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TRACKING AN ELUSIVE KILLER Test for cervical cancer is only as reliable as doctors and labs

THE BALTIMORE SUN

In an isolated section of SmithKline Beecham medical laboratory in Owings Mills, three women pore over microscopes in search of misshapen nuclei. They work in silence, occasionally getting up from the desk to enter their findings in a nearby computer.

Their mission: to locate abnormal cells, the detection of which can save a woman's life.

Their job: one of the toughest in laboratory science.

They are "reading" Pap smears, searching for cancer in cells scraped from a woman's cervix. Imagine trying to find a clump of squares in 20,000 round grains of sand poured on a desk, and you have an idea of what it's like. Now imagine trying to do that 80 times a day.

Since it was invented 40 years ago, the Pap screen has slashed deaths from cervical cancer by 70 percent. It is easy to perform and highly predictive of cancer.

It is also easy to get wrong. Much depends on the quality of the lab -- on the skill of the technicians reading the Pap smears and the conditions under which they work.

But in an era of managed care, labs are under intense pressure to slash prices to win the business of health maintenance organizations. The result is that big labs are taking over, and some worry that the consolidation will undermine quality and affect the accuracy of Pap smears.

Even under the best conditions, Pap smears fail to detect one in five cases of cervical cancer, says Diane Solomon, the chief of cytopathology, the medical specialty of examining cells, at the National Cancer Institute.

There are lots of ways that the test can miss signs of cervical cancer: the abnormal cells are obscured by blood, for instance, or the sample taken by the doctor is blurred. Or the technicians simply don't see it.

"You are looking down at literally thousands and thousands of cells on a smear on a slide. It is very labor intensive," says Howard L. Siegel, president of the Maryland Society of Pathologists and a pathologist at Greater Baltimore Medical Center.

"As humans, we make errors," he says.

4,800 die a year

The possibility for error is the reason women are urged to have the Pap annually -- it improves the chances that the cancer, which develops very slowly, will be caught in its early stages.

Every year, 18,000 women are diagnosed with advanced cervical cancer, and 4,800 women die of the disease, according to the American Cancer Society. Another 300,000 women are successfully treated for abnormalities before those develop into cervical cancer. The Pap test detects these pre-cancerous conditions while they are easily treatable.

"It is enormously effective at what it does -- the fact that it is not infallible should not put someone off," says Dr. Solomon of the National Cancer Institute. "Repeating the smear increases the safety of it."

The test starts at the doctor's office, where cells are scraped from the cervix during a gynecological exam and affixed to a glass slide. At the laboratory, the slide is treated and examined under the microscope for unusual structures or textures by a cytotechnician, a person specially trained to examine cells. Abnormal cells are forwarded to the pathologist, a doctor trained to analyze cells and tissue for disease.

It's tedious work, and it takes someone who doesn't find looking into a microscope all day monotonous. The market for cytotechnologists is extremely competitive and they are well paid -- $50,000 to $60,000 a year is typical.

"It's an extremely technically difficult test to read. It takes a tremendous amount of training and experience," says Dr. Siegel, the GBMC pathologist.

Every morning, doctors in his group meet around a five-view microscope to examine and discuss one Pap smear that someone has found difficult to read. They usually argue, he says.

Setting standards

The likelihood of errors is far greater when a lab takes on more work than it can handle.

In Milwaukee during the late 1980s, technicians at Chem Bio Corp. were reading up to 40,000 slides a year -- twice as many as is safe -- because they were being paid by the number of Pap smears they reviewed.

The lab missed clear signs of cervical cancer in the Pap smears of Delores Geary and Karin Smith, experts testified. Both women later died of cervical cancer. In April, the families of Ms. Geary and Ms. Smith won nearly $6 million in damages from the lab and a health maintenance organization, Family Health Plan.

In Maryland, labs have been restricted in the number of Pap smears they can read since 1988. Technicians can examine no more than 80 to 100 Pap smears in a 24-hour period.

Maryland also pioneered annual tests for cytotechnicians. Regulators bring a known sample of cells to the lab, watch the technician or pathologist read it, and return the sample to state offices. More than 300 technicians and pathologists take the annual proficiency tests.

Maryland's standards were later adopted for the federal law, written largely by Maryland Sen. Barbara Mikulski. The federal law took effect in 1992 and limits all labs to 100 Pap smears per day.

At SmithKline, cytotechnologists note anything questionable on the slide with green, yellow or orange markers. Then it is reviewed by the pathologist in charge.

Laboratories are required to keep test results on file for at least five years. If a smear contains abnormal cells, labs are required to re-read their own previous screenings of the patient or those done by other labs to see if abnormal cells may have been missed.

Hunting down those old slides showed Francine Joyner, 47, of Brookville in Montgomery County, just how trusting she had been.

A Pap smear in 1986 had picked up pre-cancerous cells, and she underwent a freezing of the cervix, a process that generally removes such cells. After that, she regularly went to her gynecologist to test for abnormalities.

Nothing showed up in tests done at three different labs. But Mrs. Joyner said she repeatedly complained to her doctor of bleeding episodes. Each time he blamed it on her IUD.

Finally, in early 1991, her doctor sent her for a biopsy. After three years of normal Pap smears, she was diagnosed with advanced cervical cancer. Mrs. Joyner couldn't believe it.

"Either I had developed cancer very quickly," she says, "or all the Pap smears were wrong. Well, all the Pap smears were wrong."

Within weeks, Mrs. Joyner had a radical hysterectomy. When further tests showed the cancer had spread, she received radiation treatments.

After the surgery and radiation, she could no longer stand for long hours and cut back her hours as a hairdresser. She and her husband, Joseph, a quality engineer at Goddard Space Center, used their savings to refinance their house to meet the mortgage payments. At first she couldn't stand without shaking, and when she cried, her little boy, now 11, thought she was dying, she says. "Every time I think about it, I get really angry."

Mrs. Joyner now has a Pap test and examination by an oncologist every four months. She is under a five-year watch for recurrence of cancer.

"No one believed this happened to me," she says. "I take care of myself. I am medically knowledgeable."

She is suing the lab that missed her cancer even at an advanced stage.

Costly mistakes

Cervical cancer takes four to 10 years to develop. If abnormalities are missed one year, they often can be picked up the next year -- provided a woman goes for the test every year. But many women, particularly poor women, skip two or three years, allowing the disease to take hold.

In a study published this month of 481 Connecticut women, almost 30 percent of the women who developed invasive cervical cancer over a five-year period never had a Pap smear, and another 33 percent had not had one for more than five years.

Researchers found 15 percent of the women who did have a Pap smear had an abnormal result that wasn't properly treated. Another 10 percent of the women had their tests misread as normal, according to the study, published in the June issue of the American Journal of Public Health.

Doctors share some of the blame for faulty diagnoses when their sampling practices are poor. In the past, labs have been reluctant to complain when the sample is blurred or otherwise inadequate. Now labs are required by law to reject bad samples, and many labs run seminars to show doctors how to obtain and preserve a cell sample. Still, doctors frequently ask labs to try again to read slides the lab has rejected, lab officials say. Slides are rejected only about 5 percent of the time.

Doctors' offices make other kinds of mistakes, too.

Consider the case of Teresa Ross, 34, of Baltimore, who got a letter two years ago from a lab saying that her Pap smear was normal. Good news -- except she hadn't had a Pap smear.

When she called the lab to report the mistake, it produced a slide with her name and Social Security number attached to it. Her doctor insisted she must have given Mrs. Ross a Pap smear.

"I've had two children; you don't think I'd know if I had a Pap smear?" Mrs. Ross says. She concluded the slide was mislabeled in the doctor's office. Then she found a new doctor.

Increasingly labs are taking pains to tell patients and doctors that the lab test won't catch every case of cancer. In written materials, SmithKline pointedly tells doctors not to disregard unusual symptoms if a Pap smear is returned normal.

There are many things patients, too, can do to improve the accuracy of their Pap smears, experts say. Women should schedule the test two weeks after their last period, when tissues are clearest. If endometrial cells are present in mid-cycle, they might be classified as abnormal since they usually occur around the time of a woman's period. A lot of women don't remember the date of their last period, SmithKline officials say, yet that can be critical to the diagnosis.

Women should abstain from sexual intercourse or douches for 48 hours before the exam, since either can obscure cancerous cells or cause them to shed. Women also should provide up-to-date information to their doctors about hormonal cycles or levels and unusual bleeding, which can be a sign of cancer.

"The quality of a lab test starts with the doctor-patient relationship," says Steven Lobel, director of SmithKline's Maryland lab.

Limiting workload

While the ultimate buck may stop with the doctor, the quality of the lab is critical. It depends on the experience and ability of the technicians, working conditions and internal quality control features.

At CytoDiagnostics of Baltimore, a specialty lab limited to analyzing Pap smears and cervical tissue, technicians read as few as 50 Pap smears per day. And the lab's senior readers double-check up to 40 percent of negative Pap smears, those in which no evidence of cancer has been found. (Federal law requires firms to re-examine only 10 percent of negative smears.)

Even at larger labs, technicians review far fewer than 100 Pap smears a day. It ranges between 60 and 75 at SmithKline, for instance, and 75 per day at Maryland Medical Laboratories.

Both labs double check more than 20 percent of cases, and specialists review any abnormalities.

Before managed care sent prices in Maryland so low, Pap smears were hardly profitable.

Traditional insurance companies pay about $20 for each test Medicaid pays $10, and Medicare, the federal insurance program for the elderly, pays about $7. But the tests cost $20 to $40, pathologists say.

In the war for HMO business, prices for these tests are now as low as $4 to $5. Nationally, Pap smears have become the "loss leader" of the medical laboratory industry -- the test large companies will do for a cut-rate fee to get the rest of a customer's business.

The result is that firms that specialize in the test are becoming dinosaurs.

CytoDiagnostic, for example, expects to lose 10 to 12 percent of its business this year because it can't compete with below-cost prices offered by the big labs that can make up prices with other tests. It is fighting to hold on to customers who are offered $4.25 a test with a three-day turnaround, said CytoDiagnostics owner Fran Cavanaugh. Her company charges $25 per test.

The difficulty of the test, its lack of profitability and the growing number of lawsuits over errors are beginning to drive many pathologists in Maryland and elsewhere out of the business, says Dr. Siegel.

Dr. Siegel believes there is a "world of difference" between labs that focus on Pap tests and general purpose labs. Smaller specialty labs can provide more personal service that helps in maintaining relationships between lab pathologists and the doctor.

But with Pap smears no longer profitable, the business is going to large labs where risks can be higher. The more Pap smears a person views, even if under the limits set by law, the higher the risk of an error occurring, pathologists say.

"With lower volume, I feel more comfortable," said William R. Weisburger, chief pathologist at Anne Arundel Medical Center, who has also worked at a large lab.

"Across the board where you have huge volume, you just miss some," says Harlow Case, a Washington, D.C., malpractice lawyer.

But big labs argue that size has less to do with quality than internal controls and individual expertise.

"There are those who believe practice makes perfect," says Al Reynolds, vice president and chief operating officer of MetPath, the largest Maryland lab. "Quality medicine can be done in small, medium and big labs. People who see lots of different types of cases more regularly have more expertise. But that can also happen in a much smaller lab."

Even the most painstaking technician can miss abnormal cells. Often on a second look, they see things they didn't see the first time.

"When you go back and look at the slide three times longer than you did, you possibly see something you didn't see," says Dr. Solomon of the National Cancer Institute.

A clump of 10,000 abnormal cells would be obvious. On the other hand, she says, whether anyone on a first read could detect a single cell out of 100,000 is an open question.

Yet such cases can wind up in front of a jury.

"A lot of misread smears are based on one or two cells out of thousands blown up in front of a jury," says Dr. Weisburger, who is called to testify in court cases involving Pap smears several times a year.

"I've also seen Pap smears totally blown," he says. "Some are so obvious that you wonder whether they even read them."

Improving chances of an accurate test

To improve the accuracy of your Pap smears, medical experts suggest these guidelines:

* Ask your doctor about the quality of the lab that evaluates your test.

* Have an annual Pap screen, beginning at age 18.

* Schedule the test for two weeks after your period, when tissues are clearest.

L * Abstain from sexual activity for 48 hours before the test.

* Provide your doctor with a detailed medical history, including whether you are taking birth control or hormone pills.

* Advise your doctor of any unusual bleeding or discharges, and of any past abnormal Pap test.

* If you are at risk for cancer, ask your doctor whether a second opinion on your Pap smear may be warranted. Or, ask your doctor to send your cell samples directly to a second lab of your choice. Be prepared to pay about $20 to $30.

* For additional information or a brochure describing the Pap test and questions patients should ask, call the College of American Pathologists at (800) 522-5678.

BUSIEST LABS

In 1994, these five Maryland laboratories handled the most Pap screens:

* Maryland Medical Laboratory Inc. (249,956)

* MetPath Inc.* (217,212)

* CytoDiagnostics of Baltimore (142,531)

* Cytology Services of Maryland (141,147)

* SmithKline Beecham (98,967)

* Last year, MetPath acquired Maryland Medical; the combined company will handle 600,000 tests in 1995.

RISK FACTORS

These factors increase a woman's risk for developing cervical cancer:

* First sexual contact before age 18

* Numerous sexual partners or a partner who has had numerous sexual partners

* Pregnancy before age 18

* Frequent infections that are spread by sexual activity

* Genital warts due to HPV (human papillomavirus)

* Your mother took diethylstilbestrol (DES) during pregnancy

SUN ON DEMAND

Reprints of this two-part series on lab testing and results will be available after Thursday, for $3.95. For information, call (410) 332-6800 and ask for The Sun's lab test series.

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