The 2019 modification of the International Society of Urologic Pathology prostate cancer grading system is well established for diagnosing and managing patients.¹ Recently, to avoid the “cancer label” and address the “overtreatment crisis” (which is diminishing),^2,3 some authors are calling for removing the cancer label from Gleason grade group (GG) 1.^4,5

Is it appropriate for urologists to direct pathologists who review prostate cancer specimens to change the well-established pathology cancer label of GG1 disease, regardless of other risk-assessment parameters? This would be a major step, affecting all men who currently would be offered active surveillance (AS) by telling them they do not have a cancer to surveil, as well as those who, under today’s guidelines, fall under the higher-risk GG2 category.

To justify this proposed change, they cite the precedents for low-grade bladder and thyroid cancer. These tumors are inappropriate examples, for with these tumors, the lesion has been excised and more aggressive histology ruled out.⁶ They also question the relevance of treating any patients initially diagnosed with low-risk prostate cancer because the PIVOT⁷ and ProtecT⁸ trials found no significant difference in 10- to 15-year mortality rates between patients managed with “active monitoring” vs those managed with radical treatment. In the ProtecT trial, half the patients randomized to monitoring received treatment within 10 years, and not all randomized to radical treatment were treated promptly.

A discrete choice experiment reported that patients, their partners, and healthy individuals all preferred to have a “noncancer” label applied to GG1, which increased their choice of adopting AS.^2,9 However, discrete choice experiments have limitations: participants are presented with oversimplified, hypothetical decisions; they may not be completely aware of their true preferences; they may be overwhelmed by the number of possible scenarios presented; and the choices offered may not cover their entire range of preferences. Moreover, the study populations may be nonrepresentative, rendering the results not applicable to real-world situations or across different populations.⁹ Most importantly, participants in these experiments may be unduly influenced by how the options are presented to them.

In contrast, a randomized online survey was administered to 718 men without prostate cancer, presenting them with a hypothetical scenario in which they were newly diagnosed with low-grade prostate cancer and comparing the labels of “Gleason 6 out of 10,” “grade group 1 out of 5,” or “IDLE” (ie, not cancer). Notably, IDLE was not associated with differences in anxiety or preference for active surveillance and was not a preferred disease label term compared with traditional Gleason score nomenclature.¹⁰

The proportion of men diagnosed with GG1 cancer has decreased with the use of MRI-guided biopsies.^10,11 Nevertheless, MRI scans are imperfect, as not all clinically significant cancers are visible on MRI.^11,12 Tumor grade and volume reclassification have been reported in up to 30% to 50% of GG1 tumors.^13,14,15 Even if the national rate of initial GG1 diagnoses were to decrease to 10%, it would amount to telling 30,000 GG1 patients per year in the US alone that they do not have prostate cancer.

A multifocal, heterogeneous disease, prostate cancers do not all carry the same risk; some progress at different rates.^16,17,18 Patients legitimately worry because they know that true knowledge about the biological potential of their tumor is lacking. Biopsy cores containing GG1 cancer may harbor genomic features associated with tumor grade progression and clinically aggressive behavior, or the biopsy procedure may have failed to sample more aggressive disease elsewhere in the prostate.^19,20

Studies claiming GG1 cancers can never metastasize come from radical prostatectomy series in which the early resection of the entire prostate gland cured most patients.²¹ Long-term follow-up is required to assess the clinical significance of low-grade prostate cancers.²² To accurately assess the biology of GG1 disease, outcomes with more than 20-year follow-up of patients never receiving treatment would be required—an impracticable study that is unlikely ever to be undertaken.⁶

In the PIVOT⁷ and ProtecT⁸ trials, with 10 to 15 years of follow-up, twice as many patients in the monitoring groups developed metastases. In ProtecT, 51% who developed metastases and 46% who died of prostate cancer were diagnosed at baseline with GG1 disease; the deaths occurred largely 12 to 25 years after treatment. The US SEER (Surveillance, Epidemiology, and End Results) data with 20 years of follow-up revealed that more patients diagnosed with GG1 disease died of prostate cancer than those diagnosed with GG2 or higher tumors.²³ In Sweden, the long-term prostate cancer mortality rate for GG1 patients managed with AS was 13%.²⁴

While metastatic behavior is not the only criterion for malignancy, GG1 meets all the morphologic criteria seen in higher-grade prostate cancers: the basal cell layer is absent, and there is stromal and perineural invasion that correlates with the risk of grade reclassification. Extracapsular tumor extension and seminal vesicle invasion can occur with GG1 tumors.⁶

Genomic instability drives prostate cancer, activating oncogenes and inactivating tumor suppressors. GG1 cancers can contain high genomic risk variants not found in normal prostate tissues.^19,20 High-risk genomic variants in GG1 tumors are identical to those seen with higher-grade tumors, and GG2 tumors may arise clonally from GG1 tumors.^19,20 The cancers containing high-risk variants have more adverse pathology and more frequent recurrences after treatment.^25,26 The greater the amount of GG1 cancer found in the diagnostic biopsy specimens, the more likely there are adverse genomic markers and the tumor will exhibit aggressive behavior.^26,27 Recent epigenetic evidence shows that GG1 tumor are true cancers and are clearly separate from benign prostate tissue.²⁸

Numerous unintended consequences would follow the declassification of GG1. Surveillance protocols currently recommended for GG1 cancer would be used only for patients with GG2 disease that is currently called low-intermediate-risk disease. GG2 disease is associated with a 3- to 4-fold higher risk of cancer progression than for GG1, for which the surveillance protocols should be more intensive.^29,30 The compliance rates with AS biopsies—already poor for GG1 disease—would be worse if GG1 were not called cancer.³¹ Poorer compliance rates correlate with worse outcomes, and underserved populations have lower compliance rates³²; hence, racial disparities would increase. High-volume GG1 would never trigger treatment, and pathologists incorrectly grading GG1 and GG2 tumors would result in some patients not receiving proper counseling for AS and others receiving unnecessary treatment.

Additional prediction tools are available to help overcome biopsy undersampling and genomic risk issues. PSA isoform measurements help assess the clinical significance of prostate cancer and the risk of dying from it.^33,34 Testing germline DNA for monogenic and polygenic variants more likely to be associated with aggressiveness is now available,³⁵ and somatic genomic testing of urine and biopsy specimens is gaining increased use.¹⁷ New artificial intelligence–enhanced pathology and imaging methods promise to reduce interreader variability and provide more accurate risk assessments.^36,37

The practical way forward is to continue to acknowledge overtreatment, develop evidence-based guidelines to increase the appropriate adoption and quality of AS, use these guidelines to educate patients and physicians, apply implementation science procedures to induce physicians to do the right thing, and integrate new risk parameters with the established ones.

The medical community should insist that any changes in GG classification be based on firm scientific evidence, which is now lacking. The slow initial uptake of AS in the US is not sufficient reason to change the biological definition of cancer. The current International Society of Urologic Pathology grading system classifies GG1 tumors as “1 on a scale of 1 to 5” rather than “6 on a scale of 2 to 10.” Under this classification system, patients feel more comfortable choosing AS for the lowest GG1 group.³⁸

The responsibility for proposed changes in the designation GG1 as cancer rests on urologists, radiation oncologists, medical oncologists, and pathologists; however, the ultimate authority to decide should remain in the purview of pathologists. Only 15% of pathologists support declassification.² The arguments for renaming GG1 cancer are weakening, and there is strong support for retaining the cancer designation.³⁹