ELEVATED PROSTATE-SPECIFIC ANTIGEN, ABNORMAL PROSTATE EVALUATION ON DIGITAL RECTAL EXAMINATION, AND TRANSRECTAL ULTRASOUND AND PROSTATE BIOPSY

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ELEVATED PROSTATE-SPECIFIC ANTIGEN, ABNORMAL PROSTATE EVALUATION ON DIGITAL RECTAL EXAMINATION, AND TRANSRECTAL ULTRASOUND AND PROSTATE BIOPSY Alan W. Partin, MD, PhD, and Ray E. Stutzman, MD

Prostate cancer screening for the early diagnosis of organ-confined, potentially curable prostate cancer has dramatically changed the practice of urology over the past 15 years. The introduction of prostate-specific antigen (PSA) testing, increased medical and public awareness for digital rectal examination (DRE), and transrectal ultrasonic-assisted needle biopsy of the prostate (TRUS/PNBX) has been instrumental in these dramatic changes. THE ROLE OF PSA IN DECISION MAKING REGARDING PROSTATE BIOPSY

PSA, an endogenous serum protease, has become the most important and widely used tumor marker in urologic oncology today.42 PSA, first identified nearly 3 decades ago' has been widely used in clinical practice for screening, staging, and monitoring patients with prostate cancer for over a decade.2x,.cl. h7 Since the introduction of PSA into widespread use in clinical practice for early detec-

tion of prostate cancer, there has been a marked increase in the incidence of localized disease coupled with a simultaneous decline in regional and metastatic prostate cancer between 1986 and 1996.33Although other factors are most assuredly related to this important stage shift, PSA is largely responsible. Earlydetection algorithms for diagnosing prostate cancer using PSA and DRE have increased the lead time for diagnosis of prostate cancer22 and increased the likelihood of diagnosing an organ-confined, potentially curable prostate cancer.R Both clinical and basic science research efforts over the last 2 decades have focused on improving PSA for early detection of prostate cancer. Various methods intended to optimize the measurement of serum PSA for detecting prostate cancer include (1) PSA density"; (2) PSA velocityh; (3) use of age-specific PSA references ranges4";and (4) the molecular forms (e.g., percent-free PSA) of PSA.'",", 32, O' Th'1s section focuses on the clinical usefulness (both advantages and limitations) of these optimizing techniques for the use of PSA for

From the Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland

UROLOGIC CLINICS OF NORTH AMERICA ~

VOLUME 25 * NUMBER 4 * NOVEMBER 1998

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early detection of prostate cancer. The author's also make recommendations, based on an evaluation of the present literature, for the use of these optimization techniques in 1998. These recommendations, although based on peer-reviewed published data in the literature, may change with time as better prospective multi-institutional clinical trials are reported. PSA Density

variation in the epithelial: stromal ratio between individuals.4i, '# These limitations, as well as others, have led to conflicting results regarding the clinical utility of PSA density to detect prostate cancer.', 'I The largest multicenter study investigating the efficacy of PSA density for early detection of prostate cancer reported that nearly 50%)of prostate cancers would have been missed if a PSA density cutoff of 0.15 ng/mL/cc had been used to define the need for prostate biopsy." Several authors, however, have found PSA density to be clinically useful.4, 3x, 51 In addition, Epstein and colleaguesIxdetermined that not only could PSA density improve the detection of prostate cancer, but it provided useful information in determining the aggressive nature of prostate cancers. Coupled with the number of biopsy cores that were positive, Gleason histologic score, and total serum PSA level, a PSA density cutoff of 0.15 ng/mL/cc provided useful information in determining the significance of a prostate cancer detected by biopsy.IHAt present, the use of a PSA density cutoff of 0.15 ng/mL/cc of prostate for deciding whether or not to offer a patient an initial biopsy of the prostate remains controversial. PSA density remains a clinically useful adjunctive measure to determine the need for prostate biopsy in men with normal DRE and intermediate PSA. l 4 9

PSA density, defined as the total serum PSA level measured in nanograms per milliliter ng/mL, divided by the transrectal ultrasound-determined prostate volume in cubic centimeters, was first suggested by Benson and colleagues3 from Columbia University in 1992. They introduced this concept in an attempt to correct the interpretation of PSA levels in the serum for the volume of both cancerous and normal prostate tissue. The clinical applicability of PSA density is intended to provide improved differentiation between men with benign prostatic hyperplasia (BPH) and those harboring prostate cancer. The clinical usefulness of PSA density is best observed in men with intermediate PSA levels (4.0-10.0 ng/mL). Seaman and coworkersj3 first determined that a PSA density cutoff of 0.15 ng/mL/cc would enhance the detection of prostate cancer in men with serum PSA levels in this intermediate range. Later, in a prospective evaluation, Bazinet, demonstrated the usefulness of this optimization technique in a large group of men. They determined that a PSA density cutoff of 0.15 ng/mL/cc was highly predictive of harboring prostate cancer within the gland. One limitation of this PSA optimization technique is that PSA density is dependent on the examiner's accurate ability to determine prostate volume by transrectal ultrasound. Studies have shown that, in inexperienced hands, transrectal ultrasound does not accurately determine prostate volume. However, the definition of "experienced hands" remains vague. It is well known that the presence of a median lobe of the prostate can greatly affect transrectal ultrasound-measured prostate volume, and small inaccuracies in this measurement can greatly affect the PSA density value within this important range centered around 0.15 ng/mL/cc. Furthermore, the estimated BPH volume does not always necessarily correlate with serum PSA levels due to the marked

PSA Velocity

PSA velocity measures the rate of change of PSA over time. PSA velocity allows longitudinal measurements of PSA, providing a dynamic interpretation of changes in PSA with time. Carter and colleaguesh demonstrated that PSA changes with time were greater in men with prostate cancer compared with men without cancer 5 years prior to the diagnosis of prostate cancer. PSA velocity is calculated by the equation 1/2

([PSA, - PSA,/time, in years] [PSA, - PSAJtime, in years])

X

+

with PSA, equaling first serum PSA measurement and PSA, and PSA, equal to the second and third PSA measurements. Optimum benefit of PSA velocity requires at least three PSA measurements obtained over a 2-year period.' In their initial study, Carter and associatesh suggested that a PSA velocity 2 0.75 ng/ mL/yr provided a sensitivity of 72% and a specificity of 95% and was strongly sugges-

ELEVATED PSA, ABNORMAL PROSTATE EVALUATION ON DRE, AND TRUS/PNBX

tive of prostate cancer. Others5hindependently verified that a cutoff of 0.8 ng/mL/yr accurately differentiated between men without prostate cancer or with benign disease from those with prostate cancer. Kadmon and associates"' have also confirmed that at least a 2-year observation period is required before using PSA velocity in clinical decision making. Presently, the limitations of PSA velocity include 1. It is difficult to calculate 2. PSA is not cancer specific and the known \,ariation in serum PSA that can occur over time makes the use of this technique difficult 3. PSA velocity measurements can be confounded by other factors, including ejaculation, prostatitis, prostatic instrumentation, and various pharmacologic agents 4. PSA velocity requires at least three measurements over a 2-year period before being clinically useful.

At present, PSA velocity has clinical utility in assessing the risk of prostate cancer in individuals who are being followed with serial PSAs over a 2-year period. Patients with an initial negative biopsy result, having a normal DRE and a PSA level between 4.0 and 10.0 ng/mL, can be followed and further need for biopsy determined by PSA velocity measurements. In addition, younger men (< 50 years old) who are at high risk of developing prostate cancer (e.g., family history of prostate cancer or African American descent) can be offered a prostate biopsy based on longitudinal changes in serum PSA level even if initial PSA levels are < 4.0 ng/mL.

Age-Specific PSA Reference Ranges

The age-related effect on the volume of the prostate and changes in PSA levels were not taken into account when the standard PSA reference range (0.04.0 ng/mL) was initially det~rmined.~' Oesterling and co1leagues4Oproposed an age-specific PSA reference range to improve the sensitivity of prostate cancer detection in younger men while improving the specificity of prostate cancer detection in older men. The recommended age-specific serum PSA reference ranges are 0.0 to 2.5 ng/ mL for men aged 40 to 49 years; 0.0 to 3.5 ng/mL for men aged 50 to 59 years; 0.0 to 4.5

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ng/mL for men aged 60 to 69; and 0.0 to 6.5 ng/mL for men aged 70 to 79 years.."' These age-specific serum PSA reference ranges were, however, determined on a population of men who were primarily white. Moul and associates35have recommended different agespecific PSA reference ranges for African American men. Several studies have provided evidence that age-specific PSA reference ranges should be higher for African American men compared with whites.'?, u. 35. 6s In a recent paper, Morgan and colleagues" demonstrated evidence that the "Caucasian-based" age-specific reference ranges initially recommended by Oesterling and colleagues."' would have missed approximately 40% of cancers in a large group of African American men. The African American age-specific PSA reference ranges are 0.0 to 2.0 ng/mL for men aged 40 to 49 years; 0.0 to 4.0 ng/mL for men aged 50 to 59 years; 0.0 to 4.5 ng/mL for men aged 60 to 69 years; and 0.0 to 5.5 ng/mL for men aged 70 to 79 years. In summary, age-specific PSA reference ranges d o improve the sensitivity for detecting prostate cancer in younger men (<60 years) but may result in increased numbers of unnecessary biopsies. In older men, the specificity for early detection is improved; however, prostate cancers are missed, the significance of which has yet to be determined. Further characterization of the differences in age-specific PSA reference ranges have demonstrated the need for different cutoffs for African American compared with white men. However, none of the PSA assay manufacturers nor the Food and Drug Administration presently recommend age-specific PSA reference ranges. In the clinical setting, the use of age-specific PSA reference ranges is justified, however, and the authors would recommend careful documentation of counseling with the patient of the risks and benefits of use of these age-specific PSA cutoffs within the medical record. Molecular Forms of PSA (Percent Free PSA)

Early work by Stenman and associates"" and Lilja and associates2' demonstrated the presence of various molecular forms of PSA within the circulation. They determined that PSA existed in an enzymatically inactive, uncomplex, free form varying between 5% and 50% of the total measured PSA. They also

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demonstrated that PSA could be found covalently bound to an endogenous protease inhibitor (a,-antichymotrypsin [ACT]) representing between 50% and 90'% of the total measured PSA. The exact or physiologic mechanism by which the percentage of free PSA (percent free PSA) differs in men with prostate cancer or benign disease continues to remain elusive. Various retrospective studies earlier demonstrated that the percentage of free PSA decreases as the probability of having prostate cancer increases."'.2y, 12. ho Measurement of percent free PSA provides optimal differentiation between men with and without prostate cancer for men who have total PSA levels between 4.0 and 10.0 ng/mL. The major clinical utility of percent free PSA has been to decrease the number of inappropriate biopsies for detecting prostate cancer. The majority of recommended percent free PSA cutoff levels is designed to maintain the sensitivity (number of prostate cancers detected) as high as possible (e.g., 90%-95%) while decreasing the number of inappropriate biopsies (specificity). Currently, most urologists offer and perform prostate needle biopsies for men who have total serum PSA levels greater than 4.0 ng/mL regardless of the DRE finding. Thus, these optimization techniques can provide both clinical and cost-effective economic improvements in the way we detect prostate cancer. A recent prospective multicenter trial using the Hybritech assay recommended a percent free PSA cutoff of 25% free PSA providing a 95% sensitivity and a 20% specificity for men with total PSA levels between 4.0 and 10.0 ng/mL.' Using a percent free PSA cutoff of 25% with the Hybritech would eliminate one of five unnecessary biopsies in men within this indeterminate PSA range. In addition, Vashi and colleaguesh4also demonstrated the utility of another assay and determined that percent free PSA was useful in differentiating the need for prostate biopsy. Various factors have been determined to influence the use of percent free PSA for decision making. These factors include age and prostate volume."',4hIn fact, Catalona and coworkers demonstrated that a percent free PSA cutpoint of 14% would yield a specificity of 79% in men with small (< 40 cc) prostates. In comparison, a percent free PSA cutoff of 20% yielded a 38% specificity for men with larger prostates."' Further work is required to define and characterize the relationship between percent free PSA and prostate volume and

age. Clinicians should also be aware of the ex vivo stability of free PSA in interpreting laboratory data. Woodrum and coworkers"' first evaluated the stability of free PSA under a variety of sample collection and storage conditions. They recommended the guideline of processing blood specimens (remove serum from blood clot) within 3 hours of collection and freezing ( - 20°C- - 70°C) if the sample is not assayed within 24 hours of collection. All clinicians using percent free PSA are recommended to consult the manufacturer of their assay to provide accurate information about specimen collection, processing, storage, and shipping for their particular assay. Although the majority of reported studies have found clinical use of percent free PSA, others3'',3h have found limited additional benefit for detection of prostate cancer by percent free PSA when compared to total PSA and PSA density. Morgan and associateP have shown the utility of percent free PSA as an adjunct to determining the need for repeat prostate biopsy in light of a negative initial biopsy result. Presently, the best recommended use of percent free PSA is to determine whether a patient with a total serum PSA level of 4.0 and 10.0 ng/mL would benefit from an initial biopsy or a repeat biopsy in the face of a normal DRE and at least one previous negative biopsy result. Presently, recommendations regarding the routine use of free PSA must be made on a case-by-case basis taking into account the patient's race, age, prostate volume, and family history of prostate cancer. THE ROLE OF DRE AND TRANSRECTAL ULTRASONIC PROSTATE NEEDLE BIOPSY

For years, DRE of the prostate was the primary diagnostic modality for diagnosing and staging prostate cancer.5 DRE is routinely used to evaluate the local extent of prostate cancer. Although DRE is subjective, both understaging and overstaging are found when the pathologic extent of disease is correlated with DRE findings. The sensitivity and specificity of DRE in determining organ-confined status were evaluated in a large series in which all radical prostatectomies were performed by one urologist, with pathologic evaluations completed by a single pathologist.4sWithin this series of 565 men in whom

EIXVATEII PSA, ABNORMAL PROSTATE EVALUATION O N DRE, A N D TRUS/PNBX

thc DRE suggested organ-confined disease (T2), 52% actually had organ-confined disease‘, 01'%,had capsular penetration, and the remaining 17% had either seminal vesicle or lymph node involvement. Within the same series, of the 36 men in whom extraprostatic disease was suspected on DRE (T3a), 19% had organ-confined disease, 36% had capsular penetration, and 45% had involvement of either the seminal vesicles or the lymph nodes. This represents a sensitivity of 52% and a specificity of 81% for prediction of organ-confined disease by DRE Prior to PSA testing and transrectal ultrasound (TRUS), most patients diagnosed with prostate cancer, non-organ-confined disease, and a subsequent cure with definitive therapy (radiation or surgery) was limited. Digitally directed needle biopsies of a palpably abnormal prostate were positive for cancer in only 20% to 40% of cases and 60% to 70% of those patients had non-organ-confined disease." TRUS is now the most common imaging modality for evaluating the prostate and is practiced by most active urologists on a daily basis. TRUS allows an estimation of gland volume, definition of anatomy and the margins of the prostate, evaluation of the seminal vesicles and the base of the bladder, and facilitates placement of the needle biopsy. Many prostatic carcinomas may be visualized as an hypoechoic area, distinguishable from the normal homogenous isoechoic parenchyma of the prostate. Unfortunately, not all hypoechoic areas represent cancer and some prostatic neoplasms appear to have the same echo texture as the normal prostate with TRUS. BPH and various diseases may alter the texture and consistency as well as its ultrasonic findings, (i.e., acute or chronic prostatitis, granulomatous prostatitis, urinary tract infections, prostatic calculi, prostadynia, or prior prostate surgery). TRUS alone is not an accurate modality for prostate cancer screening-it should be performed in conjunction with PSA and DRE.y Overall, TRUS appears to be no better than 65% accurate in the staging of local disease and is no better than DRE alone.'' Even when comparing TRUS and magnetic resonance imaging (MRI), the predictive value is only 50% in detecting extraprostatic extension of carcinoma. TRUS has contributed greatly to the diagnostic biopsy of the prostate compared to digitally directed needle biopsy.2o TRUS has allowed ultrasonic-guided biopsy of specifically abnormal lesions within the prostate as

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well as accurate placement of sextant systematic core biopsies to ensure adequate Sampling. The technology of the spring-loaded biopsy guns combined with TRUS-guided biopsy techniques has allowed urologists and radiologists to obtain multiple cores in a safe and relatively painless manner and has definitely increased the accuracy in diagnosing prostate cancer in both the palpably normal and abnormal prostate. TRUS with systematic sextant biopsies as well as directed ultrasonic-guided transrectal core biopsies has become the standard of care. Not all hypoechoic lesions have been found to be positive for cancer and cancer has been found in other normal echoic areas of the prostate. It is estimated that approximately 70% of cancer arise in the peripheral zone and that 50% of all prostate cancers are located in the anterior half of the prostate in either the lateral positions of the peripheral zone or the more medial and anterior located transitional zone.I8 Sixty percent of clinically diagnosed prostate cancers were hypoechoic and 1% were hyperechoic. This study,'* which was based on radical prostatectomy specimens, demonstrated that 36% of the nonpalpable tumors were visualized on ultrasound, whereas 21% of palpable tumors were not visualized. Six systematic spatially separated biopsies as reported by S t a m e has ~ ~ become ~ the standard of care. There have, however, been other studies suggesting that more directed biopsies of the prostate are indicated.sy Epstein and colleagues'* reported on 240 men who had stage Tlc disease who underwent radical retropublic prostatectomy. In the pathology laboratory, sextant and transition zone biopsies on 193 specimens were performed using the 18 gauge biopsy gun in a manner similar to the standard TRUS guided techniques of Stamey.3 The transition zone biopsies were only positive in 2.1% of the cases. Despite cancer being confirmed on the preoperative needle biopsy in all cases, 31% of the ex vivo biopsies showed no evidence of cancer on repeat sextant and transition zone biopsies in the laboratory setting. Cases with no cancer on repeat ex vivo biopsy had a 90% chance of being organ confined. The Gleason score was also lower in all cases where no cancer was seen on the repeat ex vivo biopsies. This and other studies have suggested that a consideration for more than the routine six core biopsies may be indicated. It also addresses the issue of repeat biopsy on patients whose initial biopsy has shown either

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low stage or a very small percentage of prostate cancer in only one core. Multiple cores, 12 to 18, would appear to be indicated in those cases. A recent article suggested systematic fiveregion prostate biopsy." This study reported that 40% of the patients undergoing five-region systematic biopsy had prostate cancer. The technique of biopsy calls for 13 cores in prostates smaller than 50 g and 18 cores in glands larger than 50 g. Of 119 patients, the reason for biopsy was an abnormal DRE in 14%, elevated PSA in 48%, and combined abnormalities in 38%. Of the biopsies showing cancer, 12% had an abnormal DRE, 38% had an elevated PSA, and 50'% had both abnormalities. Most important, those patients with prostate cancer, 35% had carcinomas only in the additional regions and would have remained undetected had the routine sextant core biopsies been done. There is a concern, however, that by increasing the number of multiple core biopsies, the changes of detecting clinically insignificant cancer is increased.' Repeat core biopsy has also been a controversial issue: this includes patients who have a persistently elevated PSA or abnormal DRE, a history of having had several negative biopsy results in the past, or patients who have been found to have high-grade prostatic intraepithelial neoplasm (PIN) on prior biopsies. In one series, a repeat-biopsy positive rate of 39% was reported, which is higher than most series.'" Seminal vesicle biopsies have been performed in some series; however, studies have shown that seminal vesicle biopsies in all patients are not warranted.z2If an abnormality of the base of the prostate or seminal vesicles is encountered digitally, it may be appropriate to proceed with a seminal vesicle biopsy. This may assist in staging the disease and planning therapy. Over a 27-month period, from July 1995 to October 1997, 662 TRUS and needle biopsies of the prostate were performed by one operator (R.E.S., Table 1).Over 70% of these cases were performed on patients presenting with an elevated PSA (> 4 ng) 43.4% of the patients (287 of 662) were diagnosed with cancer, 4%)(27 of 662) were diagnosed with high grade PIN with no cancer. A routine sextant biopsy of the prostate was done on the first 180 patients, all subsequent patients had at least a 12-core biopsy. All patients were seen and counseled prior to the biopsy. Men were

Table 1. TRANSRECTAL ULTRASONIC-ASSISTED NEEDLE BIOPSY OF THE PROSTATE. ~

~________

Time Period July-December 1995 Total Cancer PIN January-June 1996 Total Cancer PIN July-December 1996 Total Cancer PIN January-June 1997 Total Cancer PIN July-October 1997 Total Cancer PIN July 1995-October 1997 (27 m) Total Cancer PIN

No.

Percentage

121 51 4

42.0 3.3

136 59 2

43.4 1.5

153 62 8

40.5 5.2

162 73 10

45 6

90 42 3

46.7 3.3

662 287 27

43.4 4.0

'One operator: RES.

prescribed an oral fluoroquinolone antibiotic, the first dose given the night prior to the biopsy, the second dose the morning of the biopsy with two additional doses the night following the biopsy and the following morning. The patient was instructed to self administer an enema the morning of the biopsy and to attempt complete bowel evacuation. No dietary restrictions were placed prior to the biopsy. The patients were asked to cease taking all medications that might alter bleeding time or blood clotting (aspirin, coumadin, motrin [ibuprofin]) for 7 to 10 days prior to the biopsy. Several patients, however, continued taking aspirin up to the time of biopsy, and after appropriate counseling, elected to proceed with the biopsy. None of these patients noted any adverse bleeding. Biopsies were performed on patients who had an abnormal DRE or elevated PSA or both, more than 4.0 ng/mL. Biopsies were also performed on those individuals who had a prior biopsy and/or high grade PIN on previous biopsy. A number of patients had prior needle biopsies of the prostate with persistently elevated PSA and/or an abnormal digital rectal examination. The TRUS evaluation and biopsies were obtained with the patient in the lateral position. No oral or intravenous sedation was

ELEVATED PSA, ABNORMAL PROSTATE EVALUATION ON DRE, AND TRUS/PNBX

utilized. Two ampules of 2% Xylocaine gel were injected into the ampulla of the rectum ‘ind ‘illowed to set for several minutes. The ultrcisonic probe was introduced and the prostate was evaluated and measured in both the transverse and sagittal planes. For biopsy, the prostate was imaged in the sagittal plane. The volume of the prostate was estimated in a11 cases. Volume is established by multiplying the transverse diameter (transverse plane) by the length of the prostate and by the depth of the prostate (sagittal plane) and multiplying the sum by 0.52 (width X length x depth x 0.52 = volume). The seminal vesicles, the floor of the bladder, prostate margins, and consistency of the prostate were also evaluated. All biopsies were performed by a Bard spring-loaded biopsy gun using an 18-gauge biopsy needle. The 12 cores were taken in six areas, the initial cores as described in sextant biopsies, the lateral margins of the prostate from base to apex, and the additional six cores were taken medial to the initial sextant cores from the base to the apex. The core specimens from these six zones were sent separately, two from each area, consisting of the right base, right mid, right apex, left base, left mid, and left apex. Additional cores were taken in some cases, such as abnormal areas on ultrasound or prostates larger than 50 g. Routine biopsies of the seminal vesicles or transitional zone were not done. All patients were allowed to ambulate immediately following the biopsy and were seen again approximately 1 hour following the biopsy to ascertain that they were voiding satisfactorily without significant hematuria and had no significant rectal bleeding. In this series, less than 1%experienced a febrile episode. One patient had moderate rectal bleeding and was hospitalized, but no surgical intervention or transfusion was necessary, and less than l(% of patients had urinary retention, either secondary to prostatic swelling or blood clot urinary retention. PSA screening and DRE in selected patient populations is recommended. TRUS and needle biopsy of the prostate should be performed in those patients who meet the criteria as stated. By these modalities, the early diagnosis of prostate cancer can be established, accompanied by higher cure rates, lower morbidity, and overall reduced health care costs. ACKNOWLEDGMENTS The authors wish to thank Ms. Bonnie Baxley and Tami Pusateri tor assistance in preparation of this article.

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Ray E. Stutzman, MD James Buchanan Brady Urological lnstitute Johns Hopkins Outpatient Center, 4th Floor 601 North Caroline Street Baltimore, MD 21287-2101