Advances in Anatomic Pathology:
Prostate Cancer Staging and Grading at Radical Prostatectomy Over Time
Falzarano, Sara Moscovita MD*,†; Magi-Galluzzi, Cristina MD, PhD*,‡
*Pathology and Laboratory Medicine Institute
‡Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH
†Department of Pathology and Human Oncology, University of Siena, Siena, Italy
Reprints: Cristina Magi-Galluzzi, MD, PhD, Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue, L25, Cleveland, OH 44195 (e-mail: email@example.com).
Prostate-specific antigen (PSA) testing has been associated with a sharp increase in prostate cancer (PCA) detection after its introduction in the late 1980s. Since its launch and its implementation as diagnostic test in 1994, temporal patterns in patients' age and serum PSA level at presentation have changed, with younger patients being diagnosed at lower PSA cutoff levels. Many studies suggest that PSA screening has resulted in a profound downward migration in clinical and pathologic stage of newly diagnosed PCA, although the effect has slowed in the most recent years. The impact on tumor grading is less clear. Histologic grading of PCA, based on the Gleason system, is predictive of the biological behavior and prognosis of the tumor. If tumor progresses from low grade to high grade, the early detection would lead to a higher percentage of low-grade disease diagnosed over time. However, published data suggest that tumor grade shifts have occurred over time and are unlikely to be attributable to changes in tumor biology, but rather to changes in practice with respect to Gleason grading. This review will address PCA staging and grading trends from the pre-PSA era to the present time with emphasis on the potential role played by changes in clinical and pathologic practice.
Prostate-specific antigen (PSA) testing was first introduced by the Food and Drug Administration in 1986 to monitor for recurrence in patients who had already been diagnosed with prostate cancer (PCA) and received definitive treatment.1
The largest study on the use of PSA for PCA screening was conducted in 1991, followed by the approval of serum PSA assessment as a diagnostic test in 1994.2,3 After its establishment, PSA-based screening for PCA has led to profound changes in patients' care and in the clinical characteristics of PCA patients and in the pathologic features of the disease at the time of diagnosis. The PSA screening impact has been changing over time, from the early PSA era (1988 to 1995), through the transitional era (1996 to 2000), to the contemporary (2001 to 2006) PSA era.4
An overall downward migration of clinical and pathologic stage and an improvement of biochemical recurrence-free survival has been reported in PCA by multiple longitudinal and cross-sectional studies since PSA screening inception,5–26 whereas reduction of PCA mortality has been reported in some studies27–30 but not in others.31
Tumor grade trends across the PSA eras seem to be more controversial.12,13,16,18,19,22,32,33 Several studies have shown an apparent trend toward a higher percentage of moderately differentiated or higher Gleason score (GS) tumors,12,13,16,18,22 although other investigators have reported a relatively constant GS32,33 or a shift toward lower grade tumors over time.19
This review will present data on trends in stage and grade in the early, transitional and more contemporary PSA eras with regards to changes in pathology practice.
CLINICAL STAGE MIGRATION IN THE PROSTATE-SPECIFIC ANTIGEN ERAS
Clinical staging involves the determination of the spread of PCA at the time of diagnosis based on all information available before the first definitive treatment is performed and remains unchanged even if pathologic findings differ. Patients are currently classified according to the method of tumor detection in nonpalpable “incidental” PCA detected during transurethral resection of the prostate for clinically benign prostatic hyperplasia (classified as stage T1a or T1b), nonpalpable PCA detected by an elevated serum PSA level or an abnormal transrectal ultrasonography (TRUS) image (stage T1c) and palpable cancers detected by digital rectal examination (DRE) (stage T2). PCA extending beyond the prostate is classified as stage T3; tumor fixed or invading adjacent structures is equivalent to clinical stage T4.34
Before the measurement of serum PSA levels, PCA was diagnosed by DRE, serum prostatic acid phosphatase (PAP) assessment, and TRUS. DRE had only an estimated cancer detection rate of 1% to 2% when used as the primary detection method and up to 85% of PCA diagnosed using this method were already nonorgan confined.14,35 Stamey et al36 evaluated serum PSA and PAP in a case control analysis of men with or without PCA, and determined that serum PSA was more sensitive than PAP in PCA detection, although neither marker was specific for PCA. In the largest study on serum PSA measurement as a screening test for PCA, Catalona et al3 compared TRUS, DRE, and PSA test in PCA detection.3 In their analysis, PSA was estimated to have a higher calculated positive predictive value (40%) and greater overall accuracy (64%) than DRE or TRUS alone. Serum PSA measurement had the lowest error rate among the 3 tests, although the combination of PSA and DRE with TRUS and prostate needle biopsy (PNBx), performed in patients with abnormal findings, was suggested to provide a better method of detecting PCA than any test alone.3
The use of PSA as screening test changed the patterns of patients' care, with PNBx rather than transurethral resection of the prostate becoming the first mean of diagnosis of PCA.37 PNBx was increasingly performed in healthy, nonsymptomatic men in whom an abnormal PSA test or DRE suggested neoplasm. Thus, the clinical characteristics of the average patient at presentation changed, including a younger age at diagnosis, increased incidence of nonpalpable cancers, and decreased PSA levels.4
Data from the National Cancer Institute's surveillance, epidemiology, and end results database showed that the proportion of men aged ≤55 years at diagnosis increased from 2.3% in 1988 to 1991 to 9% in 2000 to 2003, and the median age at diagnosis decreased from 72 years in 1988 to 68 years in 2003.38 Not only were patients detected at younger ages, but also with earlier stage disease. A snapshot from the Cancer of the Prostate Strategic Urological Research Endeavor showed a growing fraction of clinically T1 PCA, steadily increasing through the early 1990s from about 17% in 1989 to 1992 to 23% in 1993 to 1995, and then more sharply in the late 1990s, with an average of 31% in 1996 to 1999, up to approximately 50% of cases recorded for the first time in 200222. The surveillance, epidemiology, and end results database shows similar overall incidence of clinical T-stage subcategories in the more contemporary PSA era (2004 to 2005) (Table 1).39 The rate of locally advanced and metastatic disease at presentation also dropped dramatically over time, although a larger proportion of young individuals harbored stage IV disease at diagnosis.40
The “PSA era effect” was initially responsible for the increasing detection of PCA with progressively more favorable prognostic features, as the more advanced, prevalent cancers were culled from the population.12
In the early 1990s a cutoff of 4 ng/mL was established for men to undergo biopsy for PSA elevations.3 Later on, the risk of PCA in PNBx performed for serum PSA levels below 4.0 ng/mL was found similar to that at 4 to 10 ng/mL with a significant risk of PCA detection increasing incrementally with increases in PSA level, acknowledging that PSA represents a continuum of risk, instead of a risk threshold.8,11 Similar findings were reported in the Rotterdam section of the European randomized study of screening for prostate cancer and in the placebo group of the prostate cancer prevention trial, studying the influence of finasteride on the development of PCA.15,17
As the PSA cutoff for recommending PNBx was lowered, a “PSA threshold-specific effect” was observed, leading to a further increase of earlier stage and incidental PCA, apparently without a significant raise in the proportion of potentially clinically insignificant PCA (organ-confined tumors, smaller than 0.5 cm3 with no Gleason pattern 4 or 5).5,41
Debate is still ongoing about whether men should be selected to undergo PNBx based on a PSA cutoff level or rather using recently established predictive nomograms, which combine several risk factors with the PSA level.42
PATHOLOGIC STAGE MIGRATION
Pathologic staging (pathological tumor-node-metastasis) is performed after surgical resection of the primary tumor and is based on gross and microscopic examination of the prostatectomy specimen and, when included, of the dissected regional lymph nodes. Pathologic staging after radical prostatectomy (RP) has been shown to be an independent prognostic factor used by the clinicians to determine the most appropriate follow-up management for individual patients.37
In the pre-PSA era, RP was a relatively uncommon procedure. In a study by Gleason and Mellinger,35 only 14.4% of patients diagnosed between 1960 and 1967 underwent RP. PSA screening, by increasing the number of clinically localized cases, increased the population of candidates to the surgical procedure,43 and the development and spreading of nerve/potency-sparing surgical techniques made the procedure more acceptable to a larger number of patients.21 As a result, the proportion of men diagnosed with PCA undergoing RP increased from about 15% in 1983 to 1984 to about 43% in 1991, with a marked increase among younger (<65 y) patients.26
A dramatic downward pathologic stage migration has been reported over time among patients diagnosed during the PSA era and treated with RP for clinically localized PCA.12,18,19,21,25,32,33,44 At our institution, Jhaveri et al25 observed a decrease in the incidence of extraprostatic extension at RP from 81% in 1987 to 36% in 1997. In a series of 2370 men who underwent RP at the Johns Hopkins Hospital, Han et al21 reported an increase in the percentage of men with organ-confined disease (OCD) from 37% in 1982 to 1991 to 61% in 1992 to 1998 and a decrease in the number of cases with positive pelvic lymph nodes (N1) from 7% to 4% in the same period. A study by Ung et al33 similarly reported a significant shift from pT3-4 to pT2 PCA, the latter representing 67% and 84% of cases in 1989 to 1996 and 1997 to 2000, respectively. Two subsequent studies from our institution showed a continued decrease in the rate of non-OCD from 66% (1987 to 1989) to 25% (2000 to 2001),18 and from 56% (1987 to 1995) to 28% (1996 to 2005) (Table 2).19
Jang et al12 reported similar results in 2241 men who were part of a large, longitudinal DRE-based and PSA-based PCA screening program. The investigators found an increase in the percentage of pathologic OCD in men diagnosed in 1996 to 2001 (75%), whose PCA were detected at a PSA threshold of 2.6 ng/mL, compared to patients diagnosed in 1989 to 1995 (69%), whose PCA were detected at the traditional cutoff of 4.0 ng/mL (Table 2).12 In the same period, in a European cohort of 557 PSA and DRE-screened patients who underwent RP between 1993 and 2001, Berger et al,32 similarly, found a significant increase of pathologic OCD from 64% in 1996 to 81% in 2001. They also observed that the percentage of OCD at RP in the patients diagnosed with PCA who had PSA levels ≤4 ng/mL ranged between 80% and 95%.32
The pathologic stage migration observed in the first 2 decades of the implementation of PSA screening is thus unquestioned, although a role has been also attributed to the concurrent evolution of preoperative diagnostic techniques, such as extended and ultrasound-guided biopsy schemes.45 The pathologic migration toward OCD was found still significant in the “contemporary” PSA era. In the study by Ploussard et al,44 pT2 cases represented 52% in 2001 to 2003, went up to 64% in 2004 to 2005, and kept increasing to 67% in 2006 to 2008 (P=0.024). These results were independent of the number of biopsy cores during the study period.44
Similarly, Dong et al19 reported a progressive decrease in non-OCD in RP specimens from 1987 to 2005 and found that the annual percentage of decrease varied, with a slow rate in the early PSA era (1987 to 1992) followed by a rapid acceleration between 1992 and 1995 and a slower downward trend between 1995 and 2005. The slowing phase of the pathologic stage migration after 1995 may represent a decreasing effect of PSA screening, but also the result of increasing use of therapeutic approaches alternative to RP for early-stage PCA, such as brachytherapy.46
TUMOR GRADE TRENDS
Histologic tumor grading based on the Gleason grading system is predictive of the biological behavior and prognosis of PCA and is used to produce standardized comparisons of end results over time. GS on PNBx is one of the most important prognostic factors, as it correlates with pathologic parameters at RP, PSA failure, lymph node status, local and distant metastases, regardless of therapy.9,47,48
Although since the introduction of PSA screening, PCA has been diagnosed in younger men with lower-stage disease and downward trends in PSA; changes in GS distribution during the PSA era are controversial.
The Gleason and Mellinger35 grading system was created in 1966 by Donald Gleason to provide a reliable, easy-to-use, grading system to assess and compare the biological behavior and response to treatment of similar groups of cancers. Gleason made further refinements to the patterns definition in 1974 and 1977. In 1993, when the World Health Organization recommended the Gleason system over other existing grading systems for PCA,49 it was already considered the de facto standard for grading in the Unites States.50 The Gleason grading system was officially endorsed by the World Health Organization in 2004.51
As a result of the widespread PSA testing over the past decade, most patients with PCA now present with clinically localized disease, and their tumors are rarely graded with GS <6, with a consequent declined incidence of low-grade PCA. Differences in PSA production in prostate tumor of different grades may have resulted in a preferential improvement of the detection of moderately differentiated tumors. Moreover, although data evaluating the temporal reproducibility of GS are scant, there is some evidence that pathologist interpretation of prostate specimens may have shifted over time to higher scores.52,53
Chism et al54 analyzed time-related changes in GS in approximately 1000 PCA patients treated with radiotherapy at a single institution between 1992 and 1997, and reported that, although the percentage of patients with GS7 and GS≥8 remained relatively constant over the study period, the changes in GS≤5 and GS6 were remarkable, with a steady decline of patients with GS≤5 mirrored by a rise of patients with GS6 PCA.
Numerous studies support the hypothesis that a shift in GS has occurred during the 1990s, with a break point around 1994 (Table 3). Two studies from our institution showed a significant increase in the proportion of patients with GS7 PCA at RP from 45% in 1987 to 1995 to 58% in 1996 to 200118 and from 48% in 1987 to 1995 to 62% in 1996 to 2005,19 respectively; meanwhile the number of cases with GS≥8 remained approximately the same over the study period (Table 3). Jang et al12 studied RP specimens from 2241 men and reported an increase in the percentage of GS7 tumors from 20% in patients diagnosed in 1989 to 1995 compared with 24% in men diagnosed in 1996 to 2001. In contrast, Ung et al33 in an earlier study found that the pathologic GS was not significantly different across intervals, and the decrease in the proportion of poorly differentiated PCA (GS≥8) from 12% in 1989 to 1996 to 6% in 1997 to 2000 similarly did not reach statistical significance (Table 3).
In the study by Derweesh et al,18 the increased incidence of GS7 cancer in RP specimens was in part attributed to the pathologic evaluation method. Until 1995, if 5% or less of the prostate tumor was Gleason pattern 4, the entire carcinoma was considered Gleason pattern 3 with a total GS of 6. Subsequently, the Gleason scoring method changed and any percentage of Gleason pattern 4 was considered as part of the GS. Such change in pathologic interpretation would contribute substantially to a decrease in the number of GS6 RP cases and an increase in GS7 cases.
Chism et al54 conducted a blind second review by a single urologic pathologist in 1998 of PNBx slides from 106 patients treated with radiotherapy between 1987 and 1993, and reported a statistically significant increase in GS in all initial interpretation, with the exception of GS≥8. Only 8% of the patients originally diagnosed with GS≤5 PCA retained the same score after reevaluation, and 44% and 30% of the original GS6 were increased to GS7 or GS≥8, respectively. The finding supports the hypothesis that a clinically meaningful shift towards higher pathologic interpretation has occurred over time and reflects a statistical artifact known as the Will Rogers phenomenon or grade migration, also referred to as “grade inflation.”
Albertsen et al55 addressed the issue of grade inflation by comparing the initial PNBx Gleason grades from 1990 to 1992 with a contemporary (2002 to 2004) GS assessment of the same sample by a single experienced pathologist, blinded to the original diagnosis, and reported a substantial shift to higher tumor grade in the retrospective contemporary evaluation. As expected, the reclassification resulted in an apparent improvement in clinical outcomes.
Recent change in the interpretation of the accepted grading system for reporting Gleason grade on biopsy could be one of the causes for the apparent altered distribution of cancer grade even in the absence of a true biologic change. The recommendation of the modified Gleason grading system of International Society of Urological Pathology 2005 for reporting Gleason grade is to give the predominant tumor pattern the first score and the highest grade the second score. There is also a growing consensus that low-grade tumors (GS≤5) should rarely, if ever, be diagnosed, on needle biopsy. However, the GS shift toward moderately differentiated tumors was evident since 2001 to 2002,53,56 as the 2005 modified Gleason grading system was a codification of an already diffuse practice among urologic pathologists.
We recently performed a blinded pathology review by a single pathologist of 471 RP specimens, 228 from an earlier PSA era (1987 to 1998) that used the Gleason grading system, and 243 from a late PSA era (1999 to 2004), and compared the results. All specimens were regraded using the modified Gleason grading system (ISUP 2005) and the cases were subdivided in 3 categories: GS≤6, GS7, and GS≥8. The re-review resulted in an upgrade of 22% and in a downgrade of 2% of cases, confirming a shift toward higher tumor grade. However, we found no significant difference in the number of cases in each of the 3 GS categories between the 2 PSA eras neither by univariable (P=0.2) or by multivariable (P=0.5) logistic regression analysis while adjusting for preoperative PSA and age, supporting the hypothesis that the grade migration is due to changes in pathologic evaluation rather than changes in tumor biology.57 Similarly, recent unpublished data from our institution have shown a decrease in the proportion of prostate cancer GS less or equal to 6 in 2005 to 2010 compared to the 1996 to 2005 period, meanwhile the percentage of GS7 tumors has remained approximately the same overtime (Table 3).
Contemporary Gleason scoring may more accurately reflect tumor prognosis than grade assignments of more than a decade ago.58 Considering that tumor grade has an important impact on outcome, any recent treatment will show improved outcome simply due to grade inflation, if the GS assignment is changing over time.
The rationale for screening is the detection of cancer at an early stage, to achieve higher rate of cure. This initially seemed true for PSA testing, yet there are no conclusive data at present to support a widespread use of PSA measurement alone as screening.
Since the introduction of PSA screening, a downward stage migration toward pathologic organ-confined cancer has been reported, with decreasing rates of tumor extending beyond the boundary of the prostate gland over time.
As far as tumor grading, the published data suggest that the shifts are unlikely to be attributable to changes in tumor biology, but rather to changes in practice patterns with respect to Gleason grading, prevalence of PSA screening, and clinical management of PCA patients. The GS shift may be in part the result of the cumulative experience of surgical pathologists with Gleason grading of prostate biopsies compared with prostatectomy specimens. As a matter of fact, the realization that a higher grade tertiary component may be of clinical significance has been instrumental in the modification of the original Gleason grading system.
Articles for this Review were selected after a search of the online PubMed database. Search terms included “PSA screening,” “time trends,” “stage migration,” “stage shift,” “Gleason grading,” or “modified Gleason grading.” The years of publication searched were 1974 to 2010, and papers selected were all full-text articles published in English. Additional sources were selected from the reference lists of the identified publications.
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