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
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.
Prostate Cancer Update, Vol. V, No. 1, Winter 2000.
Pathologists can find the website at www.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.