Is Gleason 6 Prostate Cancer, and Should It Be Treated?

Prostate cancer is one of the most common cancers among men worldwide, and the Gleason scoreplays a vital role in its diagnosis and treatment. However, how dangerous a prostate cancer case with a Gleason score of 6 is and how it should be managed have generated serious debate within the medical community.

In this article, we will discuss these debates, various expert opinions and current scientific views on evaluating and managing prostate cancer with a Gleason score of 6. We hope this discussion will be useful to patients facing prostate cancer with a Gleason score of 6, healthcare professionals trying to guide them, and general readers seeking information on the subject.

The following article is the most-read article on “ascopost.com,” the American Society of Clinical Oncology's website, closely followed by oncology professionals worldwide.

The diagnosis of prostate cancer and its treatment have long caused disagreements among oncology professionals, in politics and in patient-led civil society groups. One major debate concerns the fact that deciding whether to biopsy a man's prostate largely depends on his PSA (prostate-specific antigen) test results; however, the clinical value and accuracy of the PSA test and other prostate cancer biomarkershave long been debated, without consensus. A new controversial question about prostate cancer has emerged: is a tumor with a Gleason score score of 6 lethal, or should it be treated? In the United States alone, approximately 180,000 men are diagnosed with prostate cancer annually, and clinicians need guidance on this important question.

Is a Tumor with a Gleason Score of 6 Cancer?

Developed by Dr. Donald F. Gleason in 1966, this scoring system aims to grade prostate cancers and give clinicians an idea of the malignancy's aggressiveness. Since its introduction in 1966, the Gleason score has undergone several revisions; the most recent was made in 2014 by the International Society of Urological Pathology.

The Gleason score in brief: a pathologist examines Gleason patterns under a microscope in tissue obtained through prostate biopsy. Gleason patterns are expressed using numbers from 1 to 5. Under the microscope, in pattern 1, cancerous prostate cells resemble normal prostate glands, whereas in pattern 5, normal glandular appearances are rarely seen or absent. The higher the score, the more aggressive the biology of the cancer cells in that pattern is considered to be.

The pathologist then identifies the patterns predominantly observed in the tumor sample. The dominant pattern is called the primary pattern (it should account for more than %50 of all observed patterns). Secondary (more than %5 but less than %50) and tertiary patterns are then identified according to their frequency. For example, if the primary pattern score is 3 and the secondary pattern score is 4, the Gleason score is 3+4=7.

The oncology community is currently divided over Gleason 6 tumors.

Prostate cancer specialist Dr. Herbert Lepor, chair of urology at New York University's Langone Center, told ASCO (American Society of Clinical Oncology):

“The metastatic potential of Gleason 6 prostate cancer is a highly interesting and controversial subject. The issue is this: prostate biopsies used to be performed using ultrasound scanning of the prostate. Half of prostates described as Gleason 6 on biopsy were upgraded to Gleason 7 in surgically removed specimens because of inadequate sampling. At the same time, in men with specifically Gleason 6 in their prostatectomy specimens, no metastatic disease was seen after 10 years, suggesting that Gleason 6 cancers do not metastasize.”

“What remains uncertain is whether Gleason 6 cancers, because of their genetic instability , can develop into a higher-grade Gleason tumor and metastasize. In other words, if only a Gleason 6 tumor is present in the prostate and this does not change over time, Gleason 6 does not metastasize and therefore, by definition, would not be cancer. Unfortunately, the situation is not that simple,” he continued.

Richard J. Ablin, who has studied prostate cancer for almost 50 years in the pathology department at the University of Arizona College of Medicine in Tucson, told ASCO: “One of the first to challenge Gleason 6 was internationally recognized pathologist Jonathan Oppenheimer, who supports giving Gleason 6 a new name because Gleason 6 is a neoplasm, not cancer.

If we stop calling a Gleason 6 prostate tumor cancer, men will make fewer fear-based decisions,” he said.

Dr. Ablin stated: “The issue is not what we call Gleason 6, but whether the cancer really has the potential to progress. We must also consider the possibility of underscoring the tumor because of inadequate biopsy sampling. Prostate cancer is a heterogeneous disease. Two tumors can look the same under the microscope and have the same Gleason score, yet have different molecular profiles and clinical behavior. Researchers are now examining genetic markers distinguishing harmless Gleason 6 tumors from those that could progress to Gleason 7 or higher and metastasize. This is where we should focus our efforts.”

To shed more light on the issue, The ASCO Post team spoke with Dr. Geert J.L.H. van Leenders, a genitourinary pathologist at Erasmus Medical Center in Rotterdam, the Netherlands:

“From a pathologist's perspective, a Gleason score of 6 is cancer. Abnormal microscopic features specific to prostate cancer continually increase at a Gleason score ≥ 7. Among Gleason 6 cases, only %5 grow outside the prostate and show biochemical recurrence.”

Dr. van Leenders continued: “From a clinical perspective, it is more appropriate to estimate a tumor's potential aggressiveness in diagnostic biopsies. The issue now is not only identifying men with only Gleason 6 on biopsy; identifying men with very indolent Gleason 7 is also important. Recently, outcomes of Gleason 7 tumors without invasive cribriform or intraductal tumor growth have also been observed to be very good, reminiscent of Gleason 6 prostate tumors.”

Asked how patient selection could be improved, Dr. van Leenders said: “By observing these unusual pathological variables together with magnetic resonance imaging and reducing sample size, the likelihood of identifying people who do not require prostate cancer treatment increases.”

Sharp Disagreements

According to genitourinary surgeon Dr. Bert Vorstman, a tumor with Gleason 6 has no potential to cause death. “Nobody has died from this so-called cancer. A Gleason 6 prostate tumor lacks the molecular biological mechanisms found in cells that normally behave like cancer. Unlike a normal cancer cell, these cells have a very long proliferation process. Growing approximately 1 cm takes almost 40 years and is widely recognized as part of aging,” he said.

In Dr. Vorstman's view, PSA screening has triggered unnecessary diagnoses and treatments, many resulting in adverse side effects. “PSA screening for prostate cancer usually identifies benign tumors and Gleason 6 disease, leading to unnecessary treatments such as radical prostatectomy . This suggests that the harms of PSA testing outweigh its benefits when used diagnostically,” he stated.

Dr. Vorstman said: “Only %15 of prostate cancers have the potential to be lethal and require treatment. Because Gleason 6 does not possess the fundamental characteristics of cancer, it is a pseudocancer and poses no threat to health, does not progress to become a health risk, does not need diagnosis and requires no treatment.”

Final Words

Each year, 185,000 men in the United States are diagnosed with prostate cancer, and Gleason 6 is the grade most commonly found in biopsies of men undergoing PSA screening. It is difficult to reach consensus on whether a Gleason 6 tumor needs treatment or should simply be left alone. Some also say that identifying Gleason 6 tumors is impossible, emphasizing that in many reviews tumors initially described as Gleason 6 proved to have Gleason 6-like behavior despite being Gleason 7. Others believe that truly Gleason 6 tumors never show a tendency to metastasize.

This debate also needs a caution: historically, the male prostate has been harmed by unnecessary biopsies and surgery, resulting in very serious adverse clinical consequences for countless men. Research continues to develop genetic markers and biomarkers that can distinguish Gleason 6 from a tumor with metastatic potential. Until such markers are found, however, anxious men with Gleason 6 want to understand exactly what these numbers mean. Increasing numbers of pathologists and clinicians favor naming Gleason 6 a neoplasm rather than cancer to prevent men from becoming frightened and making hasty decisions. Perhaps pathologists and clinicians can agree on this.

Most patients need guidance on handling this situation to avoid unnecessary and potentially harmful treatment. In this context, to make the best decisions, every patient diagnosed with Gleason 6 prostate cancer should discuss risks, benefits and alternatives in detail, knowing that cancerous tumors are generally genetically unstable and tend to progress over time.

Nevertheless, despite disagreements over whether Gleason 6 prostate cancer is truly cancer, all healthcare professionals agree that Gleason 6 tumors typically grow slowly and have low metastatic potential. This generally leads to a recommendation for active surveillance in low-risk patients, although the person's health, life expectancy and preferences should be considered.

In conclusion, more genetic and biomarker studies are needed to establish a general approach to Gleason 6 prostate cancer treatment. Until then, every man diagnosed with this type of cancer should carefully evaluate potential treatment options and their risks, side effects and costs with his doctors, making the decision best suited to his health goals and quality-of-life expectations.