Twenty-five years ago, Dr. Robert Hackman performed an autopsy on a young man who had died of complications following a bone-marrow transplant for acute leukemia. A routine examination revealed that the man had enlarged lymph nodes and bone marrow that was full of abnormal-looking cells.
"When I showed the bone-marrow slides to colleagues, they agreed that the cells looked different from the original leukemia but thought that maybe it was the result of treatment," Hackman said. "Yet as we looked more carefully, I realized something else was going on."
Additional tests revealed the man had suffered from an infection with Epstein-Barr virus, a common human pathogen typically associated with mononucleosis. In the leukemia patient, with an immune system already weakened by cancer and radiation therapy, the virus triggered what is known as lymphoproliferative syndrome, causing an explosive expansion of cancer cells that spread throughout the body. Hackman later published a paper with Dr. Bill Schubach and other colleagues describing the condition.
Reflecting on this finding Hackman, now director of the center's pathology group, said that in 1978 the condition had never been diagnosed in a transplant patient at the center and had scarcely been noted in the literature.
"That case was instrumental in alerting us that we should be on the lookout for transplant patients who might be suffering from this complication," he said. "We and others adopted techniques to identify this process in cells and plasma. Since then, we've seen a few dozen cases over the years. If the diagnosis is established early enough, there are therapeutic measures we can take to treat it and minimize what could be a fatal complication."
This example of careful medical detective work illustrates the valuable role the Clinical Research Division's pathology section has played in boosting transplant cure rates from less than 20 percent in 1975 to more than 85 percent for certain cancers today. An early addition to the transplant program pioneered by Dr. E. Donnall Thomas, director emeritus of the division, the pathology group is now housed in the Seattle Cancer Care Alliance. It continues to serve patients in Fred Hutchinson's transplant program, as well as those hospitalized at the University of Washington and Children's Hospital and Regional Medical Center. In addition, the group's members are part of the Research Pathology Shared Resource for the Fred Hutchinson/University of Washington Cancer Consortium.
"Pathologists are physicians who specialize in evaluating the nature and cause of abnormal conditions by examination of tissue specimens," said Dr. George Sale, who joined Thomas' transplant team in 1974 as one of the first pathologists.
"We take a patient from first symptom and follow them through transplant," he said. "And if they don't survive, we might do the autopsy, depending on the family's wishes."
Each year, the center's team of four pathologists-whose combined careers total more than a century of experience-and their staff pore over thousands of tissue samples in search of signs of infection or toxicity so that treatment can be initiated swiftly. When samples fail to yield obvious clues about the source of the complication, pathologists are the first on the scene to identify patterns that point to the emergence of a previously undescribed infectious agent or side effect of a new drug or therapy.
For transplant patients, common complications that must be tracked include graft-vs.-host disease, a condition in which donor immune cells attack the body; liver disease due to high-dose chemotherapy; and infections caused by viruses that prey on those with compromised immune systems.
The profession involves much more than simply documenting the cause of death or poor outcome, said Dr. Howard Shulman, an investigator in the pathology section who specializes in liver toxicity.
"At the most basic level, we identify a particular problem," he said. "But our goal is to help identify patterns of complications. This generates ideas that enable us, and our colleagues, to develop and test strategies to help minimize that complication in future patients. We act as initiators in the research process."
Foremost GVHD experts
Over the past 25 years, the group's close attention to detail has contributed to insight into several of the major transplant complications, including cytomegalovirus infection and toxicity to the liver. The center pathologists are also the world's foremost experts on graft-vs.-host-disease, often analyzing tissue samples sent for analysis from around the country from doctors with limited experience in evaluating transplant-related pathology.
"We're very narrowly focused in terms of the patient population we work with," Sale said. "Yet in terms of the parts of the body that we regularly examine tissue from-which includes lung, skin, marrow, gut and liver-we are very broad."
Much of a pathologist's tissue examination relies on the microscope, an instrument that has remained the profession's most valuable tool for more than a century. Yet new technology developed over the last 20 years has accelerated the speed and accuracy of many diagnoses. Techniques for detecting viral DNA or proteins unique to abnormal cells permit many complications to be diagnosed within hours, often a critical window in which a treatment can improve a patient's chances for survival.
Dr. David Myerson, who joined the group in 1984, pioneered the application of these techniques, which had previously been used only in basic-research labs, as patient-care diagnostics. He and colleagues used antibodies and DNA probes to detect infectious agents in biopsy sections.
"In the mid-1980s, there were no antibodies available for several viruses that commonly infected transplant patients," he said. "At the time, we had treatments for some of these infections, so it was important to diagnose them quickly. We and others developed procedures using DNA probes to diagnose these infections. Prior to development of these more modern techniques, our only technique was to culture the viruses, which takes much longer."
Today, these and other techniques, such as polymerase chain reaction, or PCR, are available for rapid diagnosis of infections. In addition, patients now are routinely analyzed for common infections with a panel of antibody tests. Because the new techniques are sensitive enough to detect minute traces of a virus or other organism, ofte, a medication can be given before a pathogen has time to multiply and cause symptoms.
The nature of a pathologist's work provides little or no one-on-one contact with patients. Rather, he or she provides expert consulting to an attending physician. Still, pathologists at the Alliance are not immune from receiving emergency pages at night or on weekends.
"We have a pathologist on call 24 hours a day, 7 days a week," Hackman said. "People who don't take care of this kind of vulnerable patient population don't realize that a few hours can make a difference when it comes to identifying an infection. Some antiviral drugs, when given intravenously, can turn things around dramatically for a patient very quickly if the infection is detected in time."
Myerson said that the lack of direct patient contact does not diminish a pathologist's commitment to care.
"Despite the fact that you'll most often find us sitting in front of a microscope, if you ask one of us details about any of our patients, we'll know their case just as intimately as if we had been at the bedside."