Is Gleason 6 Prostate Cancer Really a "Cancer?"

Dr. Alan W. Partin, MD, PhD, Chairman and Urologist-in-Chief, of the Brady Urological Institute at Johns Hopkins and David Hall McConnell Professor of Urology, Oncology and Pathology, was invited to discuss the malignant potential of low-grade, Gleason 6 prostate cancer at the Urology Society of Australia and New Zealand (USANZ) 2014 Annual Meeting in Brisbane, Australia.

The controversy regarding Gleason 6 cancer stems from:

• the surge in prostate cancer diagnoses due to widespread PSA screening
• the almost universal "cure" for men with Gleason 6 (low-risk) disease 
• the question of over-treatment and/or needlessly subjecting men to the side effects of the treatments of prostate cancer (surgery or radiation) without benefit

Here we review the salient points of Dr. Partin's lecture on Why Gleason 6 is Really "Cancer"

First, there are a number of Pathological Considerations:

Morphologically it is cancer

• Cytologically (indistinguishable from higher grade cancer)
• Architecturally (ie. infiltrative)
• Perineural invasion can occur with GS6
• Extra-prostatic extension can occur with GS6
• Merges in with higher grade cancer frequently

Gleason 3+3=6 can be Infiltrative Cancer

Men with Gleason 6 make up:

• 26% of men with perineural invasion 
• 8% of men with extraprostatic extension (pT3a)
• 1% of men with seminal vesicle invasion (pT3b)

What about undergrading?
20% of Gleason 6 on biopsy are Gleason 7 or higher due to sampling error.

Second, how do we classify Gleason 6 if it's not a cancer?

What are alternative names?

• Pre-cancer
• Tumor of low malignant potential
• Tumor of borderline malignancy
• Prostatic Epithelial Neoplasia of Indeterminate Significance (PENIS)

Many of these terms are oxymorons, juxtaposing contadictory elements.

How do we rectify the risk of cancer with other clinical parameters (i.e. PSA, digital rectal examination)?

• Even though a patient may have a "Tumor of Low Malignant Potential," if their PSA is high (>10 or >20), or they have a palpable abnormality on digital rectal examination, they have significant risk of having a serious prostate cancer.  
• Other biopsy parameters like number of cores, percentage of core positivity also augment the risk of having serious cancer.
• Molecular and genetic markers (PTEN, TMPRSS2:ERG, Ki67, GPS, Prolaris, Decipher, etc.)  have demonstrated the ability to risk-stratify patients and further complicates the issue.

How do we rectify patients with Gleason 6 and Gleason 7 or higher disease?

• Patients with multiple cores of both Gleason 6 and Gleason 7 would therefore have two diagnoses: cancer and pre-cancer.
• It makes the Gleason system inconsistent as patients with Gleason 3+4, 4+3, 3+5, 5+3 have cancer, but those with Gleason 3+3 do not.

Third, it opens up a variety of medicolegal problems.

• Currently in USA am unaware of any lawsuits where 1 pathologist called Gleason 6 which on review was changed to a Gleason 7.
• Could foresee many lawsuits for cases where “non cancerous term for Gleason 6” called Gleason 7 on review (ie. missed a cancer) even though semantics. 

Fourth, how do we follow patients with "pre-cancerous" lesions?

• If  GS6 not called cancer, will a significant number of men with Gleason score 6 cancer not be followed as closely and potentially progress to un-curable cancer?
• In our Active Surveillance program where we biopsy every year (all have GS6) nearly 25% eventually progress to GS7 and require treatment.

Dr. Partin offered the following as possible solutions to this dilemma:

Improve Patient & Public Education

In squamous and basal cell cancers of the skin, patients have been educated that these are not, in general, lethal cancers and are therefore dealt with in a rational manner.  Similarly, we, as urologists, are the first physicians to see patients following their biopsy/diagnosis and its imperative that we educate our patients and the public that:

• most Gleason score 6 cancers can be followed with AS.
• “You have a very good type of cancer that in general does not cause harm if observation is organized and effective”
• “However, there is a risk that there may be more aggressive cancer in you that the biopsy missed or that the cancer could change over time so that we need to make sure we continue to closely follow you.”

Change or Include within the Gleason System a Prognostic Grade Group

• Gleason patterns 1 and 2 or scores 2-4 in the classic system are not diagnosed on needle biopsies because of poor correlation with RP grade and poor reproducibility among expert pathologists. 
• Many patients, when told they have a Gleason score 6 cancer, have read that Gleason scores range from 2-10 and worry that their tumor is in the middle.  
• Therefore, Gleason scores can be grouped and range from Prognostic Grade Group I (most favorable) to Prognostic Grade Group V (least favorable).

Gleason score <6:   Prognostic Grade Group I

Gleason score 3+4=7:   Prognostic Grade Group II

Gleason score 4+3=7:   Prognostic Grade Group III

Gleason score 8:   Prognostic Grade Group IV

Gleason score 9-10:   Prognostic Grade Group V

Pierorazio PM, Walsh PC, Partin AW, Epstein JI.  Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013 May;111(5):753-60

In summary:

• No need to change calling Gleason score 6 “ a cancer”
• Rather there is a need to change what patients think when they hear they have Gleason score 6 cancer. 
• Urologists need to reassure and educate patients. 
• Modify how we report Gleason scores to more accurately reflect their behavior. 

This Blog Entry was abstracted from the Opening Plenary & BJUI Lecture: Is Gleason 6 Prostate cancer a real cancer? at the USANZ 2014 Annual Meeting.