Pathology Consultation on Prostate-Specific Antigen Testing

Transcription

1 Pathology Consultation on Prostate-Specific Antigen Testing Jaime H. Noguez, PhD, and Corinne R. Fantz, PhD From the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA. Key Words: Prostate-specific antigen; Screening; Prostate cancer Am J Clin Pathol July 2014;142:7-15 DOI: /AJCPU6OOKL9JHEUR ABSTRACT Objectives: To provide clarity on the pros and cons of using prostate-specific antigen (PSA) as a screening tool for prostate cancer. Methods: Case scenarios and a literature review of recently published clinical trial data are presented to provide evidence of the controversy. Results: PSA is a sensitive biomarker for detecting diseases of the prostate, but it is limited in its ability to distinguish cancerous from noncancerous conditions or aggressive from indolent cancers and has resulted in a considerable amount of overdiagnosis and overtreatment. Conclusions: The analytical methodology for total PSA testing is both reliable and cost-effective, but patients should be encouraged to talk to their providers to understand the benefits and harms associated with this testing. Upon completion of this activity you will be able to: define the limitations of the serum prostate-specific antigen (PSA) test. describe new developments in PSA testing to improve specificity for prostate cancer. discuss the potential benefits and harms of population-based PSA screening. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 133. Exam is located at Case Scenarios Case 1 A 56-year-old man saw his primary care physician and relayed a history of lower urinary tract symptoms. A serum prostate-specific antigen (PSA) test was performed and his total PSA (tpsa) concentration was 12.8 ng/ml (12.8 mg/l; normal range <4.0 ng/ml [4 mg/l]). He was treated for presumed prostatitis with 30 days of oral antibiotics, at which time his serum PSA level had risen to 19.9 ng/ml (19.9 mg/l). He was diagnosed with benign prostatic hyperplasia (BPH) and prescribed an a-blocker. Physical examination at the time of presentation to the urologist revealed a small left varicocele and a large palpably abnormal-feeling prostate with firmness and nodularity. He was scheduled for urine cytology and a transrectal ultrasound-guided needle biopsy of the prostate. CME/SAM Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR 7

2 Noguez and Fantz / Prostate-Specific Antigen Testing Case 2 A 47-year-old man was screened for prostate cancer with a digital rectal examination (DRE) and a serum PSA test. His initial PSA concentration was 1.9 ng/ml (1.9 mg/l) and he continued to be screened annually. Over the course of 7 years, his PSA concentration gradually rose to 4.6 ng/ml (4.6 mg/l). The mildly elevated PSA level prompted several repeat measurements that year in 3-month intervals, which documented a steady rise to 5.5 ng/ml (5.5 mg/l) and then to 6.6 ng/ml (6.6 mg/l). He was scheduled for a transrectal ultrasound-guided needle biopsy of the prostate the following month at the age of 54 years. Questions 1. What is PSA? 2. What factors can increase serum levels of PSA? 3. What are the key characteristics of a population-based screening biomarker? 4. What are the risks and benefits of PSA-based screening for prostate cancer? 5. Why is screening for prostate cancer with a serum PSA test controversial? Background Prostate cancer is the second most commonly diagnosed cancer in American men, as well as the second leading cause of cancer death in the United States. 1 The American Cancer Society (ACS) estimated 238,590 new cases of prostate cancer for 2013 and projected that approximately 30,000 deaths will occur from prostate cancer. 1 The lifetime risk of a man developing prostate cancer is about 1 in 6, though the risk of dying of prostate cancer is significantly less. 1 Most prostate cancers are slow-growing and clinically insignificant, but others are aggressively metastatic and have an insidious course. Because of its widely variable clinical behavior, early detection through screening may be useful in reducing the incidence of metastatic prostate cancer and potentially save thousands of lives. However, when a biomarker lacks the specificity to discriminate between aggressive and indolent cancers, there is an inherent risk of overdiagnosis and overtreatment. PSA, also known as g-seminoprotein, is an androgenregulated serine protease secreted by the epithelial cells of the prostate gland. It is the most widely used tumor marker to date and remains the single most significant predictive factor for identifying men with increased risk of prostate cancer. 2,3 The active enzyme is formed by the sequential proteolytic cleavage of two inactive propeptides before entering the peripheral circulation Figure 1. The majority of PSA that enters the bloodstream is intact and quickly becomes bound to serum proteins, primarily to the protease inhibitors a 2 -macroglobulin Cell Figure 1 Prostate-specific antigen (PSA) formation in cells. ACT, a 1 -antichymotrypsin. (A2M) and a 1 -antichymotrypsin (ACT). 4,5 Free PSA (fpsa) and PSA bound to ACT, collectively referred to as tpsa, are the only immunoreactive forms of the protein and can be measured in blood using an immunoassay. 4-6 PSA bound to A2M is not measurable with immunoassay because all epitopes of PSA are masked due to encapsulation by A2M. 5 PSA is a sensitive biomarker for detecting pathologic conditions of the prostate, but its efficacy as a screening tool for prostate cancer has been challenged because of its lack of specificity. A low prevalence of prostate cancer in the general population, along with this lack of specificity, means that the predictive value of a positive serum PSA screening test is low. Therefore, a DRE is typically used in conjunction with a serum PSA test to screen for prostate cancer and to determine which patients will receive a prostate biopsy. This biomarker is also commonly used to monitor the treatment of men previously diagnosed with prostate cancer and to detect disease recurrence. Although the introduction and widespread use of serum PSA testing has revolutionized the diagnosis and management of prostate cancer, its use as a screening tool has recently become a topic of intense debate. History of PSA PreproPSA (inactive) ProPSA (inactive) PSA (active) Blood Free PSA PSA-ACT Total PSA PSA was discovered in the early 1970s and was initially described in the literature as a semen-specific protein that could be used as a marker for semen identification. 7 Shortly thereafter, a biochemically similar and immunologically identical antigen was isolated from both prostate tissue and human serum. 8,9 PSA was found in normal, benign, and malignant prostate tissue. Elevated serum levels were detected in men with BPH as well as in all stages of prostate cancer. In addition, serum levels of PSA were found to increase in proportion to the tumor burden, generating a considerable amount of interest in PSA as a potential marker for prostate cancer. 8 Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR

3 In 1986, the Food and Drug Administration (FDA) approved the use of the first commercial serum tpsa test, a chemiluminescent immunoassay using a monoclonal murine anti-psa antibody marketed as the Tandem PSA assay by Hybritech (San Diego, CA). The intended use was to monitor the progression of prostate cancer in men who had previously been diagnosed with the disease and to detect cancer recurrence after therapeutic interventions. Approximately 5 years after the Tandem PSA assay was introduced to the market, the age-adjusted absolute mortality rates for prostate cancer began to decline, which suggested that the PSA test was having a beneficial effect and was responsible for this reduction. 10 By the early 1990s, studies were under way to examine the clinical usefulness of serum PSA as a screening test for prostate cancer. 11 The results indicated that a serum PSA test used in conjunction with a DRE was superior for detecting prostate cancer compared with either test alone. 12 The FDA expanded the intended use of the Hybritech serum PSA test to include use as a screening tool in combination with a DRE in men older than 50 years or those with high risk. Based on the results of a large, multicenter trial, a PSA concentration of 4 ng/ml (4 mg/l) was selected as the threshold for performing prostate biopsies to confirm the presence of prostate cancer. 13 PSA screening resulted in a dramatic increase in the incidence of early-stage, organ-confined prostate cancers, and in turn, led to a rise in invasive treatments intended to cure aggressive localized tumors The ACS and the American Urological Association issued clinical guidelines supporting annual prostate cancer screening using both the serum PSA test and DRE. 17,18 However, a number of other professional societies including the National Cancer Institute, the American College of Physicians, and the US Preventive Services Task Force (USPSTF) did not find the data persuasive enough to recommend routine screening, citing a lack of conclusive evidence that PSA testing reduces disease-specific morbidity and mortality The incorporation of PSA screening recommendations into clinical guidelines in the absence of efficacy data from randomized trials ignited a 20-year debate. Amidst the controversy, a number of large manufacturers developed immunoassays to detect serum PSA on automated platforms, including Abbott Diagnostics, Beckman Coulter, Roche, Siemens, Tosoh, and Ortho Clinical Diagnostics. As the number of PSA immunoassays on the market multiplied, the need for harmonization became increasingly apparent. 22,23 Assay standards were developed to improve clinical interpretations and interchangeability of PSA results between laboratories and methodologies. Nearly every PSA assay on the market was calibrated with one of two standards: the traditional Hybritech standard used in the manual predecessor Tandem PSA assay or a more recently developed World Health Organization (WHO) standard. The concentrations of the purified PSA in the standards were measured using different methods, leading to a 23% difference in their concentrations. Ultimately, the results of assays calibrated with the Hybritech standard were found to be 10% to 25% higher than those calibrated with the more accurately determined WHO standard. 22,24 Differences in the clinical interpretation of PSA tests as a result of nonuniform assay calibration were first noted in 2003, but the impact had yet to be fully appreciated in the medical community. In recent years, the issue of metrologic traceability in the determination of PSA has received a considerable amount of interest. However, the conventional PSA threshold of 4 ng/ml (4 mg/l) continues to be a prostate biopsy decision criterion in several clinical guidelines despite being solely based on the Hybritech standard. Standardization efforts are still under way to increase interchangeability and minimize the misinterpretation of PSA results obtained with different assays and reference materials. Linking all PSA measurements to a common stable reference material will likely simplify an already challenging clinical decision. Diagnostic Dilemma Elevated serum PSA concentrations suggest the presence of prostate cancer, but increased concentrations are also found in benign conditions of the prostate such as BPH, urinary tract infections, and prostatitis Table 1. Furthermore, a normal PSA level cannot definitively rule out cancer. Although the Table 1 Benign Conditions That May Increase Serum PSA levels Noncancerous causes of elevated serum PSA Prostate disease Benign prostatic hyperplasia Prostatitis Prostate ischemia Clinical manipulations Digital rectal examination Prostate biopsy Transrectal ultrasound Indwelling urinary catheter Treatments Prostate surgery Radiation therapy Testosterone administration Luteinizing hormone/follicle-stimulating hormone administration (transient effect) Analytical interferences Heterophile antibodies Increased levels of kallikrein Antibody cross-reactivity Extra-prostate sources Parotid glands Periurethral glands Other Ejaculation Urine retention Riding a bicycle Urinary tract infections PSA, prostate-specific antigen. Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR 9

4 Noguez and Fantz / Prostate-Specific Antigen Testing risk of finding prostate cancer on biopsy increases with PSA levels higher than 4.0 ng/ml (4 mg/l), there is no PSA value at which assurance is guaranteed. In fact, one study showed that up to 15% of men with PSA levels lower than 4.0 ng/ml (4 mg/l) were found to have prostate cancer on biopsy. 25 The usefulness of PSA as a screening tool has been challenged primarily because of its poor specificity when serum PSA concentrations are only modestly elevated. PSA values between 4.0 and 10.0 ng/ml (4-10 mg/l) have often been referred to as the diagnostic gray-zone. When the serum PSA level is 10.0 ng/ml or higher, the specificity of the test for cancer is considerably higher than when the serum level is only modestly elevated ( ng/ml [4-10 mg/l]). 11,12 Because only 25% to 35% of men presenting with modest elevations in serum PSA levels are confirmed to have prostate cancer, a number of approaches have been taken to reduce the number of false positives. 12 New developments in prostate cancer testing have aided in discriminating early-stage cancer from noncancerous conditions but a great deal of focus has been placed on developing additional tests to distinguish aggressive from benign cancers. 26,27 Some of these tests are intended to be used in combination with the PSA test and others can be used independently. Improving PSA Specificity for Detecting Cancer As the limitations of PSA as a biomarker for prostate cancer screening became more apparent, a number of different strategies have been used to improve the performance characteristics of the PSA test Table 2 when the concentrations are in the diagnostic gray-zone, including PSA density, PSA velocity, percent-free PSA, prostate health index, and measurement of the different forms of PSA. 28,29 Although these new developments in PSA testing have been proven to increase the specificity of the PSA test for detecting cancer and reducing the high rate of false positives, it is important to note that they each have limitations of their own. Table 2 PSA Screening Test Characteristics at 4 ng/ml (4 mg/l) Cutoff for a Positive Test 28 Test Characteristic Sensitivity 21 Sensitivity for high grade cancer (ie, Gleason score 8) 51 Specificity 91 Positive predictive value 30 PSA, prostate-specific antigen. Percentage PSA Density Men who have larger prostates tend to have more prostate cells, which in turn, produce more PSA regardless of whether or not they have cancer. PSA levels can be normalized by measuring the prostate volume using transrectal ultrasonography then dividing the serum PSA concentration by the size of the prostate to calculate the PSA density. A high PSA density indicates that a relatively small volume of prostate tissue is making a considerable amount of PSA. Conversely, a low PSA density indicates that a large volume of prostate tissue is making relatively little PSA. There is evidence that a high PSA density indicates a higher risk of prostate cancer and, in general, men with both elevated tpsa and a high PSA density (>0.15 ng/ml [>0.15 mg/l]) should be monitored more closely for prostate cancer than those with low PSA density Although PSA density has been shown to increase the specificity of prostate cancer screening, evidence suggests that a 0.15 ng/ml (0.15 mg/l) cutoff for biopsy may be too high and may result in a large number of missed cancers. 33 PSA Velocity PSA velocity is the rate of increase in PSA concentrations over time. Enlargement of the prostate gland is a common part of aging, along with a corresponding slow increase in PSA levels. Studies have demonstrated that these levels tend to increase faster if a man has cancer and suggest that the more aggressive the cancer the steeper the rise The usefulness of PSA velocity is limited because it requires at least three serial measurements to reduce the background variability caused by short-term fluctuations in PSA. Sampling over longer intervals may decrease variation but may also prolong the screening process and increase anxiety. 37 In addition, the PSA velocity may be elevated if a man has multiple prostatic conditions that increase serum PSA values over time such as BPH, prostatitis, and cancer. fpsa:tpsa Ratio PSA circulates in the bloodstream either free or bound to serum proteins. The percent-free PSA is commonly used to help physicians decide how to further test for or treat prostate cancer. It is calculated by dividing the amount of fpsa (unbound) in the blood by the tpsa (bound + unbound). In general, benign conditions tend to increase the fpsa form, and cancerous conditions tend to increase the bound PSA-ACT (cpsa) form. 38,39 A percent-free PSA above 25% is considered normal, with an 8% probability of cancer; between 10% and 25% is considered intermediate, with a 16% to 28% probability of cancer; and below 10% is considered low, with a 56% probability of cancer. 40 When the tpsa is in the gray zone, the percent-free PSA can be used to decide whether to proceed with a prostate biopsy. It should be noted, however, that fpsa is not as stable as the 10 Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR

5 protein-bound form and requires strict specimen handling to reduce analytic variability. 41 Complexed PSA Men with prostate cancer tend to have more cpsa than those without. Measuring the proportion of cpsa has been particularly useful for risk stratification of men with tpsa levels in the range of 2 to 4 ng/ml (2-4 mg/l) because of the high incidence of prostate cancer in men without elevated tpsa values. 42 Multicenter studies have shown that cpsa outperforms the tpsa test for prostate cancer detection and can possibly replace it as the first-line screening test. 43,44 However, others have reported that cpsa alone is not helpful in reducing the rate of unnecessary biopsies. 45 Elevations in cpsa concentrations can be observed in patients with nonmalignant diseases and cpsa concentrations within the normal range can be observed in some men with confirmed prostate cancer. Because of such conflicting evidence, cpsa concentrations should not be interpreted as absolute evidence of the presence or absence of malignancy. Ratios of cpsa:tpsa and fpsa:tpsa have demonstrated similar areas under the curve at differentiating patients with BPH from those with prostate cancer when the tpsa concentration is between 2 and 10 ng/ ml (2-10 mg/l). 45 Therefore, the cpsa:tpsa ratio can be considered as an alternative to the fpsa:tpsa ratio for adding discriminatory power to the tpsa test. PSA Isoforms fpsa is composed of several different enzymatically inactive isoforms. Measuring these PSA isoforms may distinguish which men likely have prostate cancer and are candidates for a biopsy. In men with nonspecifically elevated tpsa concentrations because of BPH, the B-PSA isoform of fpsa is often increased. 46,47 In contrast, the pro-psa form and some of its truncated forms, particularly [-2]proPSA, appear to be preferentially elevated in the serum samples of men with prostate cancer Measurement of these PSA isoforms shows promise for lowering the rate of unnecessary biopsies but requires further analysis in larger multicenter studies. The Access Hybritech p2psa test is an FDA-approved assay for [-2]proPSA that is available on the Beckman Coulter Access Immunoassay system (Chaska, MN). An automated, two-site immunoassay for B-PSA has also been developed by Beckman Coulter for research use only. Prostate Health Index The Prostate Health Index (phi) is an FDA-approved test designed by Beckman Coulter that generates a composite score from the Access Hybritech tpsa, Access Hybritech fpsa, and the Access Hybritech p2psa tests. The test is available on the Beckman Coulter Access 2 and UniCel DxI immunoassay platforms and incorporates the results of the three individual tests into _ a single score using the formula: (p2psa/fpsa) tpsa. 52 Combining these three variables improves risk assessment for prostate cancer by providing clinicians with more information about the probability of prostate cancer in men 50 years and older with a nonsuspicious DRE result and a tpsa in the range of 2.0 to 10.0 ng/ml (2-10 mg/l). 52,53 A low phi result indicates a lower risk of prostate cancer, whereas an elevated phi indicates a higher risk and may suggest the need for a prostate biopsy. Although the phi has demonstrated superior clinical performance for the detection of prostate cancer in comparison to tpsa and percent-free PSA, it is yet to be clearly demonstrated whether this test can differentiate between aggressive cancers that need treatment and indolent tumors that can simply be monitored actively. 52 The Case for PSA-Based Screening Proponents of PSA-based screening argue that it enables the detection of more prostate cancers in the early stages so treatment can be initiated, thereby reducing the incidence of late-stage disease. Reducing the proportion of men presenting with high-risk, advanced disease saves lives, minimizes disease complications, and improves the quality of life. For men with an aggressive prostate cancer, the best chance for curing it is through early detection when it is localized to the prostate gland then treating it aggressively with surgery or radiation. The 5-year survival for men who have prostate cancer confined to the prostate gland (early stage) is nearly 100% and drops to 30% for men whose cancer has metastasized. 54 Although many early-stage cancers are not aggressive and may never cause a health problem, there is currently no way to discern aggressive from indolent cancers at detection. In addition, no existing tests are known to accurately predict which men with prostate cancer detected on PSA screening are most likely to benefit from aggressive treatment. Experts in favor of prostate cancer screening cite that the mortality rate of prostate cancer has declined by 40% since widespread implementation of PSA screening in the 1990s. 1 According to projection models, PSA screening has attributed to as much as 70% of the observed decline in mortality, which is most likely because of a stage shift. 10 The preliminary results of the large European Randomized Study of Screening for Prostate Cancer (ERSPC) trial found that through 11 years of follow-up men who underwent PSA testing had a 21% reduction in their chance of dying of prostate cancer compared with men who did not undergo PSA screening. 55,56 Similarly, the Göteborg trial observed a substantial benefit of PSA screening with a 44% reduction in cancer death when followed up after 14 years. 57 The results of a randomized, multicenter Scandinavian study found that even among low-risk men, prostatectomy offered a survival advantage Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR 11

6 Noguez and Fantz / Prostate-Specific Antigen Testing over watchful waiting. 58 Advocates of PSA-based screening contend that it has substantially reduced the incidence of metastatic prostate cancer. New evidence suggests that it saves thousands of lives and should be used despite the risk of overdiagnosis and overtreatment. 56 of serious surgical complications or death. Even the initial biopsy taken as a result of an elevated total serum PSA test can potentially cause pain, bleeding, and infection. 61 The Case Against PSA-Based Screening Although PSA screening may account for much of the observed reduction in prostate cancer mortality over the years, other factors such as changing treatment practices most certainly contributed to improving prostate cancer outcomes. Those against PSA-based screening acknowledge that it has saved many lives but contend that the absolute impact of the observed decline in prostate cancer mortality is overinterpreted for an individual man. Further, critics maintain that the well-documented problems associated with this kind of population screening are being overlooked. A number of recently published reports provide convincing evidence that PSAbased prostate cancer screening programs result in considerable overdiagnosis and overtreatment. The preliminary data from the large, randomized Prostate, Lung, Colon and Ovarian (PLCO) trial was published at the same time as the data from the ERSPC trial and highlighted the high rate of overdiagnosis associated with PSA-based prostate cancer screening programs. The PLCO trial found no significant reduction in prostate cancer related deaths after 13 years of follow-up; however, it is difficult to draw any conclusions because of the extremely high rate of PSA testing in the control arm before study entry. 59 The results of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) found no benefit in prostate cancer specific mortality associated with surgery compared with watchful waiting for patients with low-risk disease, even though the benefits in those with higher-risk disease were substantial. 60 The data from this large, randomized trial were contrary to those found by the multicenter Scandinavian study showing a considerable benefit to surgery over watchful waiting in men with prostate cancer in general. Those who recommend against PSA-based screening state that the potential benefits of screening are not greater than the expected harms. This screening ultimately puts individuals at risk of potential treatment complications by detecting and unnecessarily treating many cases of asymptomatic, slow-growing prostate cancers that may not cause health problems during a man s lifetime. Because of the high degree of uncertainty about which cancers are life-threatening and need to be treated aggressively, almost all men diagnosed with prostate cancer detected with the PSA test get treatment with surgery, radiation, or hormone therapy. These treatments may result in lasting harms such as erectile dysfunction, urinary incontinence, bowel control issues, and even a small risk Conclusions In addition to having sufficient analytic performance characteristics, a valuable screening biomarker should be cost effective and influence disease outcomes. Ideally, it should be able to detect disease at an earlier stage and guide treatment decisions that lead to a better outcome. 62 Although PSA has become the most widely used biomarker for cancer screening over the past 20 years, there has been a lack of evidence supporting the ability of the serum PSA test to reduce metastasis and cancer-specific mortality as a population-based screening tool. PSA-based prostate cancer screening was a controversial issue from the onset because decisions had been made and incorporated into clinical guidelines by some professional associations in the absence of efficacy data from randomized trials or even consensus within the field. Although PSA screening promised earlier detection and treatment of prostate cancer, evidence-based discussions of the benefits and harms of PSA-based screening were not possible until recently. In 2009, the initial results of two high-powered, prospective randomized clinical trials for PSA-based screening for prostate cancer were published. It was anticipated that the data would put an end to the 20-year debate. Unfortunately the contrasting results of these studies created more confusion than clarity. In the ERSPC trial, PSA-based screening was associated with a 21% relative reduction in prostate cancer specific mortality after a median follow-up time of 11 years, albeit at the cost of a considerable amount of overdiagnosis. 55,56 Conversely, the PLCO trial showed a higher incidence of prostate cancer in the screening group than the control group but no significant reduction in prostate cancer related deaths after 13 years of follow-up. 59 The designs of both studies were found to be flawed and the contamination rates were found to be 25% for the ERSPC trial and 77% in the PLCO trial for previous PSA testing in the control group before study entry. 55,56,59,63 Even though these studies have several limitations, they have provided some of the strongest evidence to date regarding the efficacy of PSA-based screening in reducing cancer-related mortality. Several professional societies have updated their recommendations for PSA-based prostate cancer screening to encourage shared decision making between the physician and patient. Recommendations focus on the necessity of providing appropriate patient education on the benefits and limitations of screening, so that patients will be equipped to make informed decisions regarding their health. The final recommendation of the USPSTF regarding the use of PSA for prostate cancer 12 Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR

7 screening is perhaps the most controversial aspect of the entire PSA debate. In 2012, the USPSTF amended its 2008 recommendation against screening for prostate cancer in men 75 years or older. The new statement now recommends against routine PSA screening for cancer in men of all ages who do not have symptoms highly suspicious for prostate cancer. The task force concluded that there is convincing evidence that the potential benefits of PSA-based screening are not greater than the expected harms. It has subsequently been criticized for drawing such definitive conclusions on the basis of incomplete evidence with notable limitations. Many believe that the USPSTF has a narrow view of the value of PSA, raising concerns about the potential consequences of taking a one size fits all approach by recommending against PSA screening altogether. 64 Until the final results of these trials are published, it is important that the benefits of PSA-based screening not be overinterpreted or the risks associated with overtreatment discounted. Using a shared decision-making strategy between the physician and patient is the most practical approach moving forward, given the lack of definitive screening outcome data and the considerable trade-offs of PSA-based screening. It is also of utmost importance for physicians and their patients to understand that the debate surrounding PSA testing is not about the analytic performance of the test, but rather the challenging clinical decisions made based on the test results. Case Summaries Case 1 The urine cytology findings were positive for PSA malignant cells consistent with prostate cancer and the needle biopsy showed Gleason = 7 prostatic adenocarcinoma in 12/12 cores with extensive perineural invasion. The prostatic volume was estimated at 31.2 ml on transrectal ultrasonography. Bone scan was negative for metastatic disease but computed tomography (CT) of the abdomen and pelvis revealed several rounded liver lesions and several subcentimeter lung nodules, both organs suspicious for metastasis. At this time he was started on hormonal treatment for prostate cancer including antiandrogens and luteinizing hormonereleasing hormone agonists. The serum PSA fell from 40.8 ng/ml (40.8 mg/l) to 4.9 ng/ml (4.9 mg/l) with androgen deprivation. Biopsy of the liver revealed metastatic adenocarcinoma consistent with a prostatic primary lesion. A repeat CT scan demonstrated a decrease in size of all metastatic lesions while taking androgen deprivation therapy, thus confirming the prostatic origin of these metastases. However, the cancer became androgen independent and within 3 months of the PSA nadir it had risen to ng/ml (102.2 mg/l). The patient began combination chemotherapy and demonstrated a positive response with a second PSA nadir of 35.9 ng/ml (35.9 mg/l). While the patient completed multiple additional courses of chemotherapy, his disease continued to progress, with rising PSA levels and new metastasis evident on imaging. He died at the age of 58 years just under 2 years after the initial diagnosis of prostate cancer, with a final PSA level of 2,095 ng/ml (2.095 mg/l) obtained 2 weeks before his death. Case 2 The patient underwent a transrectal ultrasound-guided needle biopsy of the prostate at the age of 54 years, which revealed Gleason = 7 adenocarcinoma in 30% of the right-sided cores and Gleason = 6 disease in 5% of the left-sided cores. The prostatic volume was estimated at 34.0 ml on transrectal ultrasonography. At this time he underwent a bone scan that was negative for metastasis. The patient was offered radical prostatectomy, radiation therapy, and watchful waiting as treatment options. He chose watchful waiting because he did not have any symptoms related to the prostate. The patient ultimately decided to self-medicate with herbal remedies for his cancer. Over the 11 years since diagnosis, the serum PSA level continued to rise to the most recent determination of 76.1 ng/ml (76.1 mg/l) without additional treatment. It can be difficult for physicians to decide how to treat individual patients because there is currently no way of determining the aggressiveness of early-stage cancers or to predict which men will respond well to treatment. The heterogeneous presentation of prostate cancer renders both diagnosis and prognosis a challenge. Risk stratification is complex though tools exist such as the serum PSA test, cancer staging by Gleason score, and multifactorial nomograms to help guide crucial decisions regarding treatment. Despite these advances, the ability to accurately predict the outcome for each patient remains severely limited as demonstrated by these two case scenarios. Although an elevated serum PSA test assisted the clinician in making the diagnosis of prostate cancer in both of these cases, it provided little information regarding the aggressiveness of the disease or the how these men would respond to treatment. Address reprint requests to Dr Noguez: Dept of Pathology and Laboratory Medicine, Emory University School of Medicine, 1364 Clifton Rd, Room G163, Atlanta, GA 30322; jaime.noguez@ emory.edu. Acknowledgment: We thank John A. Petros, MD, Department of Urology, Emory University School of Medicine, for providing case histories. References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin. 2013;63: Am J Clin Pathol 2014;142: DOI: /AJCPU6OOKL9JHEUR 13

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