A mistaken pathologist's report can lead to the wrong kind of treatment.
Knowing whether a sliver of tissue is malignant and how malignant is crucial information in determining what treatment to use for a cancer. Still, most patients accept a pathologist’s report without question and seldom ask for a second opinion. This process generally works well, but a study of biopsy slides of 6,171 patients referred to Hopkins for cancer care showed that sometimes it doesn’t. Eighty-six patients, or 1.4 percent, received significantly wrong diagnoses that would have led to unnecessary or inappropriate treatment. Magnified across the country, that error rate translates into 30,000 missed pathology analyses a year.
“We don’t want to send a panic among everybody that their biopsies are wrong,” says pathologist Jonathan Epstein, M.D. “But there’s a sizable minority, maybe 2 to 3 percent, who have a wrong diagnosis or who could have a more accurate diagnosis.”
For 20 patients in the study, a second opinion changed a malignant diagnosis to a benign one. In five other cases, a growth reported as benign was later found to be malignant. In six cases, one type of cancer had been mistaken for a different type. Such variations may influence whether someone gets surgery, chemotherapy, radiation or no treatment at all.
The differences between malignant and benign cells can be subtle, Epstein says. Sometimes the clues that tell a pathologist a cell is cancerous are hidden. What’s more, some malignancies mimic benign processes: “If you’ve seen the mimickers several times, you can recognize them and do additional studies to verify what you see. But if you’re looking at them for the first time with no experience to fall back on, they’ll likely be misdiagnosed.”
Finally, with new biopsy techniques like needle aspiration, pathologists are given much less tissue to examine. The tinier the tissue, says Epstein, the more difficult the evaluation and the greater the risk of misdiagnosis. Such findings, he stresses, underscore the importance of second opinions on biopsies, especially in the case of difficult-to-diagnose cancers like cervical, prostate and skin.
Epstein’s take-home message for community physicians? “If you get back a pathology report that you have any question about or that doesn’t seem to reflect the patient’s clinical history, get a second opinion. The same holds true if you have concerns about the experience of your pathologist on a ticklish case. Checking one more time could significantly influence your decision about what to do next.”
Throughout history, heat has been used for medical treatment. Long ago Hindus applied heated metal bars to injured parts of the body, and the ancient Greeks warmed up stones to stop bleeding. Electric needles are standard equipment today in cutting and cauterizing tissue.
Now heat is taking on a role in killing cancerous liver tumors that can’t be removed in the operating room. Called radio-frequency (RF) ablation, the treatment is promising. In a 1999 Italian study of 10 patients with metastatic breast cancer that had spread to the liver, the technique destroyed 93 percent of the lesions without any complications or return of the tumors. In another European study of 29 patients, 66 percent of liver metastases were eliminated.
“The outcomes look quite good, though it’s still too early to tell how big a role radio-frequency ablation will play in the treatment of liver cancer,” says surgeon Michael Choti, M.D., who has been performing the procedure at Hopkins for more than a year. “It’s certainly an advance in the management of this disease.”
RF ablation is ideal for patients with liver lesions that can’t be removed safely with standard surgery. To perform the procedure, he inserts a thin, electrical probe into each malignant lesion. By pulling back on the insulated shaft of the probe, he releases an array of wires from its tip into the lesion. An electrical current then heats the wires to about 100C, resulting in a slow but deadly burn.“If you cook the tumor gradually by adjusting the power, you get a wider, bigger burn,” Choti says.
One advantage of the new technique over the traditional ablative approach for liver cancer—freezing tumors through cryotherapy—is that RF ablation can be performed laparoscopically or percutaneously through the skin, whereas cryotherapy cannot because its probes are too big. RF ablation can convert the inoperable patient into a surgical candidate by destroying the smaller lesions, and it may also be used in conjunction with resection.
“I may go in [in a standard surgery] for one big tumor in the right lobe of the liver and find other small ones in the left half,” Choti says. “In the past, we would have had no treatment options, but now I can remove the right half and ablate the tumors on the left half.”
For neuropathologist Peter Burger, M.D., identifying certain brain biopsies can be like coming up with the name of one of our more obscure past presidents. Unlike specimens from familiar brain tumors, which can be as easy to recognize as a bearded Abraham Lincoln, these tough-to-pinpoint samples can be as mystifying as the 19th president of the United States: “Most of us,” Burger says, “have no idea what Rutherford B. Hayes looks like.”
Brain tumors are likely the most difficult-to-diagnose lesions in the body—yet an accurate diagnosis is critical. For starters, specimens tend to be small because of where they’re located in the brain and how they’re obtained—often with only a thin needle. “We have to recognize a complex pattern of a tumor in a very small piece of it,” Burger says.
And those pieces, particularly in tumors of children, tend to be of the Rutherford B. Hayes variety. Burger views the specimens first before reading anything about the case. If ambiguities arise, he orders additional studies to identify certain proteins common to certain tumors, or high-magnification electron microscopy to get a closer look. Or he may use fluorescent in-situ hybridization, or FISH, to obtain a genetic view.
Burger correlates the clinical and radiologic features of the case to what he sees on the slide. The biopsy, for instance, may suggest malignancy, while the symptoms say benign. He also consults with adult and pediatric brain tumor groups here, made up of neurosurgeons and neuroradiologists, in addition to neuropathologists: “Often, it’s helpful to talk to physicians to get the whole clinical perspective and not that of an isolated specimen.” Burger should know. He evaluates 1,400 cases from all over the world each year.
For six years, after every meal Christopher Burkey ate, the food and fluid in his stomach would shoot back up through his esophagus. Still, Burkey didn’t want to undergo arduous surgery to fix his reflux problem. Then out of the blue, the drug Burkey was taking to control regurgitation was linked with heart problems and banned by the FDA. Suddenly, surgery was the only option for the 33-year-old project manager from Edgewood, Md., if he wanted help for his unpleasant problem.
But luck was with this patient. He learned from surgeon Mark Talamini, M.D., that there would be no need for a large incision in an open operation. The procedure could be performed laparoscopically with a less-risky, minimally invasive approach that would also require fewer days in the hospital. Then Talamini really stunned Burkey. He said he wanted to use a robot to help him perform the surgery.
“My first thought was, ‘Gee, I hope it doesn’t malfunction,’” Burkey says.
Talamini assured his nervous patient that robotic surgery is actually safer than conventional laparoscopic surgery. In the traditional approach, surgical instruments sometimes shake as surgeons try to manually manipulate awkward, long-handled mechanical arms through tubes inserted into the abdomen. And although a video camera on one of the arms presents a picture of what’s happening internally, surgeons get a flat, two-dimensional image that limits their depth of field.
The robot that Hopkins uses, made by Intuitive Surgical, still relies on the surgeon to operate through the small ports into the abdomen. Rather than bending over the patient, however, the surgeon sits in a shell-like console several feet away. “Thanks to 3-D optics,” explains Talamini, “we get a vivid, three-dimensional picture of the inside of the abdomen.” By sliding their hands into the computer-enhanced mechanical wrists dangling in front of them, surgeons can advance, rotate, tilt and withdraw their pencil-size instruments, as well as clamp, snip and suture tissue.
“These Endo Wrists allow you to literally go around corners, behind things, around things, allowing you to work from all angles and directions,” Talamini says. “You feel like you’re inside the body using your own hands.”
The robot also has sensors that allow the surgeon at the console to feel the tissue, and it provides adjustable motion scaling in which, for example, the surgical instrument moves one inch to the surgeon’s five—allowing more precise manipulation and stitching and elimination of tremor.
Talamini applied all these features when he performed Burkey’s successful reflux operation, in which the very top of his stomach was wrapped around the outside of the esophagus and stitched to the diaphragm to keep foods and fluids in his stomach.
Robots not only make such procedures easier and safer, Talamini says, but they open the window for more complex operations like heart bypass surgery to be done without a large open incision (see sidebar). As for anxious patients like Burkey, Talamini adds, “I tell patients we have a new robot that I believe enhances what I can do in your operation. One patient said, ‘Cool, it’s great to be living in the 21st century.’ ”
Agnes Hollingsworth, 84, of Columbia, Md., was at “death’s door” with cardiomyopathy and end-stage heart failure when she came to Hopkins in October 1999. “She was terribly short of breath, and large volumes of fluid had accumulated in her lungs. Her heart simply wasn’t working,” says her cardiologist, Ronald Berger, M.D., Ph.D.
But when Berger implanted a pacemaker in Hollingsworth’s heart, she began a dramatic turnaround. “My lips and face got color, my eyes unglazed, I was able to eat and walk up and down steps,” Hollingsworth says. “Within a week, I stopped using my walker.”
Originally used to fix electrical abnormalities in people with slow heart rhythms, Berger and cardiologist David Kass, M.D., are finding that the pacemaker can successfully resynchronize weak and struggling hearts in heart failure patients whose only treatment options typically have been drugs or surgery. In a recent study by the two specialists of 22 heart failure patients, Berger and Kass found that attaching a pacing wire to the left ventricle improved the heart’s ability to contract and pump out blood by an average of 35 percent. (In the conventional pacemaker, the wire is attached to the right ventricle.) Patients whose hearts had the largest amount of timing discord, whose hearts were often the weakest, benefited the most from a pacemaker.
“The problem we set out to solve was determining which heart failure patients would respond best to pacemakers,” Kass says, since 400,000 new cases of the problem are diagnosed each year in this country. “The devices are expensive and permanent, and the patients are so sick we can’t afford to waste time.”
Because Hollingsworth responded well to an electrode placed on her left ventricle, Berger implanted a pacemaker under her collarbone and threaded a wire from the battery through veins to the surface of the ventricle. This electrode anticipates within 120 milliseconds when a heartbeat is about to start, and stimulates the region. Rather than wobbling and struggling to send blood out of the body because of a delay in contraction, Hollingsworth’s heart, according to her pulse pressure, began to pump efficiently. And it’s been doing so for the past year.
“Today, I’m doing everything a person can possibly do—travel, go out to lunch, go to the movies,” Hollingsworth says. “My life has really started over again.”
In the early 1980s, plastic surgeon Robert Spence, M.D., discovered that tissue expanders used in breast reconstruction could also help patients with badly burned faces. These silicon sacs, which are inserted under the breast through a mastectomy scar and then injected weekly with saline to stretch the skin, could expand skin on burn patients’ shoulders, too. As a result, they created ideal facial grafts. Until then, burn specialists had been using unstretched shoulder skin that tended to shrink and discolor to replace grossly disfiguring scars. Also, they had to take a thin layer of skin from the leg to patch the wound left on the shoulder. Tissue-expanded skin gets around that.
“I’m able to take the full thickness of the skin, which doesn’t change color or shrink as much. When I put it on the face it looks more like normal skin,” Spence says. “I make enough skin to cover the face and to close the shoulder, too.”
Now, Spence has gone a step further by flapping the shoulder skin up to the face, which allows him to retain the skin’s blood supply and natural appearance. First, he removes the scarred skin from the patient’s face and uses it as a pattern on the expanded shoulder tissue. He cuts along the lines of this template—but not entirely. He keeps a portion of the skin to bridge the graft and its blood supply to the face. After blood flow is restored to the flap, Spence severs the bridge. Because there is less shrinkage and discoloring, the result is a more natural appearance than any previous skin graft gives.
“Because the blood supply comes with a flap,” Spence says, “the skin doesn’t change at all." GL
For a man who has to get out of bed to go to the bathroom four or five times a night because of an enlarged prostate, the traditional treatments have been surgery to reduce the size of the gland and drug therapies to relax smooth muscles in the prostate. But surgery has drawbacks like a hospital stay, two-week recovery and risks of impotence and incontinence. Medicines bring side effects like headache and nausea. “The cost of taking a pill every day for the rest of your life is an important issue, as well,” notes urologist Alan Partin, M.D.
Now, a non-invasive outpatient treatment is showing remarkable success in stopping too-frequent urination without the perils of the other approaches. The treatment uses advanced microwave technology to treat enlarged prostate tissue and relieve symptoms. “About 65 to 70 percent of the patients have long-term relief,” Partin says.
After the urethra is anesthetized, a catheter containing a microwave antenna is guided through the urethra to the prostate. When ultrasound confirms that the antenna is at the right location, a balloon at the end of the catheter is inflated to hold the antenna in place. Chilled water is then circulated to cool and protect the urethra as the microwave is powered up to heat and shrink diseased tissue. This cooling system also guards against urethral pain from any residual heat. A small probe also is inserted into the rectum, which has temperature sensors that continually measure rectal temperatures during treatment and turn the microwave off should they get too high.
The procedure typically takes about 60 to 90 minutes, but Partin and his team have shortened it to 28 minutes with the same results. Patients are thrilled with the results. The technique can end years of pill-taking for the problem.
For the first time, researchers have used stem cells to restore movement in mice.
You wouldn’t believe how overjoyed we were to see those feet move,” says neurologist Douglas Kerr of his reaction to watching a laboratory mouse wiggle first one then the other of its paws. The display was scientific proof of a principle with heart-quickening therapeutic possibilities.
Kerr and a team of Hopkins researchers had been able to restore movement to newly paralyzed rodents by injecting stem cells into the animals’ spinal fluid. Test mice and rats had been paralyzed by an animal virus (the Sindbis virus) that specifically attacks their motor neurons and which normally permanently destroys the ability to move the legs and feet, as neurons leading from the spinal cord to muscles deteriorate. Yet 50 percent of the stem-cell treated rodents recovered the capability to place the soles of one or both of their hind feet on the ground. “It may not seem like a major difference,” says Kerr, “but in the paralyzing neurological diseases, small steps—being able to stand, to move a leg, for example—take on great significance.”
The accomplishment, according to neurology researcher Jeffrey Rothstein, may lead most immediately to improved treatments for patients with such diseases as amyotrophic lateral sclerosis (ALS) and spinal motor atrophy (SMA). “Under the best circumstances,” he says, “we’d hope to use stem cells in early clinical trials within two years.”
The study is especially significant because it’s one of the first examples where stem cells may restore function over a broad region of the central nervous system, notes Kerr, who led the research team. “Most use of neural stem cells so far has been for focused problems such as stroke damage or Parkinson’s disease, which affect a small, specific area.”
In the rodent study, though, the stem cells the researchers injected migrated to broadly damaged areas of the spinal cord. “Something about cell death is apparently a potent stimulus for stem cell migration,” Kerr explains. “Add these cells to a normal rat or mouse, and nothing migrates to the spinal cord. In this study of 18 rodents, the researchers seeded the stem cells by injecting them into the animals’ cerebrospinal fluid via a hollow needle at the base of the spinal cord—like a spinal tap in reverse. Within several weeks, the cells migrated to the ventral horn, a region of the spinal cord containing the bodies of motor nerve cells.
Kerr says that after eight weeks the researchers saw “this limited ability to move in half of the mice and rats.” From 5 to 7 percent of the stem cells that migrated to the spinal cord appeared to differentiate into nerve cells, he adds. “They expressed mature neuronal markers on their cell surfaces. Now we’re working to explain how such an apparently small number of nerve cells can make such a relatively large improvement in function.
Kerr speculates that it could be that fewer nerve cells are needed for movement than has been suspected. The other explanation is that the stem cells themselves haven’t restored the nerve cell-to-muscle units required for movement but that, instead, they protect or stimulate the few undamaged nerve cells that still remain. The researchers now are pursuing this question in the lab.
The rodents infected with the Sindbis virus are a tested model for SMA, the most common inherited neurological disorder and the most common inherited cause of infant death. In the disease, children are born weak and have trouble swallowing, breathing and walking. Most die in infancy, as motor nerves leading from the brain to the spinal cord as well as those from the cord to muscles deteriorate. The disease eventually creates whole-body paralysis and death.
“It’s an exciting time to be a practicing neurologist,” Kerr says. “For the first time, we can conceive of using stem cells not only to halt neurologic disease, but also to restore function.”