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Nomenclature Matters: What Should the Future Be for Gleason Grade Group 1?

The term “cancer” dates to the time of Hippocrates, when the crab (karkinos)-like cutaneous manifestations of advanced tumors heralded incurable disease, pain, decline, and death. Today the term denotes an incredibly diverse spectrum of conditions, all characterized by abnormal cell division and growth—and nearly all by the capacity for metastasis—but varying very widely in aggressiveness and kinetics of progression. In the era of microscopy and histopathology, each cancer now has its formal criteria for diagnosis, and clinicians recognize the variable meaning of each. To the public, however, the connotation of the diagnosis “You have cancer” has changed only to an extent in the modern age.

In the case of prostate cancer, prostate specific antigen (PSA)-based early detection and the years-to-decades lead time associated with screening has radically changed the clinical meaning of the diagnosis. Countless research articles and reviews on prostate cancer begin by citing the fact that it is the most common non-cutaneous cancer diagnosed among men in the US and in many other countries.

Yet even the hundreds of thousands of cases diagnosed each year do not reflect the true incidence of these neoplasia at the histologic level: autopsy studies demonstrate that nearly half of all White men have detectable cancer cells in their prostates by their 80s, and of Black men by their 70s. These cells are identifiable in 20-30% of men even in their 30s.1 While aggressive sub-variants of prostate cancer continue to kill more men than any cancer except lung cancer, these are a small minority of those diagnosed, and a smaller fraction still of the autopsy-detectable lesions.

In 2022, can we tell the difference? In most cases, absolutely yes. High grade prostate tumors – those assigned Gleason grade group (GG) 4 and 5, most with GG3, and a subset with GG2 (particularly those with expansile or large cribriform histology) are cancers as understood by the public and most clinicians: they grow, they can metastasize, and they can kill. Pure GG1 lesions, on the other hand, are not. They may grow in infiltrative or invasive patterns histologically, and share a few molecular features with more aggressive cancers (as can histologically normal prostate tissue), but they never metastasize. They do not reflect the genotypic or phenotypic characteristics which allow other cancers to spread and pose no meaningful threat to life. If GG1 looks like a duck but neither walks nor quacks, is it a duck? Or merely a decoy?

The question that follows is: If GG1 has few if any molecular and none of the clinical features of cancer as understood by patients, should we continue to call it “cancer”? Key thought leaders have called for changes in nomenclature for low-risk prostate—and breast—cancer as far back at least as 2009,2 and recent editorials have renewed the discussion.3,4

To be clear, GG1 absolutely is not a “normal” finding and may co-exist with or antedate higher grade neoplasia. A man with GG1 needs monitoring with PSA tests, imaging, and repeat biopsies—in order words, active surveillance—regardless of nomenclature. Active surveillance is already rising steadily as first line management for GG1, but over 40% of men with this diagnosis still receive radical therapy, and treatments vary massively across individual urology practices and providers.4 A change in nomenclature would help substantially. Some men with GG1 would still be reasonable candidates for immediate treatment—mastectomy is after all routinely offered to women based on premalignant breast findings or even adverse genetics alone—but the bar to justify up-front treatment would be appropriately higher.

As a field, we are already, in an important de facto sense, categorizing GG1 as noncancer. Multiparametric MRI and multiple blood and urine tests now exist to improve decision-making about biopsy for men with elevated PSA, and in some settings are already used as routine standard of care. These tests explicitly dichotomize the predicted outcome as high grade cancer (GG≥2) vs negative or GG1. If we expect only GG1 will be present, we do not biopsy. These efforts to reduce over­diag­nosis are succeeding: low-risk prostate cancer as proportion of prostate cancer diagnoses has been falling steadily since a peak of nearly 50% in the early years of this century.5 So if in contemporary practice GG1 is a more or less inadvertent diagnosis incidental to a search for high-grade cancer, why do we brand these patients with a “cancer,” with all the psychological, clinical, and financial implications of that diagnosis?

A final point is that a change in nomenclature would very likely save many thousands of lives through broader endorsement and implementation of routine prostate cancer screening. The antipathy to screening by the USPSTF, the AAFP, and others has reflected many misinterpretations of the evidence base, but at its core has been driven by the harms associated with overdiagnosis and overtreatment. Indeed, in its update from a “D” to a “C” recommendation in guarded support of shared decision-making, the USPSTF was explicit that the change was driven in part by rising rates of active surveillance and less pervasive overtreatment.6

Every man who dies of prostate cancer missed an opportunity to be screened and cured when the cancer was still organ-confined, and screening rates for men before age 60 remain quite low. If and when we can demonstrate that overtreatment—and its antecedent overdiagnosis—are relics of the past, the evidence in favor of screening would be unassailable. Imagine a future in which early baseline screening is nearly universal, potentially lethal cancers are found and treated early, and overtreatment is vanishingly rare. A change in nomenclature could bring this future much closer to reality, and Urology should light the path.

Written by: Matthew R. Cooperberg, MD, MPH, Professor of Urology, Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, UCSF Department of Urology, University of California, San Francisco, California

References:

  1. Jahn, J. L., Giovannucci, E. L. & Stampfer, M. J. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen-era. Int. J. Cancer 137, 2795–2802 (2015).
  2. Esserman, L., Shieh, Y. & Thompson, I. Rethinking screening for breast cancer and prostate cancer. JAMA 302, 1685–1692 (2009).
  3. Eggener, S. E. et al. Low-Grade Prostate Cancer: Time to Stop Calling It Cancer. J Clin Oncol JCO.22.00123 (2022) doi:10.1200/jco.22.00123.
  4. Cooperberg, M. et al. MP43-03 Active surveillance for low-risk prostate cancer: Time trends and variation in the AUA Quality (AQUA) registry. J Urology 207, e740 (2022).
  5. Cooperberg, M. R., Lubeck, D. P., Mehta, S. S. & Carroll, P. R. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 170, S21-5; discussion S26-7 (2003).
  6. Bibbins-Domingo, K., Grossman, D. C. & Curry, S. J. Bibbins-Domingo JAMA 2017 317_1949-1950 The US Preventive Services Task Force 2017 Draft Recommendation Statement on Screening for Prostate Cancer An Invitation to Review and Comment.pdf. JAMA 317, 1949–1950 (2017).