April 4, 2000
Value of Second Opinions Is Underscored in Study of Biopsies
The New York Times on the Web: Science
A Second Examination Can Reveal Subtle Differences
Join a Discussion on Health in the News
By LAURIE TARKAN
Marty Katz for The New York Times
Dr. Jonathan I. Epstein of Johns Hopkins studied biopsy results for people suspected of having cancer and found seriously flawed diagnoses in 2 to 3 percent of the cases.
fter having a biopsy taken of a suspicious lump, a patient usually puts his fate in
the hands of a person he has never met: a
Off in a lab somewhere, the pathologist
decides whether a sliver of tissue is benign
or malignant, and if cancerous, how aggressive the disease is, decisions that are pivotal
to the treatment. But most people don't
know anything about the pathologist, don't
ask for his credentials or those of the laboratory, or ask for a second opinion.
For most patients, this hands-off approach works well. But according to a study
that reviewed the biopsy slides of 6,171
patients referred to Johns Hopkins Medical
Institutions for cancer treatments, 86 patients had diagnoses that were significantly
wrong and would have led to unnecessary or
The rate of error was 1.4 percent, which is
low, but not insignificant. At Johns Hopkins
alone, it would be equal to about one cancer
patient a week with a wrong diagnosis, and
across the country could add up to a conservative estimate of 30,000 mistakes a year.
For 20 patients, a second opinion changed
a malignant diagnosis to a benign one. In
five other cases, a growth reported to be
benign was later found to be malignant, and
in six cases one type of cancer had been
mistaken for a different type. These results,
published in December in the journal Cancer, are consistent with previous studies.
Some types of cancer, though, like ovarian, cervical, skin or lymphatic, are more
difficult to diagnose and are somewhat
more prone to errors. In an earlier study at
Johns Hopkins, a review of the slides of
cancer patients referred for prostate surgery found major errors in 6 of 535 men,
sparing them from surgery.
In a 1998 study at the University of Texas
Southwestern Medical Center in Dallas, a
review of ovarian, uterine, cervical and
vulvar biopsies found major errors in 2
percent of the cases, leading doctors to
cancel six operations and five chemotherapy treatments. And a 1997 review of patients
who went to the University of Texas M. D.
Anderson Cancer Center for second opinions
of their brain and spinal cord biopsies found
major errors in 8.8 percent of cases.
The researchers did not include more
minor errors in rating how fast-growing and
how advanced a cancer was. These so-called
grading and staging errors are more common and can affect how aggressively a
patient is treated.
"We don't want to send a panic among
everybody that their biopsies are wrong,"
said Dr. Jonathan I. Epstein, the study's
lead author and professor of pathology, urology and oncology at Johns Hopkins. In fact,
the majority of people who have been told
they have cancer do indeed have it and are
getting the correct treatment, he said.
"But," he added, "there's a sizable minority, maybe 2 to 3 percent, who have a wrong
diagnosis or who could have a more accurate diagnosis."
Typically once a biopsy is taken, the
specimen is sent to a commercial laboratory or a hospital's in-house laboratory.
Though there is a general perception that
pathology is an exact science -- that a cell is
either malignant or not -- the differences
between malignant and benign can be subtle
and interpretations can be subjective. In
some cases, spotting a malignancy is easy,
but in others, the clues that tell a pathologist
a cell is cancerous are well concealed.
Experts attribute the majority of the errors to the many benign mimickers of cancer and the reverse: malignancies that
mimic benign processes. One patient at
Johns Hopkins received a diagnosis of skin
cancer of the ear and was told that a section
of the middle ear had to be removed. The
pathologist who reviewed the slide found
that it was a simple fungus infection.
"Pathologists who have a lot of experience can recognize the mimickers, whereas
a pathologist who's not as experienced may
confuse the two and make a misdiagnosis of
cancer," Dr. Epstein said .
The pathologist's job is only getting more
difficult as doctors move toward less invasive procedures that are designed to disturb
the body as little as possible. Using needles
to remove samples from the prostate and
breast, for instance, surgeons are eking out
the smallest possible amount of tissue, often
no thicker than the nib of a pen, giving
pathologists much less to examine.
"We rely on seeing how the abnormal
cells differ in their growth and appearance
from normal cells," said Dr. John E. Tomaszewski, director of surgical pathology
at the University of Pennsylvania Medical
Center. "That may get lost if you have a
very small piece of tissue. What was an easy
diagnosis of a large piece of tissue becomes
a very difficult diagnosis on a small piece of
Moreover, as the options for treating cancer have multiplied, it has become important not only to make the diagnosis of cancer, but to subclassify tissue and grade it as
more or less aggressive and advanced.
"These are very delicate classifications,
and to some extent subjective and dependent on the experience of the pathologist,"
said Dr. Juan Rosai, who recently was chief
of pathology at Memorial Sloan-Kettering
Cancer Center but became chief of pathology at Italy's National Cancer Institute. The
difference in grade could influence whether
someone gets surgery, chemotherapy, radiation, or no treatment.
As the field of pathology grows
more challenging, hospitals are
adopting new strategies and some
health experts are advocating more
stringent rules for diagnoses.
Dr. Epstein and his co-authors, for
example, are advocating that when a
diagnosis has been made at another
institution, hospitals require an in-house pathologist to examine a patient's slides before beginning treatment. "Hospitals shouldn't trust
somebody else's diagnosis to treat a
patient," Dr. Epstein said.
Many comprehensive cancer centers and academic medical centers
already have this type of policy in
place, though it is not always followed by some doctors. Among
smaller hospitals, only some have
Some experts believe hospitals
should even go a step further by
insisting that every biopsy, not just
referrals, be seen by at least two sets
Large academic centers typically
have a daily conference to discuss
difficult cases, and specimens can be
viewed by a few experts through a
multiheaded microscope. These centers also have many subspecialty
pathologists, experts in gynecological cancer, for instance, who tend to
consult with each other informally.
Some small institutions require
two pathologists to be involved in
every cancer diagnosis, whereas others recommend that the practice be
used only with cancers that are more
difficult to diagnose. Some hospitals
randomly send 10 percent of slides to
outside labs for quality control, Dr.
Even where there are no formal
procedures requiring them to do so,
it is common for pathologists to show
ambiguous slides to colleagues or to
send them out to a nationally recognized expert for review.
Some experts question whether
there is reason to require widespread use of second opinions. "On
an individual basis, getting a second
opinion is obviously a good thing to
do, but on a health-care-wide basis,
where you're asking the question of
cost effectiveness, this is a difficult
question," Dr. Tomaszewski said.
One solution may be to set guidelines specifying which types of cancers and cases are more difficult and
should be routinely reviewed. Cancers with a higher likelihood of misdiagnosis include those that are gynecological and lymphatic, as well as
leukemia, sarcomas, and those of the
prostate, skin, liver and kidney.
Patients can take it upon themselves to request second opinions on
their biopsies. And some pathologists
have seen an increase in requests for
second opinions made directly from
"It's such a devastating diagnosis
with so much implication for treatment that I think it's perfectly reasonable to have a second opinion,"
says Dr. William Hoskins, deputy
physician and chief for disease management at Sloan-Kettering.
Dr. Epstein added: "If I were a
patient and was diagnosed with a
malignancy, I would get a second
opinion before undergoing any major
surgery, chemotherapy or radiation.
And if I had a negative biopsy on an
organ that's known to have a higher
rate of error I'd also get a second