Experts debate the pros and cons of a ‘noncancer’ nomenclature change
January 2025—Whether grade group 1 prostate cancer should be renamed to “noncancer” was the center of debate on a CAP podcast last fall led by Gladell P. Paner, MD, in discussion with Ming Zhou, MD, PhD, and Rajal B. Shah, MD. Dr. Paner is professor of pathology and surgery, University of Chicago Pritzker School of Medicine, and director of the genitourinary pathology service and of the reproductive endocrinology and infertility laboratory, UChicago Medicine.
Dr. Zhou is professor and vice chair of oncological pathology and director of the urological pathology service, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York. Dr. Shah is a senior pathologist and Dr. Charles T. Ashworth professor of pathology at UT Southwestern Medical Center, Dallas. He is president of the Genitourinary Pathology Society.
Dr. Paner said there may seem to be two sides to the debate to rename grade group 1 prostate cancer but that there’s only one. “That is the side,” he said, “that wants to achieve the best care for patients with prostate cancer where both those who are in favor of and against renaming belong.” The conversation follows.
Dr. Gladell Paner: Dr. Zhou, can you provide a brief historical background on how the idea of renaming grade group 1 prostate cancer came about and what the benefits for patients are?
Dr. Ming Zhou: Several groups in 2012 proposed removing the cancer label from grade group 1 cancer, and the rationale behind the proposal is multifold. The first reason is that the biology of prostate cancer has evolved significantly over the past several decades. With contemporary screening, detection, and management, low-risk grade group 1 cancer has become a disease of excellent prognosis. This is true for grade group 1 cancer diagnosed in both radical prostatectomy and biopsy. For example, in radical prostatectomies, grade group 1 cancer rarely invades out of the prostate gland, and seminal vesicle invasion is even rarer. It is incapable of metastasizing to lymph nodes and other distant sites. The 15-year cancer-specific survival is almost 100 percent. If the low-risk grade group 1 cancer is diagnosed in prostate biopsies, the prognosis is also excellent. The 15-year cancer-specific death rate is about one to two percent regardless of treatment modalities—active surveillance, surgery, or radiation. Therefore, the low-risk grade group 1 cancer should be managed conservatively using active surveillance protocol.
However, this is not the case at the present time. Despite the initial enthusiasm, the current intake rate for active surveillance plateaus at 50 percent and, more importantly, about 40 percent of patients with a low-risk cancer choose immediate surgery or radiation. But aggressive treatment for low-risk cancer amounts to overtreatment, which itself has serious and negative implications not only for patients but also for society as a whole. It is for these reasons that removing the cancer label from the grade group 1 cancer was proposed. The hope is by doing so, it will stop patients from rushing to make a treatment decision and give them time to research to find out about their disease, and ultimately to make an informed treatment decision.
There are several benefits to removing the cancer label from the grade group 1 cancer. The first is to decrease the overdiagnosis and overtreatment of a low-risk cancer and thereby reduce the psychological and financial burden on patients and their families, and to minimize the side effects associated with treatment. It can also decrease the burden on the health care system as a whole.
Dr. Gladell Paner: Dr. Shah, what are the histologic and molecular features of grade group 1 prostate cancer that will make it a cancer, and what challenges will pathologists encounter in renaming, especially in biopsy samples?
Dr. Rajal Shah: One of the strongest rationales for considering grade group 1 prostate cancer as a cancer is that it shares many morphologic and canonical molecular alterations that are associated with higher-grade prostate cancer. Like high-grade prostate cancer, grade group 1 prostate cancer has a uniform loss of basal cells. Cytologically, it is indistinguishable from high-grade cancer. Its architecture is similarly infiltrative with frequent perineural invasion. Rarely one may also encounter extraprostatic tumor extension. It often merges with higher-grade cancer. As we know, grade group 1 prostate cancer also exists on a molecular continuum with higher Gleason-grade cancer. Similar to high-grade prostate cancer, overexpression of alpha-methylacyl-CoA racemase, loss of PTEN, GSTP1 downregulation, and TMPRSS2::ERG gene fusions are also present in grade group 1 prostate cancer. Some of these alterations, specifically PTEN loss, are substantially less common in grade group 1 prostate cancer, but overall the similarities support the similar pathways of tumor development and progression.
I believe that removing the cancer label from the grade group 1 prostate cancer would have significant challenges for and impact on the pathologist’s practice. We know that grade group 1 is composed of pure Gleason pattern 3 and is an integral part of the five-grade group system. It is the lowest grade that pathologists assign to prostate cancer. Removing the lowest grade may cause an artificial shift toward higher grading.
There will also be inconsistencies and confusion in prostate cancer reporting. Pathologists typically receive multiple-core or multipart prostate biopsies. In this setting, it is common to see that one core has a grade group 1 and the other core a grade group 2 or higher, and this could be coming from the same tumor, for example, an index tumor. So from a practical viewpoint, how would that biopsy be signed out? Do we call part of the same tumor cancer and part not?
The Genitourinary Pathology Society surveyed its members and 82 percent of 196 respondents were opposed to removing the cancer label from the grade group 1 prostate cancer. Of the respondents who opposed the name change, 72 percent were concerned that renaming a grade group 1 as a noncancer could result in significant modifications in diagnosis, grading, and reporting practices of prostate cancer [Zhou M, et al. Urol Oncol. 2023;41(2):62–64].
Dr. Gladell Paner: The crux of the challenge is that fundamentally grade group 1 prostate cancer is histologically cancer, and it’s hard to go against that. Dr. Zhou, are there ways to overcome these challenges while renaming grade group 1 prostate cancer in biopsy?
Dr. Ming Zhou: Yes, there are, but let me first clarify that I am not arguing that grade group 1 cancer is not cancer; I agree with Dr. Shah that grade group 1 is cancer. What I’m arguing for is to change the name for the sake of patient management. By dropping the cancer label and calling it a name that is somewhat short of cancer but still significant, pathologists acknowledge their uncertainty regarding the biological behavior of grade group 1 cancer diagnosed in the biopsy. It is very likely to be a disease with a good prognosis that doesn’t need aggressive treatment, but it may also be an aggressive disease that needs aggressive treatment. We need more time to do more studies to be certain before patients pick the right treatment for themselves.
Dr. Shah has mentioned a few challenges that the pathologists and other teams will encounter if we rename grade group 1 cancer. The first is that pathologists may be inclined to overgrade a grade group 1 to grade group 2. The answer here is to clarify the grading criteria. For example, one of the difficult areas in Gleason grading is how to grade poorly formed glands. It is not uncommon to see a grade group 1 with a few poorly formed glands being overgraded as grade group 2. It is a mistake that may have important clinical implications because it may preclude patients from getting on active surveillance. About 10 years ago, Dr. Shah and I put forward a grading recommendation for poorly formed cancer glands [Zhou M, et al. Am J Surg Pathol. 2015;39(10):1331–1339].
The second challenge Dr. Shah raised is that renaming a grade group 1 cancer may cause confusion and inconsistency in cancer reporting. But I’m proposing that we drop the cancer label and call it something like prostatic neoplasm. Pathologists will still provide Gleason score, grade group, and tumor volume measurements. If the entire case has only grade group 1 cancer, we’ll add a comment: The tumor has uncertain biological behavior. It may represent a tumor of good prognosis or carcinoma. Additional workup is needed. If other parts of the same biopsy have grade group 2 or higher cancer, then this comment may not be needed and can be omitted.
Dr. Gladell Paner: Dr. Shah, what are the potential negative impacts of renaming grade group 1 from the patient’s perspective? And how about to the surgical pathologist?
Dr. Rajal Shah: I believe there will be several negative consequences of renaming grade group 1 as a noncancer, both from the patient’s and the pathologist’s perspective. First, the patient’s perspective. In multiple-core biopsies, it is quite common to see prostate cancer with different grade groups in separately submitted cores. One core may be grade group 1; another core could be grade group 2 or higher. In a setting like this, we call the grade group 1 a noncancer and the other grade group 2 or higher a cancer. So patients might assume they have two separate tumors. That is one fundamental confusion that, in my opinion, would be a significant one—that I might be dealing with two separate tumors. In addition, there will be significant anxiety in patients about whether they have cancer or not. That has the potential to create a lot of second opinions.
The acceptance of active surveillance treatment in the United States for grade group 1 is less than optimal, but in some European countries, it’s almost in the range of 95 to 100 percent. So the success of this treatment depends on a committed and motivated patient who comes for regular follow-up. It is logical and expected that renaming grade group 1 as not cancer will lead to less compliance with the follow-up.
Finally, we may end up reclassifying some of the noncancer proliferation as cancer in follow-up biopsies. We know that a subset of grade group 1 prostate cancers in current practice may end up being grade group 2 or 3, which could be due to tumor progression or grade progression or sometimes unsampled higher-grade cancer in the initial biopsy. In this situation, it may become difficult to explain to the patient what happened. From a pathologist’s perspective, the threshold between grade groups 1 and 2 is often blurry and not without interobserver variability.
If the cancer label is removed from grade group 1, in borderline situations between grade group 1 and grade group 2, pathologists may choose a defensive practice and err on the side of calling grade group 2 to avoid the potential consequences of missing a significant cancer. In the Genitourinary Pathology Society survey, 74 percent of pathologists raised concern about pathologists’ overgrading of grade group 1 to grade group 2 to avoid a situation of potential litigation.
Dr. Gladell Paner: To your point, then, there is potential migration in grading towards the higher grade group 2, instead of grade group 1, especially for those borderline cases.
Dr. Ming Zhou: One of the issues is when prostate biopsies have several parts that have different grade groups—one part grade group 1, the other grade group 2—if you rename the grade group 1 as noncancer, the patient may be confused. I want to be clear that if we rename a grade group 1 cancer as something else, I would not call it benign. I want to use a terminology that is not cancer but yet significant enough—for example, prostatic neoplasm—such that patients and doctors understand it is not something benign, it’s not benign prostatic tissue, and it’s not something for which patients can be told they need not come back. It is still significant and they need to come back for further and additional workup.
You raise the possibility of the pathologist not calling grade group 1 cancer, then a patient coming back for follow-up during which grade group 2 or higher cancer is detected and how the discrepancy would be explained. This is not unprecedented for pathologists who regularly deal with situations like that. For example, if a patient has a prior diagnosis of cancer and comes back for a repeat biopsy that is negative, we don’t tell the patient, “You no longer have cancer.” We just explain to the patient that this is part of the sampling issue related to the prostate biopsy.
Dr. Gladell Paner: In the Genitourinary Pathology Society survey, of those who supported a change in the nomenclature (18 percent), 51.5 percent of respondents supported the name change for radical prostatectomy only, and 34 percent for both biopsy and radical prostatectomy. All of these are low numbers. But my point is that the type of specimen or the situation affects the idea of renaming, as shown by this data. Is renaming possible if a grade group 1 prostate cancer, the entire lesion, is fully examined in a radical prostatectomy specimen?
Dr. Ming Zhou: The Genitourinary Pathology Society and International Society of Urological Pathology surveyed their members on whether the grade group 1 cancer should be renamed as noncancer, and only 12 percent of the members supported it. Of those supporters, only 50 percent support the renaming in radical prostatectomy specimens. So if you do the math, only about six percent of the responding members support the renaming of the grade group 1 cancer in the radical prostatectomies.
That said, I am fully behind it. I support dropping the cancer label and renaming grade group 1 cancer for the reasons I explained earlier. The grade group 1 cancer in radical prostatectomies has excellent prognosis. The extraprostatic extension is rarely reported, in about four percent of the cases. Seminal vesicle invasion is even rarer, reported in less than 0.05 percent of the cases. Grade group 1 cancer is incapable of lymph node and distant metastases. Long-term survival is also excellent, approaching 100 percent. For these reasons I support removing the cancer label from the grade group 1 cancer in the radical prostatectomies.
But there are two key issues here. If we choose to drop the cancer label from the grade group 1 cancer in the radical prostatectomy specimens, we need to make sure that, number one, the radical prostatectomy specimens are submitted in their entirety and examined by pathologists. Number two, pathologists need to use strict contemporary grading criteria for the grade group 1 cancer, especially for the poorly formed glands. We need to follow the recommended criteria for grading poorly formed glands as grade group 1. If you just see a few poorly formed glands that are right next to well-formed glands, it’s not Gleason pattern 4; it’s still Gleason pattern 3 and therefore grade group 1 cancer.
Dr. Rajal Shah: I agree with what Dr. Zhou said. In fully examined radical prostatectomy, I would fully support that grade group 1 prostate cancer can be classified as a noncancerous proliferation. In one of the largest multi-institutional studies, examining more than 14,000 radical prostatectomies with grade group 1 prostate cancer, not a single patient died of disease or had metastatic disease to their lymph nodes. This observation has also been validated by other studies, indicating grade group 1 prostate cancer is virtually incapable of metastasis and has a limited capacity to extend outside of the prostate, suggesting that in this scenario we could call it noncancerous proliferation. However, this scenario is completely different in the biopsy setting, where we cannot know with certainty whether a patient harbors only pure grade group 1 prostate cancer.
Dr. Gladell Paner: The controversy arose because there is overtreatment of low-grade or indolent prostate cancer. So the question is, Dr. Shah, what steps from the pathologist’s perspective would help alleviate the overdiagnosis and overtreatment of grade group 1 prostate cancer?
Dr. Rajal Shah: First let me emphasize that there is universal agreement among pathologists and clinicians that grade group 1 prostate cancer should not be overtreated and active surveillance should be the default option for its management. It is also important that pathologists remain a critical part of this debate. However, the burden of alleviating overdiagnosis and overtreatment of grade group 1 prostate cancer does not rest on pathologists alone. The optimal detection of indolent prostate cancer would require a multidisciplinary team of clinical colleagues—urologists, radiologists, and pathologists. We need to ensure that the patient does not have unsampled high-grade or clinically significant cancer through careful clinical evaluation—multiparametric imaging studies, adequate biopsy sampling, targeted and systemic sampling, careful morphological examination by an expert GU pathologist, and in some situations molecular studies as well. So grade group is only one of the many prognostic factors that influence prostate cancer outcomes.
Instead of focusing on the name change from grade group 1 to noncancer, the focus of debate can be shifted to better educate patients to understand their cancer diagnosis and how we can refine the risk stratification to identify patients with grade group 1 who can be followed conservatively or who may need treatment eventually. Currently, two leading uropathology societies—Genitourinary Pathology Society and International Society of Urological Pathology—are collaborating on a joint white paper addressing the definition of indolent prostate cancer and the limitations of its optimal detection specifically in a biopsy setting.
Dr. Ming Zhou: I agree with both of you that we need to reduce the overdiagnosis and overtreatment of the low-risk grade group 1 cancer, and it takes entire patient care teams to do that. That includes oncologists, urologists, radiologists, pathologists, and even patient advocacy groups. However, pathologists can play an oversized role in this process. And we do have precedence in pathology in which we change the name of the disease entities to provide better patient management. For example, in kidney cancer there is a form of clear cell renal cell carcinoma with extensive cystic changes and it has an excellent prognosis. No recurrence or metastases have been reported after surgical resection; therefore, the name has been changed to multilocular cystic renal neoplasm of low malignant potential. The cancer label was dropped and it conveys the message that this is a tumor of excellent prognosis and the patient does not need excessive postoperative follow-up or treatment.