The issue is not what we call a Gleason 6, but whether it has the potential to progress. Researchers currently are looking at genetic signatures that can differentiate a nonthreatening Gleason 6 from one that will progress to Gleason 7 or higher and possibly metastasize.— Richard J. Ablin, PhD, DSc (hon)
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The diagnosis and treatment of prostate cancer have long been a source of controversy among the oncology community, the political sector, and patient advocacy groups. Most notably, the decision to biopsy a man’s prostate gland rests largely on his prostate-specific antigen (PSA) test numbers, the accuracy and clinical value of which have been hotly debated for decades, and still no consensus has been reached. A new controversial question has arisen in prostate cancer: Is a tumor with a Gleason 6 score a potential killer, or should it be left alone? About 180,000 American men are diagnosed with prostate cancer each year, and their clinicians need guidance on this critical question.
Is a Gleason 6 Tumor Cancer?
Created in 1966 by Donald F. Gleason, MD, the purpose of the Gleason score is to grade prostate cancers and provide clinicians insights into the extent and aggressiveness of the malignancy. Since its inception in 1966, the Gleason score has undergone several modifications; the most recent is known as the 2014 International Society of Urological Pathology modified Gleason grading system. In short, the grading system looks at the primary and secondary most predominant growth patterns of tumor cells and then allocates each finding a number of 1 to 5; adding these two numbers assigns the tumor’s Gleason score. The oncologic community is currently riven over the pathologic status of a Gleason 6 score tumor.
Herbert Lepor, MD
Prostate cancer expert Herbert Lepor, MD, Urology Chief of the New York University (NYU) Langone Medical Center, commented to The ASCO Post: “The metastatic potential of Gleason 6 prostate cancer is a topic of great interest and controversy. Here is the problem. Historically, prostate biopsies were obtained by randomly sampling the prostate under ultrasound guidance. We have reported that half of prostates that were Gleason 6 on biopsy were upgraded to Gleason 7 or higher in prostatectomy surgical specimens due to inadequate sampling. We also reported that no men with exclusively Gleason 6 in the prostatectomy specimen developed metastatic disease within 10 years after radical prostatectomy, suggesting Gleason 6 cancers do not metastasize.”
Dr. Lepor continued: “What is unknown is whether Gleason 6 cancers on the basis of genetic instability can evolve into a higher Gleason tumor and then metastasize. So if we knew that a prostate harbored only Gleason 6 disease and over time the disease would not de-differentiate, then Gleason 6 disease would not metastasize and by definition would not be a cancer. Unfortunately, this is not so simple.”
Richard J. Ablin, PhD, DSc (hon), Department of Pathology, University of Arizona College of Medicine, Tucson, who has investigated prostate cancer for going on 50 years, told The ASCO Post, “One of the first people to tackle the issue of the Gleason 6 was internationally regarded pathologist Jonathan Oppenheimer, MD, who strongly proposes that we come up with a new term for the Gleason 6, which is a neoplasm, not cancer. By doing so, we take away the ‘C’ word, and men will be less likely to make a fear-driven decision.”
Dr. Ablin continued: “The issue is not what we call a Gleason 6, but whether it has the potential to progress. We also have to be wary of undergrading the tumor. Prostate cancer is a heterogeneous disease. Two tumors can look alike under the microscope and have the same Gleason score, but they can have a different molecular profile and demonstrate different clinical behaviors. Researchers currently are looking at genetic signatures that can differentiate a nonthreatening Gleason 6 from one that will progress to Gleason 7 or higher and possibly metastasize. This is where our efforts should be applied.”
Better Selection Needed
From a pathologist point of view, Gleason score 6 is prostate cancer. Its aberrant microscopic features are continuous with Gleason score ≥ 7 tumors.— Geert J.L.H. van Leenders, MD, PhD
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To shed further light on this issue, The ASCO Post recently spoke with Geert J.L.H. van Leenders, MD, PhD, a urogenital pathologist at the Erasmus Medical Center, Rotterdam, the Netherlands: “From a pathologist point of view, Gleason score 6 is prostate cancer. Its aberrant microscopic features are continuous with Gleason score ≥ 7 tumors; about 5% grow beyond the prostate and show biochemical recurrence. In fact, studies showing minimal if any metastatic potential of Gleason 6 have all been performed on radical prostatectomies, so patients had been treated for their disease, and the entire specimen was available for pathologic review.”
Dr. van Leenders continued: “From a clinical point of view, it is more relevant to estimate tumors’ potential aggressiveness at diagnostic biopsies. Namely, circa 2% of men with Gleason 6 at biopsy will develop metastasis, probably due to missing a higher-grade tumor component in the prostate (sampling artifact). The current challenge is to identify those men not only with Gleason 6 but also with Gleason 3+4=7 at biopsy who have indolent tumors. We recently found that Gleason 3+4=7 without invasive cribriform and intraductal tumor growth at biopsy has an excellent outcome, reminiscent of Gleason 6 prostate cancer.”
Asked how we can perform more accurate patient selection, Dr. van Leenders said: “Monitoring these adverse pathologic variants together with the use of multiparametric [magnetic resonance imaging] to minimize the sampling artifact will lead to better selection of patients who do not have to undergo treatment for their prostate cancer.”
Since the Gleason 6 lacks the hallmarks of a cancer, it is a pseudocancer, not a health risk; does not progress to become a health risk; needs no detection; and needs no treatment.— Bert Vorstman, MD, MS, FAAP, FRACS, FACS
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However, according to genitourinary surgeon Bert Vorstman, MD, MS, FAAP, FRACS, FACS, a Gleason 6 tumor has no lethal potentiality. “No man has died from this so-called cancer. It lacks a number of molecular biological mechanisms normally found in cancerous-behaving cells. Unlike a typical cancer cell, this cell has a very long doubling time at 475 ± 56 days, so from mutation to a growth of about 1 cm in diameter takes some 40 years, and this disease is a recognized part of the aging process as some 50% of 50-year-old-men (60% of 60-year-olds, and so on) will exhibit areas of prostate ‘cancer.’”
Dr. Vorstman believes that population-based PSA screening has promoted overdiagnosis and needless treatments, many of which have debilitating side effects. “The non–cancer-specific PSA test mainly detects benign and Gleason 6 disease, leading to unnecessary treatments such as ill-founded and debilitating radical prostatectomy. This is the main reason the U.S. Preventive Services Task Force (USPSTF) concluded that the PSA test’s benefits were outweighed by its harms,” he declared.
Dr. Vorstman concluded: “Only the 15% or so of the high-grade forms of prostate cancer are potentially lethal, and only they demand detection (but commonly make little or no PSA change) and treatment. Since the Gleason 6 lacks the hallmarks of a cancer, it is a pseudocancer, not a health risk; does not progress to become a health risk; needs no detection; and needs no treatment.”
Each year, approximately 185,000 American men are diagnosed with prostate cancer, and the Gleason 6 is the most common grade of disease among those men who underwent PSA screening. Reaching consensus about whether a Gleason 6 tumor should be treated or left alone is a nuanced and complicated process. Some argue that it is impossible to define Gleason 6 disease and cite studies showing that postoperative examination revealed that a percentage of these tumors were actually Gleason 7 (mainly the 3+4 Gleason 7, which behaves like the Gleason 6). Others cite longitudinal studies demonstrating that true Gleason 6 grade tumors never demonstrate metastatic propensity.
This debate needs to be informed with one caveat: The male prostate gland has historically been abused by unnecessary biopsies and surgical procedures, which have had serious clinical consequences for countless men. There are current research efforts looking for a reliable genetic marker or biomarker that will differentiate a true Gleason 6 tumor from one that has metastatic potential. However, until we reach that point, anxious men presenting with a Gleason 6 need clarity on what that number means for them moving forward. A growing number of pathologists and clinicians strongly favor renaming the Gleason 6 cancer with a term, such as neoplasm, which does not scare men into hasty decisions. Perhaps clinicians and pathologists can come to agree on that. ■
Disclosure: Dr. Vorstman owns shares in an outpatient surgery center, health-care mutual funds, and Sonablate. Drs. Lepor, Ablin and van Leenders reported no potential conflicts of interest.