason score or Gleason sum is obtained by adding the primary and secondary grades together. As Gleason grades range from 1 to 5, Gleason scores or sums thus range from 2 to 10. Well-differentiated tumors have a Gleason sum of 2–4; moderately differentiated tumors have a Gleason sum of 5–6; and poorly differentiated tumors have a Gleason sum of 8–10. Historically, tumors having a Gleason sum of 7 have sometimes been grouped with the moderately differentiated tumors and at other times with the poorly differentiated tumors. One point that needs to be clarified is that the primary Gleason grade is perhaps the most important with respect to placing patients in prognostic groups. This is most important in assessing patients with a Gleason sum of 7. Patients with a Gleason sum of 7 who have a primary Gleason grade of 4 (4 + 3) tend to have a worse prognosis than those who have a primary Gleason grade of 3 (3 + 4). Many clinical series have failed to distinguish between these two populations and, therefore, caution must be exercised in reviewing these series. Gleason grades 1 and 2 are characterized by small, uniformly shaped glands, closely packed, with little intervening stroma. Gleason grade 3 is characterized by variable-sized glands that percolate between normal stroma. A variant of Gleason grade 3 is referred to as a cribriform pattern. Here a small mass of cells is perforated by several gland lumens with no intervening stroma. This results in a cookie-cutter-like appearance of cell nests. The border of these cribriform glands is smooth. Gleason grade 4 has several histologic appearances. The characteristic observation common to all Gleason grade 4 patterns is incomplete gland formation. Sometimes glands appear fused, sharing a common cell border. At other times sheets of cell nests are seen or long cords of cells are observed. Cribriform glands can also occur in Gleason grade 4, but the cell masses are large and borders tend to appear ragged, with infiltrating fingerlike projections. Gleason grade 5 usually has single infiltrating cells, with no gland formation or lumen appearance. Comedocarcinoma is an unusual variant of Gleason grade 5 carcinoma that has the appearance of cribriform glands with central areas of necrosis. The TNM staging system for CaP is presented in Table 22–3 (American Joint Committee on Cancer, 1997). Note that with respect to the primary tumor categorization (T stage), the clinical staging system uses results of the DRE and transrectal ultrasound (TRUS), but not the results of the biopsy. Some examples to illustrate this staging system follow. If a patient has a palpable abnormality on one side of the prostate, even though biopsies demonstrate bilateral disease, his clinical stage remains T2a. If a patient has a normal DRE, with TRUS demonstrating a lesion on one side and a biopsy confirming cancer, his clinical stage is also T2a (using results of DRE and TRUS). A T1c cancer must have both a normal DRE and a normal TRUS. Another popular staging system from a historical perspective is the Whitmore-Jewett staging system. One modification of this system is presented in Table 22–4 to assist the reader in the review of older published series. This system predates the use of TRUS and thus does not incorporate its findings. Patterns of Progression The pattern of CaP progression has been well defined. The likelihood of local extension outside the prostate (extracapsular extension) or seminal vesicle invasion and distant metastases increases with increasing tumor volume and more poorly differentiated cancers. Small and well-differentiated cancers (grades 1 and 2) are usually confined to the prostate, whereas large-volume (> 4 cm3) or poorly differentiated (grades 4 and 5) cancers are more often locally extensive or metastatic to regional lymph nodes or bone. Penetration of the prostatic capsule by cancer is a common event and often occurs along perineural spaces. Seminal vesicle invasion is associated with a high likelihood of regional or distant disease. Locally advanced CaP may invade the bladder trigone, resulting in ureteral obstruction. Of note, rectal involvement is rare as Denonvilliers' fascia represents a strong barrier. Lymphatic metastases are most often identified in the obturator lymph node chain. Other sites of nodal involvement include the common iliac, presacral, and periaortic lymph nodes. The axial skeleton is the most usual site of distant metastases, with the lumbar spine being most frequently implicated. The next most common sites in decreasing order are proximal femur, pelvis, thoracic spine, ribs, sternum, skull, and humerus. The bone lesions of metastatic CaP are typically osteoblastic. Involvement of long bones can lead to pathologic fractures. Vertebral body involvement with significant tumor masses extending into the epidural space can result in cord compression. Visceral metastases most commonly involve the lung, liver, and adrenal gland. Central nervous system involvement is usually a result of direct extension from skull metastasis. Clinical Findings Symptoms Most patients with early-stage CaP are asymptomatic. The presence of symptoms often suggests locally advanced or metastatic disease. Obstructive or irritative voiding complaints can result from local growth of the tumor into the urethra or bladder neck or from its direct extension into the trigone of the bladder. Metastatic disease to the bones may cause bone pain. Metastatic disease to the vertebral column with impingement on the spinal cord may be associated with symptoms of cord compression, including paresthesias and weakness of the lower extremities and urinary or fecal incontinence. Signs A physical examination, including a DRE, is needed. Induration, if detected, must alert the physician to the possibility of cancer and the need for further evaluation (ie, PSA, TRUS, and biopsy). Locally advanced disease with bulky regional lymphadenopathy may lead to lymphedema of the lower extremities. Specific signs of cord compression relate to the level of the compression and may include weakness or spasticity of the lower extremities and a hyperreflexic bulbocavernosus reflex. Laboratory Findings Azotemia can result from bilateral ureteral obstruction either from direct extension into the trigone or from retroperitoneal adenopathy. Anemia may be present in metastatic disease. Alkaline phosphatase may be elevated in the presence of bone metastases. Serum acid phosphatase may be elevated with disease outside the confines of the prostate. Tumor Markers—Prostate-Specific Antigen (PSA) Serum PSA has revolutionized our ability to detect CaP. Current detection strategies include the efficient use of the combination of DRE, serum PSA, and TRUS with systematic biopsy. Unfortunately, PSA is not specific for CaP, as other factors such as BPH, urethral instrumentation, and infection can cause elevations of serum PSA. Although the last two factors can usually be clinically ascertained, distinguishing between elevations of serum PSA resulting from BPH and those related to CaP remains the most problematic. Numerous strategies to refine PSA for cancer detection have been explored. Their common goal is to decrease the number of false-positive test results. This would increase the specificity and positive predictive value of the test and lead to fewer unnecessary biopsies, lower costs, and reduced morbidity of cancer detection. Attempts at refining PSA have included PSA velocity (change of PSA over time), PSA density (standardizing levels in relation to the size of the prostate), age-adjusted PSA reference ranges (accounting for age-dependent prostate growth and occult prostatic disease), and PSA forms (free versus protein-bound molecular forms of PSA). PSA Velocity PSA velocity refers to the rate of change of serum PSA. A retrospective study has shown that men with prostate cancer have a more rapidly rising serum PSA in the years before diagnosis than do men without prostate cancer. Patients whose serum PSA increases by 0.75 ng/mL/y appear to be at an increased risk of harboring cancer. However, PSA velocity must be interpreted with caution. An elevated PSA velocity should be considered significant only when several serum PSA assays are carried out by the same laboratory over a period of at least 18 months. PSA Density PSA levels are elevated approximately 0.12 ng/mL per gram of BPH tissue. Thus, patients with enlarged glands due to BPH may have elevated PSA levels. The ratio of PSA to gland volume is termed the PSA density. Some investigators advocate prostate biopsy only if the PSA density exceeds 0.1 or 0.15, while others have not found PSA density to be useful. Problems with this approach include the facts that (1) epithelial-stromal ratios vary from gland to gland and only the epithelium produces PSA, and (2) errors in calculating prostatic volume may approach 25%. The positive predictive value of PSA density is slightly higher than the use of a PSA level > 4 ng/mL in several series (30–40% vs. 20–30%). Age-Adjusted Reference Ranges for PSA Age-adjusted PSA values for normal men are presented in Table 22–5 (Oesterling JE et al, 1993). It is thought that the rise in PSA with increasing age results from prostate gland growth from BPH, the higher incidence of subclinical prostatitis, and the growing prevalence of microscopic, clinically insignificant prostate cancers. Age-adjusted reference ranges increase the sensitivity in younger patients and increase the specificity in older patients. Concerns over the general applicability of these reference ranges have been raised because they were derived from US midwestern white men. Racial Variations in CaP Detection Although much evidence of racial variations in the incidence and mortality of CaP has been noted, little information is available on possible racial variations for cancer detection strategies. Recent reports have proposed different PSA density and age-specific reference ranges for African Americans and whites. Molecular Forms of PSA The most recent refinement in PSA has been the recognition of the various molecular forms of PSA—free and protein-bound. Approximately 90% of the serum PSA is bound to alpha-1-antichymotrypsin, and lesser amounts are free or are bound to alpha-2-macroglobulins. In the latter form, no epitopes to the antibodies used in the current assays are available, while PSA bound to alpha-1-antichymotrypsin may have 3 of its 5 epitopes masked. Early studies suggest that prostate cancer patients demonstrate a lower percentage of free PSA than do patients with benign disease. A large multicenter study has reported that in men with a normal DRE and a total PSA level between 4 and 10 ng/mL, a 25% free PSA cutoff would detect 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients and generally were less threatening in terms of tumor grade and volume (Catalona et al, 1998). Further validation studies with definition of optimal cutoff levels for different assays are needed, and issues such as possible racial variations in these levels must be addressed. Prostate Biopsy Systematic sextant prostate biopsy was the most commonly employed technique used in detecting CaP. Biopsies are usually obtained under TRUS guidance, from the apex, midsection, and base of each side of the prostate at the midsagittal line halfway between the lateral border and midline of the gland (Hodge et al, 1989). Information from sextant biopsies has mainly focused on cancer detection and has been underutilized for cancer staging. Several investigators have demonstrated some utility of systematic sextant biopsies in predicting extracapsular extension and risk of relapse following radical prostatectomy. Refinement in systematic biopsy strategies to increase cancer detection rates is ongoing. It is clear that more extensive biopsy schemes that sample the lateral aspect of the prostate increase cancer detection (Eskew et al, 1997; Presti et al, 2000). Such extended biopsy schemes are critical in patients undergoing repeat biopsy (Chon et al, 2002). Imaging TRUS TRUS is useful in performing prostatic biopsies and in providing some useful local staging information if cancer is detected. Almost all prostate needle biopsies are performed under TRUS guidance. This allows uniform spatial separation and sampling of the regions of the prostate and also makes lesion-directed biopsies possible. If visible, CaP tends to appear as a hypoechoic lesion in the peripheral zone. TRUS provides more accurate local staging than does DRE. The sonographic criteria for extracapsular extension are bulging of the prostate contour or angulated appearance of the lateral margin. The criteria for seminal vesicle invasion are a posterior bulge at the base of the seminal vesicle or asymmetry in echogenicity of the seminal vesicle associated with hypoechoic areas at the base of the prostate. TRUS also enables measurement of the prostate volume, which is needed in the calculation of PSA density. Typically, a prolate ellipsoid formula is used: ( Endorectal Magnetic Resonance Imaging The reported staging accuracy of endorectal coil magnetic resonance imaging (MRI) varies from 51% to 92%. While rendering high image quality, the endorectal coil MRI appears to be operator dependent, requiring education and expertise. Costs associated with endorectal MRI are also high, and until this methodology demonstrates superiority in providing clinical information that alters patient management, its use should be limited. Attempts to identify patients who could potentially benefit from this imaging are ongoing. Axial Imaging (CT, MRI) Cross-sectional imaging of the pelvis in patients with CaP is selectively performed to exclude lymph node metastases in high-risk patients who are thought to be candidates for definitive local therapy, whether it be surgery or irradiation. Both MRI and computed tomography (CT) are used for this purpose. Patients identified as having lymphadenopathy on imaging may undergo CT-guided fine-needle aspiration. If lymph node metastases are confirmed, such patients may be candidates for alternative treatment regimens. However, the incidence of lymph node metastases in contemporary radical prostatectomy series is low (< 10%). In addition, imaging is costly and its sensitivity is limited (30–40%). Various criteria can be used to identify patients for axial imaging, including negative bone scans and either T3 cancers or a PSA > 20 ng/mL and primary Gleason grade 4 or 5 cancers. Analyses of several contemporary series of patients with clinically localized prostate cancer suggest that the risk of lymph node metastases is low and that its risk can be quantified on the basis of serum PSA, local tumor stage, and tumor grade. The serum concentration of PSA correlates well with cancer volume and stage. However, considerable overlap exists, making the use of serum PSA alone inaccurate for clinical staging in most patients. Use of serum PSA in conjunction with tumor grade and stage adds considerable sensitivity and specificity to the prediction of lymph node status compared with the use of PSA alone. Several investigators have published nomograms and probability curves that aid in predicting pathologic stage (Partin et al, 1997; Narayan et al, 1995; Bostwick et al, 1996). Bone Scan When prostate cancer metastasizes, it most commonly does so to the bone. Soft tissue metastases (eg, lung and liver) are rare at the time of initial presentation. Although a bone scan has been considered a standard part of the initial evaluation of men with newly diagnosed prostate cancer, good evidence has been accumulated that it can be excluded in most of these men on the basis of serum PSA. Oesterling and colleagues have conducted studies to assess the ability of serum PSA to predict bone scan findings (Oesterling JE et al, 1993). On the basis of their results, bone scans can be omitted in patients with newly diagnosed, untreated prostate cancer who are asymptomatic and have serum PSA concentrations < 10 ng/mL. Molecular Staging Molecular staging refers to the detection of circulating prostate cells in the peripheral blood of men with CaP. The application of reverse transcription–polymerase chain reaction (RT-PCR) uses peripheral blood samples and attempts to identify the presence of the messenger RNA to PSA. If detected, this is indirect evidence of prostate cells in the peripheral circulation. However, the clinical significance of positive RT-PCR test results at the present time is unknown. Numerous tumor systems have been identified that shed tumor cells into the circulation, but this finding is not always indicative of metastatic disease or treatment failure. Further studies are needed before the widespread application of this methodology. Differential Diagnosis Not all patients with an elevated PSA concentration have CaP. Other factors that elevate serum PSA include BPH, urethral instrumentation, infection, prostatic infarction, or vigorous prostate massage. Induration of the prostate is associated not only with CaP, but also with chronic granulomatous prostatitis, previous TURP or needle biopsy, or prostatic calculi. Sclerotic lesions on plain x-ray films and elevated levels of alkaline phosphatase can be seen in Paget disease and can often be difficult to distinguish from metastatic CaP. In Paget disease, PSA levels are usually normal and x-ray findings demonstrate subperiosteal cortical thickening. Screening for CaP The case for CaP screening is supported by the following: The disease is burdensome in this country; PSA improves detection of clinically important tumors without significantly increasing the detection of unimportant tumors; most PSA-detected tumors are curable; prostate cancer mortality is declining in regions where screening occurs; and curative treatments are available. Although the benefit of screening was recently shown in one randomized Canadian study, several questions have been raised about the data analysis (Labrie et al, 1999). Two large randomized clinical trials to assess the benefit of screening are ongoing. In the Prostate, Lung, Colon and Ovarian Trial (PLCOT), 74,000 men have been randomized to annual DRE and PSA screening versus no screening. Results are anticipated in 2006. A larger trial involving 190,000 men in the European Randomized Study for Prostate Cancer Screening is anticipated to provide results in 2008. The efficacy of treatment is being examined in Scandinavia, where two randomized trials compare watchful waiting with radiation therapy or radical prostatectomy. A similar trial, Prostate Cancer Intervention Versus Observation Trial (PIVOT), is under way in the United States. Such trials, although imperfect, may give us the information we need before prostate cancer screening and treatment can be recommended with confidence. In summary, many factors must be considered by both clinicians and their patients who are contemplating screening for prostate cancer. The information provided should attempt to answer such questions as the likelihood that an unscreened asymptomatic man will be adversely affected by prostate cancer in his lifetime, whether the screening test will lengthen or improve the quality of life, the chances of having a false-positive result and its consequences, the value of a normal result, and the recommendations of various experts. Based on available data, our bias has been that relatively young, healthy, asymptomatic men are encouraged to undergo screening. Screening is highly encouraged in certain populations with a higher disease prevalence or higher mortality rates, such as African American men or men with a significant family history of CaP. If CaP is detected, patients are carefully counseled regarding the benefits and risks of all treatment options, including watchful waiting. At the present time the data suggest that if screening is done, the combination of DRE and serum PSA is best. Treatment Localized Disease General Considerations The optimal form of therapy for all stages of CaP remains a subject of great debate. Well-designed, randomized trials comparing various modalities for localized disease are lacking. Treatment dilemmas persist in the management of localized disease (T1 and T2) because of the uncertainty surrounding the relative efficacy of various modalities, including radical prostatectomy, radiation therapy, and surveillance. Currently, treatment decisions are based on the grade and stage of the tumor, the life expectancy of the patient, the ability of each therapy to ensure disease-free survival, its associated morbidity, and patient and physician preferences. Watchful Waiting No randomized trial has demonstrated the therapeutic benefit of radical treatment for early-stage prostate cancer. Patients with prostate cancer are often older and may have concomitant illnesses. In addition, the small, well-differentiated prostate cancers commonly found in this population are often associated with very slow growth rates. Several studies have shown that surveillance alone may be an appropriate form of management for highly selected patients with prostate cancer (Table 22–6). However, most patients in such series are older and have very small, well-differentiated cancers. Even in such a selected population, cancer death rates approach 10%. In addition, end points for intervention in patients on surveillance regimens have not been defined. Radical Prostatectomy The first radical perineal prostatectomy was performed by Hugh Hampton Young in 1904, and Millin first described the radical retropubic approach in 1945. However, the procedure remained unpopular because of frequent complications of incontinence and impotence. The rebirth of radical prostatectomy has resulted from a better understanding of the surgical anatomy of the pelvis. Description of the anatomy of the dorsal vein complex resulted in modifications in the surgical technique leading to reduced operative blood loss. In addition, improved visualization made possible a more precise apical dissection, allowing better reconstruction of the urinary tract and improved continence. Eversion of the bladder mucosa before anastomosis ensures a mucosa-to-mucosa apposition. Anatomic dissections have led to a better understanding of the prostate apex anatomy and its relationship to the distal urethral sphincteric mechanism. Description of the course of the cavernous nerves enabled modifications of the surgical technique, resulting in preservation of potency. The prognosis of patients treated by radical prostatectomy correlates with the pathologic stage of the specimen. Distant metastasis is inevitable in patients with positive lymph nodes. A high percentage of patients with seminal vesical involvement at radical prostatectomy are destined to distant failure. Fortunately, the number of patients with these adverse prognostic factors undergoing surgery is decreasing because of better candidate selection based on appropriate use of preoperative clinical parameters. Several investigators have established nomograms to predict final pathologic stage at radical prostatectomy based on the serum PSA level, clinical DRE stage, and Gleason sum derived from the biopsy. Patients with organ-confined cancer have 10-year disease-free survival ranging from 70% to 85% in several series. Those with focal extracapsular extension demonstrate 85% and 75% disease-free survival at 5 and 10 years, respectively. Patients with more extensive extracapsular extension demonstrate 70% and 40% disease-free survival at 5 and 10 years, respectively. High-grade tumors (Gleason sum > 7) have a higher risk of progression than do low-grade tumors. Disease-free survival at 10 years for patients with Gleason sum 2–6 tumors is in excess of 70%; for Gleason sum 7, 50%; and for Gleason sum > 8, 15%. Positive surgical margins significantly affect only tumors with extensive extracapsular extension. The role of neoadjuvant hormonal therapy in men with localized CaP is currently being studied. Several investigators have reported a decrease in the number of positi |
/6) x (anterior-posterior diameter) x (transverse diameter) x (sagittal diameter). TRUS is also used in the performance of cryosurgery and brachytherapy (see below).