Autopsy studies of men without known prostate cancer suggest that a substantial reservoir of prostate cancer that does not cause symptoms or death exists within the population. The majority of these cancers are Gleason 6 tumors and are frequently detected by prostate-specific antigen–based prostate cancer screening. There is strong evidence from longitudinal cohort studies of men with both treated and untreated Gleason 6 prostate cancer to suggest that Gleason 6 disease, when not associated with higher-grade cancer, virtually never demonstrates the ability to metastasize and thus represents an indolent entity that does not require treatment. Whether Gleason 6 has a propensity to progress to higher-grade cancer is still under investigation. Because the term “cancer” has historically been used to represent a disease state that leads to progressive illness that is uniformly fatal without treatment, we believe Gleason 6 disease should not be labeled with this term. Our challenge now is to develop the technology to differentiate true Gleason 6 disease from the higher grades of dysplasia with which it can be associated.
The first known recorded descriptions of malignant tumors are found in the Edwin Smith Papyrus, written in Egypt in approximately 3,000 BC. The word “cancer” did not appear until approximately 2.5 millennia later, when Hippocrates invoked the Greek word karkinos, or “crab,” to describe tumors he observed, possibly because of their propensity to insinuate into surrounding tissues and adhere tenaciously, as if by the use of claws. Roman physicians continued to liken cancers to the crab and translated the Greek term into the Latin word cancer. For the subsequent 2,000 years, the clinical entity of cancer remained a disease that was recognized primarily in its locally advanced or metastatic stage, when it was almost uniformly fatal.
The rapid advances in diagnostic technology of the later part of the 20th century meant that for the first time the detection of cancer was possible when the disease was confined to the organ of origin and amenable to cure. In some cases, technology enabled abnormalities at the subclinical level to become detectable years before recognition of the clinical entity of cancer. The benefits of screening and early intervention have been consistently demonstrated in certain cancers, such as cervical and breast cancer.[2,3] For other malignancies, including adenocarcinoma of the prostate, the risk/benefit ratio is controversial and more difficult to quantify. It is now widely recognized that a substantial proportion of screening-detected prostate cancers are unlikely ever to become clinical cancers during the lifetime of the patient. This phenomenon, the detection of a condition that would not go on to cause symptoms or death, is referred to as “overdiagnosis.”
The current paradigm for screening and detection of prostate cancer has resulted in overdiagnosis for several reasons. First, the instrument for prostate cancer screening, the prostate-specific antigen (PSA) blood test, uses a nonspecific serum marker that is elevated not only in prostate cancer but also in a host of benign prostate conditions, resulting in substantial false-positive results. Second, the confirmatory test, the prostate biopsy, is performed by taking random but systematically directed biopsies of the prostate in men with an elevated PSA level. Random biopsy risks both the detection of indolent cancers and the failure to diagnose clinically significant cancers. Because it is known from autopsy series that between 30% and 40% of prostate glands in men > 50 years of age harbor microscopic foci of Gleason 6 cancers that appear to be of no clinical significance, it is likely that a substantial proportion of cancers detected through this pathway will never become clinically significant.[7-9] Of the cancers identified through this pathway, approximately one-half are Gleason 6.
Legitimate concerns over the potential harms of overdiagnosis and overtreatment resulting from this paradigm led the US Preventive Services Task Force to recommend against PSA screening for all men. Others have advocated surveillance-based strategies for a disease that is thought to have a potentially indolent course.
For more than 5,000 years, the clinical entity of cancer has implied a process of invasion, destruction, metastasis, and death. Assigning a diagnosis of cancer to a patient instills intense fear of an almost inevitable demise unless aggressive attempts are made to eradicate the disease. But today our current diagnostic armamentarium has given us the ability to aggressively identify and treat pathologic cancers, the majority of which are not likely to cause harm. It is time to reappraise whether these indolent abnormalities should be labeled with the term “cancer.” Concern about overdiagnosis has become especially focused on Gleason 6 disease, given multiple lines of evidence suggesting that the majority of Gleason 6 disease, while demonstrating the ability to invade pathologically, does not appear to have the propensity to invade clinically. If this is the case, is Gleason 6 disease truly a cancer?
Gleason Grading System
The purpose of staging and grading cancers is to provide insights regarding the extent and aggressiveness of the malignant process. Since its initial description in 1966, the Gleason scoring system has become the most widely accepted system for the pathologic grading of prostate adenocarcinomas, largely because of its consistent reproducibility and robust ability to independently predict disease outcomes.[13-15] This system assigns a grade to the tumor based on the tumor architecture viewed under relatively low power (4–10×). The more the glandular architecture deviates from normal, the higher the Gleason grade. A Gleason score takes into account that prostate cancer is often multifocal and that there are different Gleason patterns even within a single index lesion. The most predominant (primary) and second most predominant (secondary) patterns of tumor glandular architecture are identified, and each is assigned a grade of 1 to 5. The Gleason sum, or score, is obtained by adding these primary and secondary Gleason grades together.
Since its initial description, the Gleason system has undergone several modifications and clarifications. The most recent modification occurred in 2005 and established the contemporary system, known as the 2005 International Society of Urological Pathology (ISUP) modified Gleason system. Several changes from the previous version should be noted. In the modified 2005 system, Gleason patterns of 1 or 2 are rarely, if ever, diagnosed, particularly for needle-biopsy specimens. The reasons for this include low interobserver agreement for Gleason patterns 1/2 even among uropathologists, poor correlation between needle-biopsy and radical prostatectomy specimens for these grades, and fear that the diagnosis of these well-differentiated patterns may lead to overtreatment. In addition, in the modified 2005 system the majority of cribriform glands, as well as ill-defined glands with poorly formed lumina, have been removed from the pattern 3 category and are now considered higher-grade and are thus assigned to pattern 4, both increasing the stringency for making the diagnosis of purely pattern 3 and expanding the pattern 4 category.
These subtle modifications to the Gleason system have resulted in two noteworthy changes. First, the virtual elimination of patterns 1 and 2 narrows the Gleason score from a 9-point scale (2–10) to a 5-point scale (6–10). Second, and more importantly, the increased stringency for the diagnosis of purely pattern 3 disease means that men who receive a diagnosis of Gleason 3+3 disease using the modified 2005 system are likely to have less aggressive tumors than men who received a diagnosis of Gleason 6 disease in years past, and as such are likely to have improved oncologic outcomes.
Epidemiologic Support for the Concept of Clinically Insignificant Prostate Cancer
All available evidence suggests that there is a substantial reservoir of prostate cancer within the population that does not result in clinical symptoms or death. The best evidence for the existence of such a reservoir comes from studies examining prostates obtained from autopsies, as well as studies of specimens obtained during cystoprostatectomy performed for aggressive bladder cancer in which the prostate is removed incidentally. Autopsy studies from multiple countries have demonstrated a prevalence of undiagnosed prostate cancer in the population that ranges from approximately 18% to 40%. Of these incidentally detected cancers, at least 80% were exclusively Gleason pattern 3 disease.[9,18] Specimens from cystoprostatectomy performed for bladder cancer exhibit a somewhat higher rate of malignancy overall, ranging between 41% and 54%, but the prevalence of high-grade elements is also quite low, with > 70% demonstrating only Gleason pattern 3.[19,20]
Taken together, these studies reveal the presence of a large reservoir of prostate cancers, the majority of which are Gleason 6, which exist in the population and do not cause clinical symptoms or death. Many of these prostate cancers could potentially be diagnosed by PSA screening and random systematic biopsy, suggesting that a substantial proportion of Gleason 6 disease detected by PSA screening represents disease that may never lead to metastasis or death.
How Reliable Is Our Detection of Gleason 6 Disease?
Before the PSA screening era began in the late 1980s, prostate cancer was usually diagnosed by directing a biopsy needle into a nodule detected at the time of a digital rectal examination. In most cases, the nodule occupied a significant proportion of the gland. Often, gross extracapsular disease was evident at the time of diagnosis. Low-grade cancers were rarely diagnosed unless they were incidental findings at the time of transurethral prostatectomy for benign disease.
The detection of prostate cancer in the PSA era requires a random biopsy technique because transrectal ultrasonography (TRUS) does not reliably identify the site of clinically significant disease. Therefore, many Gleason 6 cancers identified on biopsy coexist with higher-grade disease missed by random biopsy. Mufarrij et al examined the prostates of 205 and 771 men who met the Epstein or Klotz criteria, respectively, for active surveillance and who underwent radical prostatectomy. By definition, all of these men had Gleason 6 cancers on prostate biopsy. Between 45.9% and 47.2% had Gleason grade 4/5 disease, and 7.8% to 10.9% had evidence of extracapsular extension. The 5-year biochemical-disease–free survival was estimated to be 83.2% to 92.9% despite curative intervention. Others have confirmed the unreliability of Gleason grading attributable to random biopsy, which remains an essential limitation in assigning men to active surveillance.
It is therefore almost impossible to define the natural history of diagnosed Gleason 6 disease, since almost one-half of these cases are truly Gleason 7 or higher disease at the time of diagnosis. Thus, it is unclear whether disease progression in men presumed to have Gleason 6 disease is due to progression of the Gleason 6 elements or represents a consequence of coexisting higher-risk disease.
Does Untreated Clinical Gleason 6 Disease Cause Symptoms or Death?
Several studies that examined the natural history of untreated prostate cancer diagnosed in the pre–PSA screening era have suggested that men with Gleason 6 cancers are at risk for prostate cancer–specific mortality beyond 10 years of follow-up.[24,25] The majority of the Gleason 6 disease was T1a/b disease, which was identified at the time of transurethral resection of the prostate (TURP) for benign disease. Today, it is extremely rare to diagnose T1a/b disease because fewer TURPs are performed and those undergoing TURP have been prescreened with PSA testing. The results of the natural history studies in the PSA screening era are also problematic because many of the cases were likely misclassified at the outset because of the aforementioned limitations attributable to the random-systematic tissue sampling guided by TRUS.
Albertsen et al estimated that men who received a diagnosis of Gleason 6 disease in the pre-PSA era and were managed conservatively had approximately a 30% (23%–37%) prostate cancer mortality rate after 20 years, but this study is potentially flawed and may not be applicable to contemporary cohorts for multiple reasons. First, no PSA measurement was available at the time of diagnosis. Second, the majority of cases were detected following TURP, which does not sample the peripheral zone, where most cancers reside. Third, a substantial number of patients did not undergo a metastatic evaluation at the time of diagnosis. Bone scans were performed in only 30% of patients, and confirmation of a normal serum acid phosphatase level was obtained in only 53% of patients.
Thirty-year follow-up data were recently published on a cohort of 223 patients who received a diagnosis in the pre-PSA era and who were all managed conservatively. This study included 65 patients with Gleason 3–6 disease, and 70 patients classified as low risk based on the World Health Organization grading system (an alternative grading scheme to the Gleason system). Metastatic disease developed in 9 of these 70 low-risk patients, 8 of whom died of prostate cancer during the 30-year period. The progression to metastatic disease and death from prostate cancer per 1,000 person-years in this series were 14.1 and 12.4, respectively. This translates to 1,000 men with Gleason 6 disease followed for 10 years, of whom 14 would progress to metastatic disease and 12 would progress to death. Even these favorable results are likely an overestimate of the risk of men who receive a diagnosis of Gleason 6 disease in the current era because the risk stratification of men in this study was based on TURP specimens and fine-needle aspiration. TRUS-guided biopsy and PSA measurement were not available at the time of their initial stratification. It is likely that misclassification took place; thus, many of these men probably had some component of higher-grade disease.
Additional insights about the natural history of Gleason 6 disease can be derived from long-term follow-up of men who select active surveillance. Interpretation of these studies requires the recognition of the significant rate of undergrading in these series due to the current limitations in risk stratification. The majority of active surveillance protocols include only patients with low-volume Gleason 6 disease; thus, disease progression in these cohorts may be a surrogate for the natural history of untreated Gleason 6 disease. These studies have consistently demonstrated a rate of progression on subsequent biopsy ranging from 12% to 38%.[11,22,26-28] However, these data are somewhat difficult to interpret. While they may represent progression of disease over time, the well-documented propensity of TRUS-guided biopsy to undergrade tumors means that a substantial proportion of this upgrading is likely attributable to sampling error of the initial biopsy, meaning that the higher-grade disease was present but missed at the time of initial biopsy. Despite this, true grade progression, and not simply upgrading on subsequent biopsy due to sampling error, does appear to take place in certain cases. Sheridan et al evaluated 241 men with Gleason 6 disease on active surveillance, of whom 45 (18.7%) showed an increase in grade on subsequent biopsy. Of these 45 men, 24 (53%) progressed within 24 months, suggesting that these men likely had higher-grade disease from the outset. The additional 21 men who progressed did so after 2 years and after multiple prior biopsies, which points to one of three possibilities. First, these foci may represent Gleason 6 disease that had progressed in grade to Gleason 7. Second, and equally plausible, independent foci of Gleason 7 may have arisen de novo. Third, it is possible that preexisting small foci of Gleason 7 grew to the extent they became detectable by the random biopsy technique only after several years of follow-up and repeat biopsy.
With reported median follow-up ranging from 22 to 82 months, current active surveillance cohorts remain immature at this time, and longer follow-up will be necessary to draw definitive conclusions. Thus far, cancer-specific survival among these cohorts has been > 97%, and there are no data to suggest inferior outcomes after delayed radical therapy, as compared with immediate therapy.
1. Hajdu SI. A note from history: landmarks in history of cancer, part 1. Cancer. 2011;117:1097-102.
2. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366:687-96.
3. Sasieni PD, Cuzick J, Lynch-Farmery E. Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Co-ordinating Network for Cervical Screening Working Group. Br J Cancer. 1996;73:1001-5.
4. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102:605-13.
5. Loeb S, Gashti SN, Catalona WJ. Exclusion of inflammation in the differential diagnosis of an elevated prostate-specific antigen (PSA). Urol Oncol. 2009;27:64-6.
6. Steinberg DM, Sauvageot J, Piantadosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol. 1997;21:566-76.
7. Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int J Cancer. 1977;20:680-8.
8. Soos G, Tsakiris I, Szanto J, et al. The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study. Eur Urol. 2005;48:739-44.
9. Stamatiou K, Alevizos A, Agapitos E, Sofras F. Incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in Greek male population: an autopsy study. Prostate. 2006;66:1319-28.
10. Shao YH, Demissie K, Shih W, et al. Contemporary risk profile of prostate cancer in the United States. J Natl Cancer Inst. 2009;101:1280-3.
11. US Preventive Services Task Force. Available from: http://www.uspreventiveservicestaskforce.org/
12. Thompson IM, Klotz L. Active surveillance for prostate cancer. JAMA. 2010;304:2411-2.
13. Bailar JC 3rd, Mellinger GT, Gleason DF. Survival rates of patients with prostatic cancer, tumor stage, and differentiation—preliminary report. Cancer Chemother Rep. 1966;50:129-36.
14. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974;111:58-64.
15. Stephenson AJ, Scardino PT, Eastham JA, et al. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2005;23:7005-12.
16. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-42.
17. Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst. 2005;97:1248-53.
18. Erbersdobler A, Bardenhagen P, Henke RP. Numerical chromosomal anomalies in latent adenocarcinomas of the prostate. Prostate. 1999;38:92-9.
19. Mazzucchelli R, Barbisan F, Scarpelli M, et al. Is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant? Am J Clin Pathol. 2009;131:279-83.
20. Pettus JA, Al-Ahmadie H, Barocas DA, et al. Risk assessment of prostatic pathology in patients undergoing radical cystoprostatectomy. Eur Urol. 2008;53:370-5.
21. Mufarrij P, Sankin A, Godoy G, Lepor H. Pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy. Urology. 2010;76:689-92.
22. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011;29:2185-90.
23. Klotz L. Active surveillance for favorable-risk prostate cancer: who, how, and why? Nat Clin Pract Oncol. 2007;4:692-8.
24. Albertsen PC, Hanley JA, Fine J. 20-Year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005;293:2095-101.
25. Popiolek M, Rider JR, Andren O, et al. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol. 2013;63:428-35.
26. Eggener SE, Mueller A, Berglund RK, et al. A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol. 2013;189:S19-25; discussion S25.
27. Bul M, Zhu X, Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63:597-603.
28. Dall’Era MA, Konety BR, Cowan JE, et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer. 2008;112:2664-70.
29. Sheridan TB, Carter HB, Wang W, et al. Change in prostate cancer grade over time in men followed expectantly for stage T1c disease. J Urol. 2008;179:901-4; discussion 04-5.
30. Donin NM, Laze J, Zhou M, et al. Gleason 6 prostate tumors diagnosed in the PSA era do not demonstrate the capacity for metastatic spread at the time of radical prostatectomy. Urology. 2013;82:148-52.
31. Miyamoto H, Hernandez DJ, Epstein JI. A pathological reassessment of organ-confined, Gleason score 6 prostatic adenocarcinomas that progress after radical prostatectomy. Hum Pathol. 2009;40:1693-8.
32. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am J Surg Pathol. 2012;36:1346-52.
33. Whittemore AS, Keller JB, Betensky R. Low-grade, latent prostate cancer volume: predictor of clinical cancer incidence? J Natl Cancer Inst. 1991;83:1231-5.
34. Penney KL, Stampfer MJ, Jahn JL, et al. Gleason grade progression is uncommon. Cancer Res. 2013;73:5163-8.
35. Sowalsky AG, Ye H, Bubley GJ, Balk SP. Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Res. 2013;73:1050-5.
36. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644-8.
37. Kovtun IV, Cheville JC, Murphy SJ, et al. Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res. 2013;73:3275-84.
38. Kobayashi M, Ishida H, Shindo I, et al. Molecular analysis of multifocal prostate cancer by comparative genomic hybridization. Prostate. 2008;68:1715.
39. Epstein JI. Editorial comment. Urology. 2013;82:152-3.
40. Rouse P, Shaw G, Ahmed HU, et al. Multi-parametric magnetic resonance imaging to rule-in and rule-out clinically important prostate cancer in men at risk: a cohort study. Urol Int. 2011;87:49-53.
41. Irshad S, Bansal M, Castillo-Martin M, et al. A molecular signature predictive of indolent prostate cancer. Sci Transl Med. 2013;5:202ra122.