As I flashed back and forth between these opposing views, I was reminded of an optical illusion that at one moment looks like a beautiful young woman and the next moment like a crooked-nosed hag. With so little good data to go on, people see what they hope to see.
Seeking perspective, I wondered what fraction of the human bone pile had actually been picked. I asked three anthropologists to estimate the total number of ancient and prehistoric skeletons that have been discovered over the years and made available for study by the world’s scientists. Perhaps 250,000, I was told, not much more than the population of a small city. That includes partial skeletons—and often only single skulls, which were the only bones many early anthropologists thought worth saving. Very few of the specimens have been scrutinized for cancer.
Take this number and compare it with the total number of people who have ever lived and died. A demographer at the Population Reference Bureau made a rough calculation. By A.D. 1, the earth’s cumulative population had already approached 50 billion, and the number had nearly doubled to 100 billion by 1850. I was surprised by the magnitude. So much for the common notion that as many people are alive today as all who came before us.
Dividing 250,000 skeletons by 100 billion people you arrive at a few ten-thousandths of 1 percent. That is roughly the sample size on which our knowledge of ancient cancer is based—a sparsely dotted Rorschach you can choose to read two ways.
Chapter 4
Invasion of the Body Snatchers
On October 9, 1868, a patient identified in a style common to Russian novels and medical case reports as Richard J—was admitted to Melbourne Hospital with a diagnosis of “rheumatism and debility.” He was weak, in other words, and his joints and muscles hurt. Almost anything could have been wrong. Beneath the skin of his chest and abdomen were about thirty lumps “varying in size from that of a bean to that of a small orange.” There were two more tumors, one between his shoulder blades and the other on his inner left thigh about four inches above the knee. Over the next five months he wasted away, and after he died tissue from the tumors was prepared for examination under a microscope.
The physician in residence, Thomas Ramsden Ashworth, described what he saw: “large and beautifully pellucid cells” with distinctive features that left a deep impression on his mind. Because of the prevalence and the aggressiveness of the cancer, he was curious to see what the man’s blood looked like, so he drew a sample. Floating among the red and white corpuscles, he was surprised to find cells that looked exactly like those inside the tumors. How did they get there? The blood sample had been drawn from a vein in the good leg, not the one that had been visibly affected by cancer.
The identity of the malignancy wasn’t determined. An expert who examined the cancer had never seen one like it. More important to the history of medicine was the final observation in Ashworth’s report: “The fact of cells identical with those of the cancer itself being seen in the blood may tend to throw some light upon the mode of origin of multiple tumours existing in the same person.” He allowed for the possibility that the tumors might have formed spontaneously in the blood, either before or after death. Many physicians believed that cancer spread by secreting “morbid juices.” But Ashworth suggested a more original hypothesis: that cancerous cells themselves had found their way into the bloodstream and transplanted themselves in distant locations. “One thing is certain, that if they came from an existing cancer structure, they must have passed through the greater part of the circulatory system.” From the bad leg to the good leg, where they were ready to grow.
It was only in the nineteenth century that doctors had come to understand cancer as a disease involving abnormal cells. Hippocrates referred to “metastatic affections” traveling through the body. But he attributed cancer and other disorders to an imbalance of the body’s four humors—blood, phlegm, yellow bile, and black bile, which were cosmically in tune with air, water, fire, and earth and with the primal qualities, hot, dry, wet, and cold. Those were the joints along which he carved up the world. If produced in excess, black bile (also called melan cholo) clotted to form tumors—an idea that was carried by Galen through the Middle Ages.
This conceptual stranglehold was loosened in the seventeenth century when René Descartes saw a connection between the recently discovered lymphatic system and cancer. This was a major advance—lymph, unlike black bile, was something that actually existed and could be observed—but there was still a long slog ahead. Veering off in the wrong direction, physicians began hypothesizing that tumors consisted of rotten lymph—not much of an advance over the notion of clotted melan cholo. A Parisian surgeon, Henry François le Dran, came closer to the modern view, proposing in 1757 that cancer began in a specific location—it was not some general malaise of the body—and then was transported in some form through the lymphatic channels, the blood, and sometimes into the lungs. The idea was slow to develop. Later on, metastases were thought to be transmitted by “irritations” traveling along the lymph vessel walls. Even the nervous system was said to be involved, dispatching signals to remote locations and causing the same kind of tumors to form. Comparing cancer with leprosy and elephantiasis, some scholars were certain that it also spread from body to body, that it was a contagious disease.
By the early nineteenth century physicians had noticed that “cancer juice” extracted from tumors consisted of tiny globular shapes. But the resolution of their microscopes was not sharp enough to show that they were actually observing biological cells. Helped by improvements in optical lenses, Johannes Müller, a German physiologist, made a crucial leap. In a book published in 1838, On the Nature and Structural Characteristics of Cancer, and of Those Morbid Growths which May Be Confounded with It, he laid out what came close to being a cellular theory of cancer. He saw with his microscope that a tumor consisted of cells, but he believed that they originated not from other cells but from a primitive fluid called blastema flowing throughout the body. Like his colleagues he couldn’t shake the seductive image of tumors as some kind of clot.
Müller’s student, Rudolf Virchow, took the next step, embracing the dictum Omnis cellula e cellula—all cells arise from other cells, including those that are cancerous. But when it came to explaining how cancer spread through the vessels he stumbled. He carefully considered the possibility that the process might involve “a dissemination of cells from the tumours themselves.” But he found the notion of metastasis by “conveyance of juices” more plausible. Virchow also believed that all cancer arose from connective tissue, which we now know to be true only for the sarcomas, which account for a small portion of tumors. The German surgeon Karl Thiersch helped discredit that idea in the 1860s, showing that carcinoma arises from epithelial cells. Going further, he offered laboratory evidence that a tumor spreads by shedding its own cells, which migrate to other places. Thiersch is the source of one of the most depressing observations about cancer I have come across: “Cancer is incurable because it cannot be cured; the reason that we cannot cure it is because it is incurable; therefore, if by chance one should happen to cure it, it must be that there was no cancer.”
As I tried to trace the flow of ideas that led to the modern theory, I was struck by how hard it is to tease out the subtleties of what any one person, no longer available for questioning, truly believed. It seems strange that doctors thought of cancer as a malign disposition of the whole body rather than a localized disease. But cancer would often be noticed only after it had broadcast itself far and wide. The idea of morbid juices sounds quaint and unenlightened, but there was a real question of how cancer cells, in their travels through the bloodstream, squeezed through the tiny capillaries of the lungs. The answer is still not entirely clear today. As always in science, people were playing with ideas, and more than one at a time. Streams of hypotheses emerged from hundreds of scientists as they engaged in slow-motion debate. The alternative to summarizing and schematizing and leaving names out is to take a plunge as deep as the German physician Jacob Wol
ff’s. His tightly packed, elaborately detailed treatise, The Science of Cancerous Disease from Earliest Times to the Present, was published in four volumes beginning in 1907. They encompass 3,914 pages. An introduction to the first volume, the only one available in English, suggests that the reader “may or may not wish to compare [the work] with the magnitude of Pliny’s Natural History.” Who knows what gems lie forgotten there?
By the time Thomas Ashworth saw what appeared to be circulating cancer cells, the modern theory of metastasis was falling into place. Next to be discovered was that these migrants would not take root just anywhere. After studying hundreds of cases of fatal breast cancer, Stephen Paget, an English surgeon, observed in 1889 that the malignancy usually traveled to the liver even though it could have just as easily reached the spleen. Metastasis was apparently not entirely a random event in which a cancer cell happened to become trapped by the narrows of a capillary or some other obstruction and then started to grow. It required the right environment. He was reminded of how plants replicate on the back of the wind. “When a plant goes to seed, its seeds are carried in all directions,” he observed. “But they can only live and grow if they fall on congenial soil.” This has become known as the seed and soil theory of metastasis: Different kinds of cancer seeds prefer different bodily tissues.
Despite Paget’s insight, the belief persisted that it was nothing more mysterious than the layout of the vascular plumbing that determined where a cancer spread. The mechanics was clearly an important factor. There is a direct venous route from the colon to the liver, and the liver is the most frequent site of metastasis for colon cancer. Even if liver tissue didn’t provide especially fertile conditions, it would soon be swamped by so many malignant cells that a few might chance to thrive. But other metastases are harder to explain. Bladder cancer cells often head straight for the brain.
As Paget’s observations suggested, there had to be more to the process than proximity and dumb luck. In 1980 Ian Hart and Isaiah Fidler demonstrated this with a classic experiment involving laboratory mice. First they grafted fragments from different organs—kidney, ovary, and lung—beneath the animals’ skin or within the muscle fibers and waited for capillaries to sprout, connecting the foreign tissue to the bloodstream. Once the grafts had taken hold, they injected the mice with melanoma cells that had been tagged with a radioisotope so that their paths could be followed through the body. While the malignant cells were equally likely to reach any of the three locations, cancers developed only in the lung and ovarian tissue.
A video I came across made these mysterious journeys seem a little less abstract. Beneath the microscope lens the edge of the tumor resembled a colony of tiny insects—the restless cancer cells. I knew I was watching a stochastic, mindless process, but it was impossible not to ascribe intentions and even feelings to the little devils. Some of them would venture timidly a short way from home. Startled by the foreignness, most quickly retreated to the safety of the pack. But occasionally a few particularly brave cells would crawl their way toward a blood vessel. The odds of making it very far were grim. When they become detached from their substrate, normal cells panic and initiate a preprogrammed suicide routine. The process is called anoikis, from the Greek word for “homeless.” Some cancer cells apparently evolve the ability to overcome this fatal lonesomeness, but when they finally make it into a vessel, most will perish immediately in the river of blood—smashed against a vessel wall, pinched to death in an impassable strait, called out and destroyed by officious immune cells. So many dangers. I thought of the movie Fantastic Voyage, where a tiny team of doctors in a shrunken submarine faces one peril after another while exploring the human bloodstream. I thought of the great efforts experimental biologists take to keep cells alive in petri dishes. Some research suggests that the swimming cancer cells can surround themselves with a phalanx of platelets (blood-clotting cells) for protection during the journey. Or if stuck inside a capillary, some cancer cells may be able to jettison enough of their cytoplasm to slim down and squeeze through.
However they survive the journey they still must find a berth downstream. Here again most will perish. In other experiments with radioactively tagged cancer cells, researchers found that after twenty-four hours only 0.1 percent were still alive and that less than 0.01 percent went on to form tumors. The odds seem almost comforting, but of all the seeds a tumor can shed, it takes only one to start another cancer.
Cells are so particular about where they live that science still struggles to understand metastasis. How do the malignant cells decide where to go, and what counts for them as hospitable soil? Tissue similar to that found in the original tumor would surely be the most desirable, and yet cancer in one breast rarely moves on to the other breast. Nor does cancer in one kidney often spread to the opposite one. According to some theories, cancer cells wandering the corridors of the circulatory system are looking for a particular address—a molecular “zip code” identifying the organ where they are likely to thrive. Cancers are usually capable of replanting themselves, with varying success, in several kinds of tissue. In the Darwinian struggle inside a tumor different lineages may evolve specific genetic programs, priming them for survival inside the brain or, alternately, for a new life in the lungs. The primary tumor might smooth the way by secreting chemicals into the blood that help create a premetastatic niche downstream, a more hospitable place for the progeny to grow. There is even speculation that the travelers can bring their own soil with them—healthy cells from home that will assist in the colonization.
Once the cancer cells arrive at a promising location, a whole new cascade of events begins. They exchange signals with the natives—the cells of the tissue they are set to invade—recruiting their help in coming ashore. If cooperation is not forthcoming, the interlopers might lie dormant for years or decades until they are reawakened. When they have finally established their first colony, some will move on to other sites, and they may even return to the mother tumor to rejoin the battle at home. This self-seeding might help explain the recurrence of cancers that surgeons are confident they had completely excised. Metastasis—what would seem to be a messy, haphazard matter of tumors shedding cells willy-nilly into the bloodstream—turns out to be exquisitely and horrifyingly precise.
Besides the blood, there is another course the seeds can follow—from the tumor through the lymphatic vessels, making themselves known, as they did with Nancy, when they begin congregating inside a lymph node. I don’t remember learning about the lymph system in school, this primitive, insect-like sewer system. It has no heart, sluggishly draining clear, watery waste from the cracks between cells, waste that is filtered along the way by the lymph nodes. Pushed and pulled by contracting muscles and osmotic pressures, the lymph eventually makes its way to the rushing blood, connecting with veins in the neck and shoulders. Evolution in its opportunistic way has found another use for the lymphatic canals: to transport immune cells called lymphocytes. These collect in the lymph nodes, rapidly mushrooming in number when confronted with foreign tissue—bacteria, viruses, cancer cells, enemies to destroy.
Malignant cells gain a pathway to the bloodstream when a tumor acquires the ability to initiate angiogenesis, growing its own capillaries. Tumors can also learn to induce lymphangiogenesis, creating connections to the lymphatic system. They may even send signals to a nearby lymph node, instructing it to sprout more vessels to accommodate the forthcoming invasion. The lymphatic system—this key component of the body’s immunological defenses—becomes co-opted. The first sign is a tumor—a lump—growing inside a lymph node, the barrier whose very purpose is to stop such attacks. That apparently is what had happened with Nancy. It was why we were sitting, on what was probably a perfectly good autumn day, in an office at the university cancer center in Albuquerque.
For all the high-tech scanning and laboratory assays, the precise nature of her metastasis was confirmed by a procedure almost medieval in its barbarity: an endometrial curettage—scraping cells, in this
case without an anesthetic, from the lining of the uterus for pathological scrutiny. To help endure the pain she was given a tongue depressor to clench between her teeth. After all the waiting, the procedure had to be done in a rush. We had been referred to a gynecological oncological surgeon, a specialist among specialists and a rising star in his field. He was leaving the next day for two weeks. To schedule surgery as quickly as possible the lab work had to be ready for his return. The results were what everyone by now had suspected: The cells from the uterus resembled those that had been found in the lymph node of her right groin.
On the scale of medical horrors learning that one has uterine cancer can be relatively good news (that is how far life had plunged). Most cases by far are endometrioid adenocarcinomas—cancer of the epithelial cells of glandular tissue. Unlike ovarian cancer, it is usually noticed early and the five-year survival rate can be as high as 90 percent if the malignancy has not advanced beyond the uterine lining. If it has the odds are lower. When there is metastasis to the nearest lymph nodes (sentinel nodes, they are called, for they are the first line of defense against the errant cells) the likelihood of survival can drop to 45 percent—and if the cancer has advanced as far as an inguinal node, as it had with Nancy, to 15 percent. But those were just averages. Nancy’s youth gave hope for a better than normal outcome. She was strong and could tolerate a regime of treatment—“regime” is precisely the right word—at least as aggressive as the cancer: multiple rounds of sickening chemo followed by burning radiation. But first would come the surgery. A hysterectomy, of course, and removal (“dissection”) of suspect lymph nodes. The surgery would also be exploratory with the aim of identifying and excising any other tissues the cancer might have invaded.
The operation was scheduled for early November, still weeks away. All that time to imagine the cells as they continued to multiply, trying out new combinations of mutations. We went to a lawyer to draw up living wills and medical powers of attorney. Nancy’s youngest brother flew in from the East Coast to be with us. One night shortly before surgery we were sitting together in a Thai restaurant (it’s strange the details one remembers) pretending to be enjoying dinner. During the meal Nancy mentioned that she had noticed a lump that day in the inguinal node of her left leg. The good one. Remembering this now I think of that 1868 paper by Thomas Ashworth: One thing was certain. Moving through her lymphatic system, the cancer cells had reached the other side of her body. And they had found hospitable soil.
The Cancer Chronicles Page 7