For millennia, cancer was defined clinically—usually late in its course—and was understood by physicians, patients, and the public to be a lethal diagnosis associated, more than anything, with spread preceding death. For fewer than 200 years we have defined cancer based on histopathologic rather than clinical findings, but still, historically, only after a symptomatic tumor was identified. Only recently have screening and biopsy allowed pathologists access to small samples of tissue years or decades before a neoplasm would be clinically apparent—if ever. At the same time, our understanding of carcinogenesis, progression, and prognosis has progressed far beyond hematoxylin-and-eosin staining, but diagnostic standards and nomenclature have not kept pace.

In the case of prostate cancer, diagnostic tools now clinically available for patients with negative biopsy and rising PSA are based on changes in methylation in histologically normal tissue; more recently, spatial transcriptomic studies have demonstrated that molecular changes accumulate progressively before anything is apparent to pathologists, and in fact the changes separating “cancer” from “normal” are fewer than those between different adjacent areas of visually normal but preneoplastic tissue.¹ The loss of the prostate glandular basal cell layer—the hallmark of a diagnosis of carcinoma—should be understood in contemporary parlance as a hallmark of neoplasm, not malignancy.

Prostate cancer biology reflects a continuum from normal to premalignant molecular changes to Grade Group (GG) 1 to higher grade adenocarcinoma with progressive capacity to spread. We should recognize that drawing the cancer line between the second and third state has always been arbitrary from a biological and clinical standpoint, and there is no particular reason the line could not move 1 step to the right. Doing so would dramatically improve the quality of care for men at risk of prostate cancer.

GG1 in the prostate is so exceptionally prevalent on autopsy studies (50% of Black men by their 70s and White men by their 80s)² it might be considered a normal feature of aging. Modern imaging and liquid biomarkers as secondary tests for those with elevated PSA explicitly dichotomize the anticipated biopsy outcome as GG ≥ 2 vs negative or GG1. In using these tests we are implicitly advising patients that if only GG1 is present, neither we nor they want know about it—and in the era of such testing, low-grade disease has fallen from half of new diagnoses to fewer than 20%.³ GG1 is rapidly devolving to an inadvertent finding whose diagnosis is entirely incidental to efforts to identify clinically meaningful cancer (ie, many but not all cancers GG2 and higher). So when we accidentally diagnose GG1, should we really be assigning these patients cancer labels? When we do, particularly for a universally indolent entity, the harm to a patient seems exponentially greater than the benefit.

Broad agreement across guidelines now supports active surveillance as preferred management for GG1. Even in the era of image guidance, prostate biopsy can undersample a cancer, and a subset of GG1 tumors will progress to higher grade disease over the years. Therefore, were GG1 called something other than cancer, surveillance should change minimally, if at all. Confirmatory biopsy, follow-up PSAs, imaging tests, and biopsies would remain essential. The only key clinical change would be that rates of immediate radical treatment for GG1 should drop far below the current 40%.³ That is not to say the treatment rate should be even close to zero; cases of strong family history of early lethal disease, for example, might justify preemptive treatment of GG1. After all, by analogy, thousands of women annually undergo prophylactic mastectomy and oophorectomy based on genetic risk alone.⁴

Concerns have been raised that absent a cancer diagnosis, men would not be conscientious about surveillance protocols, but these are theoretical, not empirical. Patients with colon polyps undergo endoscopic surveillance at increased frequency, and many nonneoplastic conditions indicate surveillance even with invasive procedures. In any case, PIVOT and ProtecT would suggest that for low-risk disease, surveillance even at reduced intensity relative to current US guidelines would not result in many missed opportunities for needed cure of progressive disease. To be clear, the number of men who would die of prostate cancer specifically because they did not take a GG1 diagnosis seriously, and who would have been more compliant given a cancer diagnosis, is doubtless above zero—but probably not by very much. How many men must experience needless psychological suffering, financial distress (loss of life insurance, increase in premiums), and adverse effects of avoidable treatment in pursuit of these few?

Besides, a change in nomenclature would very likely save many thousands of lives annually in the US alone. Many men who die from clinically significant, high-grade, “real” prostate cancer missed a window of opportunity to be screened, detected early, and cured. PSA is an incredibly useful test when used early—yet well under half of men get a baseline test before 60. The hostility to prostate cancer screening from the USPSTF (US Preventive Services Task Force) and other primary care thought leaders over the past 15 years is multifactorial in origin but substantially reflects the impact of overdiagnosis and overtreatment on the public health.

Improvements in overtreatment rates were cited directly in the USPSTF revision of their recommendation from a “D” to a “C” in 2018,⁵ but we clearly have a long way to go. If we substantively address overtreatment as well as upstream overdiagnosis, the ratio of benefits to harms would likely improve to the point of being unquestionable. If primary care providers make PSA screening recommendations and decisions knowing their patients are at a greatly reduced risk of overdiagnosis, lives ultimately saved through a nomenclature change would outnumber those lost by orders of magnitude.

GG1 is not normal—but neither is it cancer. It is a premalignant finding indicating close surveillance but rarely immediate treatment. In 2023, its definition and label should reflect this contemporary understanding of its place on the biological continuum.