Vital Signs: The Aretha Franklin Test

By Daniel C. Weaver|Thursday, March 02, 1995
RELATED TAGS: CANCER
Hey, hey. What's up, doc?

I glanced up from the microscope into the face of Greg Jackson, radiologist. We were in the CT scanner room, where I was examining tissue extracted from a tumor in a young woman's chest.

Something's up, I replied, but I don't know just what.

I thought you pathologists knew it all, teased Greg.

Well, this time I don't. I've still got scar tissue and those strange glands in the biopsy--but I can't figure out what they have to do with her lung tumor. Go ahead and do one more needle biopsy and maybe I'll find something else.

Our patient, Mrs. Henley, was a young mother with two sons, and until a week earlier she had been perfectly healthy. Now she lay on the hard table of the CT scanner believing she had cancer, because that's what most people believe when a doctor tells them they have a tumor. But the word tumor is descriptive, not diagnostic; it is used to describe any unusual mass. When the tumor is in the lung, the cause might be cancer, pneumonia, a foreign object, or a genetic fluke. The precise nature of Mrs. Henley's tumor was what Greg and I were trying to figure out.

Mrs. Henley's nightmare had begun the previous Saturday afternoon while she was playing with her sons in the park. She had just put her younger boy on the teeter-totter when she suddenly gasped for air, fell to her knees, and grabbed her right side. Her breathing was shallow and rapid, and it hurt whether she breathed in or out. Her husband brought her in to the emergency room at a local hospital.

In a healthy person there are only two likely reasons for sudden shortness of breath: a collapsed lung or a foreign object blocking the flow of air. When the ER doctors tapped on the right side of Mrs. Henley's chest, they heard a drumlike echo instead of the normal dull thud. That suggested that her lung had collapsed, filling the surrounding chest cavity with air. An X-ray confirmed the suspicion. They also found a tiny bit of fluid in her right lung cavity. But they didn't find anything that would explain the collapsed lung or the extra fluid.

The ER doctors extracted the fluid with a syringe and sent it to the lab for analysis. After the removal of the fluid, Mrs. Henley's lung reexpanded. But an X-ray revealed a dense, forbidding mass in the bottom part of her right lung. To the radiologist on duty, it looked like cancer. Yet cancer alone is unlikely to cause a lung to collapse.

One of life's ironies is that the only reason we can breathe at all is that our lungs inhabit a vacuum. Imagine that the lungs are a balloon and the chest is a vacuum jar. The air pressure in the balloon is greater than the air pressure in the jar. Break the jar or puncture the balloon, and the air pressure across the balloon, and the jar becomes the same. The same thing happens when the lung or the chest wall is punctured. The naturally elastic fibers of the lung collapse just like a popped balloon. Once a lung has collapsed, the patient gasps for air.

So far, we knew two things. Something had produced a mass in Mrs. Henley's lung, and something had punctured the lung.

The next step was to look over the lab results. When Dr. Dreiser, the local pathologist, had first examined the fluid drawn from the lung, he had found a mix of strange glands and blood. He suspected that the fluid, the hole in the lung, and the mass in the chest were all caused by the same thing: adenocarcinoma--a type of glandular cancer that may either have grown in her lung or spread from some hidden site. But it would take a biopsy of the lung tumor to confirm the diagnosis. That's why Mrs. Henley was referred to our hospital, and that is what Greg and I were doing that Thursday morning in the radiology department.

We were using a CT scanner, one of modern medicine's most sophisticated instruments, to pinpoint the tumor in Mrs. Henley's chest. A CT scanner takes a series of X-rays in a rotating plane and then reassembles them to form a three-dimensional image of the body. Using the image from the CT scan to guide him, Greg inserted a thin needle through the skin directly above the tumor and drew out a few drops. I smeared those drops of blood and cells on a glass slide and stained them with two dyes.

Staining is one of cell biology's oldest techniques. One dye stains the nucleus of a cell a deep midnight blue; the other stains the rest of the cell--the cytoplasm--a brilliant sunset red. Judging from the pattern and color of the cells, the pathologist must make the final diagnosis.

Benign or malignant, good news or bad--it must seem so simple to decide. And many times for the pathologist it is. The malignant cells scream out CANCER: their nuclei are misshapen like deformed faces; their cytoplasm, filled with tissue-destroying enzymes, is swollen like a bloated belly; and their growth is murderously uncontrolled. But sometimes cancerous cells are sneaky little devils, artfully dressed like wolves in sheep's clothing, stealthily insinuating themselves around healthy cells until they can silently throttle them. The pathologist's task is to decide whether the odd-looking cells are good guys in a bad mood or charming, handsome mass murderers like Ted Bundy.

Dreiser suspected cancer, but I wasn't so sure. There are many signs of cancer, none of them definitive on their own. A cell with a large nucleus filled with dark, distorted DNA is one sign of a malignant cell. The rapid growth and spread of these cells to other organs is another. But the single most helpful sign in deciding whether cells are benign or malignant is what I call the Aretha Franklin sign: R-E-S-P-E-C-T. If the odd cells--no matter how tortured or ugly or proliferative--show respect for themselves and respect for their neighbors, they are overwhelmingly likely to be benign.

To my eye, Mrs. Henley's unusual-looking cells showed this respect. They were neatly arranged in little groups that didn't disrupt the functioning of other cells. Their nuclei didn't look as dark and densely packed as the nuclei of cancerous cells, which often have twice the normal amount of DNA. Moreover, these cells didn't have the shoved-around look of misshapen nuclei and squashed cytoplasm that often betrays the presence of cancer. These cells might be misbehaving, but I wasn't so sure they were cancerous. They just seemed lost. But what were they doing in the lung? Why did they punch a hole in it? And why did they make a mass like a cancer?

Another ten minutes of thought got me no closer to an answer. Greg, the last pass through the lung was it. You certainly hit it. I've just got to think what it means.

I considered the possibilities: Cancer? Infection? A genetic disorder? Cancer, whether it arises in the lungs or arrives from elsewhere, is certainly the most common cause of lung tumors--but not in 27-year-old women. Besides, the cells I saw here just didn't look like cancer. They were a bit ugly and distorted, but they passed the Aretha Franklin test. Yet I couldn't be certain. Perhaps this was an extraordinary kind of cancer that violated this most important rule of biology. Or perhaps this was a hamartoma--a rare genetic aberration in which the normal proportion of benign lung cells is out of whack. But that would require the presence of two or more kinds of cells, and I saw only one. And it would not explain the presence of blood in the fluid. Was this an infection? If so, why did she have no history of pneumonia or even a fever? I decided to sleep on it.

In the morning I began again with the slides of Mrs. Henley's lung tumor. I placed the slide of cells under the microscope and scanned across the cellular horizon. Enmeshed in a sea of blood were deep blue nuclei arranged in circles like wagon trains on a dusty red desert. I switched to a higher magnification to get a closer look. The nuclei were large and evenly blue, arranged in discrete ovals and circles. In the cytoplasm were tiny bubbles--a sign of secretions from the mysterious glands.

But just knowing there were glands in Mrs. Henley's lung tissue didn't help me much. Glands are very common in nearly every organ. They coat the gullet, lungs, and womb, and they make sweat, milk, and tears. The cells that make up glands are easy to spot because they cluster in rings, forming a hole to let out their secretions. The inner surface of the lungs normally contains glands that secrete fluids to prevent the lungs from drying out. But one place that glands absolutely don't belong is on the outer surface of the lungs, where there is no place to discharge their secretions. That's where Mrs. Henley's funny-looking glands were. I knew they didn't belong there, but that was all I could say for sure. Who were these guys? What were they doing? What were they trying to secrete?

I flipped back to the lower magnification, then switched once more to the higher magnification and peered again at these midnight blue cells. This time I saw something I hadn't noticed before. Just to the side of the wagon trains of blue cells were small, narrow, spindle-shaped companions stained a very pale blue. It suddenly dawned on me who these small companions were. They were stromal cells, a kind of cell that supports many organs. The presence of stromal cells beside the puzzling glands could mean only one thing. This wasn't cancer. This was endometriosis.

Endometriosis is a strange and, to the pathologist, wondrous disorder. The endometrium is a thin coating of glands and stromal cells that lines the uterus. Occasionally--and for unknown reasons--these benign cells migrate from the lining of the uterus to other parts of the body. Usually they spread across the surface of the ovaries or fallopian tubes. But occasionally they can spread to the belly button, the skin, or in rare cases, to the surface of the lung. No matter where they spread, no matter how far from the endometrium, these cells will often still respond to a woman's hormonal cycle.

When a woman's hormones signal the start of the menstrual cycle, the growth of the endometrial cells--estranged or not--is disrupted, and the endometrial lining decays. When that sloughing begins, it ruptures the tiny blood vessels that support the endometrial lining, which starts the menstrual flow. When endometrial tissue is growing outside the uterus, however, this cellular sloughing can damage the surrounding tissue. If the endometrial tissue is growing on the fallopian tubes, it can cause infertility. In Mrs. Henley's case, the endometrial growth damaged the surface of the lung, causing the bleeding we had detected. And if there is enough abnormal growth, it may form scar tissue or even punch a hole in the thin, lacy surface of the lung. That kind of growth would also explain Mrs. Henley's collapsed lung and lung tumor.

When I called Greg to fill him in, he was surprised and pleased that we had at last found the source of the mysterious glands. Later in the day I went upstairs to Mrs. Henley's floor and read over her chart. When I stopped by her room, I found her lying in bed on her left side, a position that probably relieved some of the pain in her right lung.

Hello, I'm Dr. Weaver, one of the specialists here, I began. Would you mind if I ask you a few questions?

Go ahead. I'm feeling much better now that the doctors told me what it really is.

From what I read on your chart, I see that you've had shortness of breath many times with your periods. Did your doctor ever try to figure out what was going on?

No, we just thought I had bad cramps.

Well, did the shortness of breath ever go away for several months in a row?

Sure, she replied, when I was pregnant with each of my boys.

Just as the stromal cells had gone undetected, sometimes the truth lies before us, just too obvious to see.

Later Mrs. Henley's gynecologist explained to her the ways to treat endometriosis. Basically, there are just two methods, and neither works very well. One treatment uses hormones to alter the signals the endometrium receives, essentially creating a state of false pregnancy. The other uses lasers to burn away the excess endometrial growth. Mrs. Henley chose the hormonal treatment, and for a few months at least she has had no recurrence. But endometriosis is rarely eliminated for good. Symptoms can return even if the most common sites of growth--the ovaries and uterus--are completely excised. Until there is a cure for endometriosis, the best that Mrs. Henley can hope to achieve is an uneasy truce with her disorder.
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