The Pathologists' Troubleshooter
Jonathan Epstein "wrote the books on the diagnosis and prognosis of prostate cancer. He's one of the reasons our work in prostate cancer is so well respected."
Detecting prostate cancer in a biopsy is, on a much smaller scale, about as easy as finding a needle in a haystack. With a needle. Consider this: The prostate gland is roughly the size of a large strawberry and in it, a patch of cancer-the average cancerous prostate has about seven-is about the size of a strawberry seed. To make diagnosis even more challenging, the cancer cells that are found generally tend to be hard to interpret; thus, biopsy is often a hit-and-miss affair. And yet, the pathologist's judgment is a major part of the treatment decision-making. Is it cancer? Sometimes, the answer is clear. But sometimes, the best the pathologist can say is that it's "atypical."
Enter pathologist Jonathan Epstein, M.D., who is world-renowned for his expertise and accuracy in judging prostate cells. A pioneer in the budding specialty of urologic pathology, Epstein also has the distinction of holding the world's only endowed chair in this field. This year, he became the Rose-Lee and Keith Reinhard Professor of Urologic Pathology. "He's unsurpassed in what he does," says Patrick C. Walsh, M.D., director of the Brady Urological Institute. The idea of a chair for urologic pathology was his-a way to honor and support Epstein's considerable research contributions. "In general, pathologists are the unsung heroes," he explains. "Patients sit in their doctor's office and receive some of the most important information they'll ever hear in their lives-the verdict on whether or not they have cancer-and it comes from the pathologist, a person they'll never know." Walsh wants Epstein to be-well, sung. "Jonathan Epstein wrote the books on the diagnosis and prognosis of prostate cancer. He's one of the reasons our work in prostate cancer is so well respected: Our patients start with the scientific opinion of the best pathologist in the world." It is Epstein's pathology work, for example, that gives remarkable continuity to the Partin tables, developed at Hopkins by urologists Alan Partin and Walsh as a means of estimating the exact extent of prostate cancer (read story).
Epstein discovered that he had a knack for deciphering prostate cancer cells in 1982, during his pathology internship at Hopkins. Fresh out of the Boston University School of Medicine, Epstein was tapped by Joseph Eggleston, then head of surgical pathology, to work with urology. "They had a project, a very tedious project, where you actually had to circle cancer cells under the microscope. It would take hours." Epstein recalls it vividly-mainly because he had a case of shingles at the time. "I was in tortuous pain, and I was sitting there without a shirt on, because I couldn't have a shirt touch the shingles, circling these cancer cells forever."
The study was published in Cancer, and the Brady urologists, impressed with his stoicism as well as his work, kept right on collaborating with Epstein. He finished his residency at Hopkins, did a fellowship at Memorial Sloan- Kettering, came back to Hopkins to serve as Chief Resident in pathology, joined the faculty, and now is a professor in pathology, urology, and oncology.
Epstein was a full-time urological pathologist before there was such a thing. "When I started out, there was absolutely no such specialty," he says. At national pathology meetings, "there would maybe be three talks and a handful of posters on prostate cancer," and Epstein's own work would account for at least two of those. "Last year, there were 150 posters and talks. There were no fellowships back then; now there are seven or eight in the country. There's a Urological Pathology Society, there's now the Journal of Urological Pathology-so it's really coming into its own." Epstein gets calls from around the country from hospitals looking for urological pathologists, and as yet, "there are not enough of us around."
For hundreds of pathologists and urologists, and thousands of their patients, Epstein remains the fallback position-a rock in the unsteady world of hollow-core needle biopsies. Which begs the question: What is it about prostate cancer that makes it so tough for pathologists to interpret? "Of all biopsies," explains Epstein, "prostate biopsies are probably the hardest. You're dealing with such a limited amount of tissue." Until very recently, a prostate biopsy consisted of just six needle cores of tissue, taken from throughout the gland; at Hopkins and many other centers, it's now routine to take 12 samples, more if a prostate is particularly enlarged. Even so, the cancer is often wafer-thin, a veneer over healthy tissue. (Using the strawberry image, it's not only a tiny dot, it's a flimsy one.) And the veneer itself is often maddeningly ambiguous-so, not only can the biopsy needle overshoot and miss the cancer, the cancer cells it does get don't always match the pictures in the textbook.
Under the microscope, prostate cancer looks a bad work of modern art. Imagine countless shades of gray, some nearly white, some nearly black, most subtle variations of indeterminate shades somewhere in between, spilled onto a canvas. It's a mess, a jumble of cells that run the gamut from the almost ordinary-looking to cells that are so poorly differentiated and obviously diseased that they could never be considered normal. Worse, cells taken from one part of the prostate may look one way, and those from another part may look completely different.
When a biopsy is labeled "atypical" this happens in about 5 percent of biopsies at most institutions, says Epstein-it means that a pathologist sees "something that could be cancer, but isn't sure that it's definitely cancer." For many patients, the next step is having a repeat biopsy-and the value of this is often questionable, he says. "The problem is, in about 20 percent of cases, the biopsy can miss cancer-so even if it's negative, it doesn't mean the patient doesn't have cancer. In fact, the cancer can be extensive."
Compounding the diagnosis are cells that are not cancerous, but not normal, either. Epstein has shed considerable light on these "funny-looking cells"-called PIN, or prostatic intraepithelial neoplasia. PIN cells, found in the tissue lining the prostate, are abnormal, and they are strongly linked to prostate cancer. Like cancer, PIN has its own distinct patterns, and high-grade PIN, Epstein believes, is a marker for prostate cancer. "We'll often find high-grade PIN next to cancer." If high-grade PIN is found but cancer is not, instead of indicating that a man's prostate is cancer-free, the more likely scenario is that cancer may have been missed, and a man should have another biopsy. Epstein's research continues to define these not-quite-cancerous cells; in fact, he just discovered a new form of high-grade PIN, which he named after its resemblance to a hobnail.
The other end of this vexing spectrum, Epstein has found, is that many pathologists seem just as likely to over-diagnose cancer. "There are many mimickers of prostate cancer under the microscope, and people not as familiar with prostate biopsies can diagnose cancer when it's not." About six to eight men who come to the Brady Urological Institute each year with a diagnosis of prostate cancer are found to have been misdiagnosed. But even biopsies that seem straightforward deserve another look; Epstein and colleagues have shown this in studies looking at the reproducibility of Gleason scores in the general pathology community, comparing the biopsy's Gleason grade to the actual prostate specimen removed during surgery.
Another issue is that at most hospitals, pathologists don't have the luxury of specializing in prostate cancer. "Even in academic centers, maybe five percent would have somebody whom I would say is a urological pathologist." Epstein recommends that any man about to undergo treatment for prostate cancer get a second opinion from a pathologist. "It's just as important as getting a second opinion for surgery or radiation," he notes. In a recent six-month period, Epstein and colleagues looked at 3,000 consults, "almost 700 of which were sent at the request of either the patient or the urologist. Overall, we changed the diagnosis about 35 percent of the time-which to me was quite striking, because these were not cases where the pathologist even had a problem."
In an effort to improve prostate cancer diagnosis, Epstein and colleagues devised a tutorial for the Internet-a website for pathologists.
(See Prostate Cancer Update, Vol. V, No. 1, Winter 2000. Pathologists can find the website atwww.pathology.jhu.edu/prostate.) "The key to getting better diagnoses is education," he says; thus, he also teaches pathologists, urologists, oncologists, doctors-in-training, and even patient groups worldwide.
So far, more than 2,000 pathologists have taken his short course. Epstein is encouraged by this, and by a change he has noticed in the kinds of biopsies he's receiving. Now, the consult cases that he is getting are more difficult. And this, he believes, is a good sign.