The pathologist has just looked under the microscope at 12 tissue samples from your prostate. What’s in there? First, there are normal cells. Pathologists can tell that they’re normal, because they are round and uniform, with well-defined edges and clear centers. As cancer progresses, the cells become more oblong; then more irregular. The edges get blurred, and eventually, the outside shapes start to get weird; so do the insides. What once looked like pebbles drawn with a fine-tip pen, as the cancer gets more aggressive, ends up looking like ragged clumps of algae drawn with a fat crayon.
But wait – there’s more! A sample of prostate cells might also include “atypical” cells, which are a big question mark. They’re not normal, but the pathologist can’t definitely report that they’re cancerous, either. They’re just suspicious.
Note: This is one reason why you may want to get a second opinion on your biopsy slides from a pathologist who is an expert in prostate cancer. Having your slides sent to another pathologist is a lot cheaper than having a repeat biopsy just to get more conclusive information.
Your biopsy might also show cells called “high-grade PIN” (PIN stands for “prostatic intraepithelial neoplasia”). These are abnormal cells. They’re not benign, and they’re not cancerous themselves; however, Nobody really knows what to do with them; some evidence suggests that high-grade PIN might actually be cancer. However, other studies have shown that some PIN might be reversible with diet. Currently, if a man’s biopsy shows the presence of high-grade PIN, his urologist will probably want to do a repeat biopsy.
The Gleason Score: The cells within the prostate are so chaotic that it wasn’t until the 1960s – when a pathologist named Donald Gleason, using the low-powered microscope of the day, came up with a brilliant solution. He figured out a way to describe the cancer. Basically, Gleason said, you can’t make sense of every single cancerous cell, but there seem to be some identifiable patterns here. He labeled each cancer pattern 1 through 5. Which pattern was the most common? Which pattern was second most common? Gleason figured out that if he added those two types together, this score, now known worldwide as the Gleason score, would be a pretty accurate way to determine how aggressive the cancer cells are.
Gleason’s original system had more than 25 different possible combinations. This was simplified into a new system, called “Grade Groups,” originally proposed in 2013 by Jonathan Epstein at Johns Hopkins. The World Health Organization accepted Epstein’s system in 2016. Here’s what you need to know:
Grade Group I: Gleason score 3 + 3 = 6. Gleason 6, according to renowned Johns Hopkins urologist Patrick Walsh, M.D., “is as good as it gets.” Epstein describes cancer in Grade 1 as having “an indolent nature, and no metastatic potential.” Many men in this category can safely choose active surveillance.
Grade Group 2: Gleason score 3 + 4 = 7. Some men in this category may also be candidates for active surveillance, or for radiation therapy instead of surgery, depending on their age, extent of cancer, and general health.
Grade Group 3: Gleason score 4 + 3 = 7. The score is the same, but there is a difference – more pattern 4 than 3 – and this cancer needs to be treated with surgery or radiation.
Grade Group 4: Gleason score 8, and Grade Group 5: Gleason scores 9-10.
These are high-grade tumors. In the past, Gleason scores 8-10 were combined, but Epstein separated them because they have significantly different prognoses.
Now, what does all this mean? In an ideal world – one where men start getting screened for prostate cancer in their forties – prostate cancer is caught early. Let’s say a 58-year-old man, who otherwise is in very good health, is diagnosed with Gleason 6 disease. “If he has surgery [i.e., prostatectomy], and we look at his prostate and there’s nothing but Gleason 6 cancer, that man is effectively cured,” says Johns Hopkins urologic pathologist Angelo De Marzo, M.D., Ph.D. One Johns Hopkins study showed that out of 14,000 men who had surgery and were found to have Gleason 6 cancer confined to the prostate, “zero of those 14,000 men had lymph node metastases. No one at Hopkins has ever died of prostate cancer if he had Gleason 3 + 3 cancer.”
In fact, some doctors have been questioning whether Gleason 3 + 3 disease should even be called cancer. Not so fast, says De Marzo, for one very important reason: “The malignant potential seems like it’s not there, but there are lots of reasons to keep calling it cancer, and the biggest one is that if men have Gleason 6 on their biopsy, and you take out their prostate, between 20 and 40 percent of them will actually turn out to have a higher-grade tumor. The biopsy missed it.”
Another important reason is uncertainty: Does the cancer change over time? Say a man has Gleason 6 cancer on a biopsy, and a year later, Gleason 7 is found. You might think, “Well, that Gleason 7 was there all the time, and it was just missed.” But are you sure? Nobody knows the answer to this question for certain. “There are some suggestions that cancer grade can progress,” says De Marzo. “Theoretically, it can happen. We just don’t know what fraction of the high-grade cancers started out as low-grade.”
It’s like those drawings you may have seen of the “Evolution of Man,” where there’s an ape, then a Neanderthal-type knuckle-dragger, then a basic human. Does high-grade cancer spring forth as a Gleason 9? Or did it start out as something that’s easier to treat?
In the future, De Marzo believes, we will be able to make much better-informed decisions. Some blood tests using molecular tools can help determine whether cancer shows aggressive potential; De Marzo anticipates that urine tests will prove even more helpful. “The prostate is directly connected to the urinary system. I think urine will eventually beat blood as a test, in a few years.” One such test is called PCA3. The basic PSA test is prostate-specific, but not cancer-specific. PCA3 is cancer-specific. Although it is not meant to replace the PSA test, it can be used as another test to help determine if a repeat biopsy is needed. If the PCA3 score is low, the odds of a positive biopsy are lower.
Molecular-based tests won’t replace the Gleason grading system, De Marzo notes. But they will add to it, reducing unnecessary biopsies, making biopsies smarter by targeting where to stick the needle, highlighting aggressive cancer that needs to be treated, and helping give peace of mind to men who truly have indolent cancer that may not ever need to be treated.
The Gleason score, based on what the cells actually look like, is like a mug shot of cancer. So think of a bunch of mug shots, hanging on the wall of shame at the Post Office. The biggest problem here is that not all pathologists are equal in their ability to look at thousands of mug shots and say, “that one’s a criminal,” or “that one’s not really such a bad guy.” Nationally, “there’s a big variability in the expertise of the pathologist reading prostate biopsies,” says De Marzo. “It can be very difficult. But it’s not good to have a situation where not all patients get their biopsy read by a true expert.” Molecular tests will help make sure that “everyone gets the same answer. You can’t argue with the future of molecular testing. It will help level the playing field.”
But the biggest key to understanding what’s actually in the prostate, says De Marzo, is going to be better imaging. Read more about prostate MRI here.