This Strange Cancer Of Mine

I was recently diagnosed with a rare cancer, formerly considered by many an autoimmune disease. Only recently has a consensus emerged as to its classification as a cancer. From my own research I have concluded that it is both a cancerous disease and an autoimmune disorder, the two are not mutually exclusive.

The source of the cancer/immune dispute is the nature of the cells involved. They are called Langerhans cells. When I first saw the name “Langerhans” in the biopsy report, I felt a sense of dread. From my undergraduate days I have associated Langerhans cells with the pancreas, where they control insulin levels. It wasn’t diabetes that worried me, though; it was the specter of pancreatic cancer. But my Langerhans cell cancer was noticed by a dermatologist, strange lesions on my scalp.

Turns out that the Langerhans cells in my pancreas and the Langerhans cells eating the skin of my scalp are not related. Or rather, related only because a man named Paul Langerhans discovered both. He first discovered, in 1868, the skin cells that have gone rogue in me. (While an undergraduate at the University of Berlin Medical School!) A year later came his discovery of the pancreatic insulin regulating cells that also bear his name. Both discoveries occurred before he was 23 years old.

But Langerhans did not rest on his laurels. He later conducted pioneering research on leprosy, tuberculosis and the immune system. Langerhans eventually contracted tuberculosis because of his research on that disease. He knew there was no cure but sought relief from his symptoms in the warm Madeira Islands. But unlike Hans Castorp in The Magic Mountain, he did not seek repose. Rather, he continued to actively practice medicine, and, what I find most endearing, availed himself of the opportunities his new environment afforded and became a celebrated marine biologist in his later years. Sadly, tuberculosis-related complications caused his death at the age of 41. A remarkable man, a remarkable life.

Because of their neuron-like shape, called dendritic, the cells Langerhans first identified were long thought to be part of the peripheral nervous system. This mistake delayed any further insight into their true nature. It wasn’t until nearly 100 years after their discovery that any progress was made in that regard, foremost in recognizing Langerhans cells as part of the immune system, but a truly singular component.

Metchnikov and the other face of Langerhans cells

Langerhans cells come in two guises. Langerhans discovered the dendritic form. In the dendritic mode, Langerhans cells are innate immune cells that connect the innate immune system to the acquired immune system. In the presence of pathogens, dendritic Langerhans cells migrate to the lymph nodes and prime, through “antigen presentation”, the B cells of the acquired immune system to manufacture and release the appropriate antibodies.

The other form of Langerhans cells is called macrophage, which is Greek for “big eater”. As macrophages, Langerhans cells consume foreign invaders—bacterial fungal or viral—and dead cells, through a process called phagocytosis. For some background on the macrophage mode I need to discuss another remarkable individual, Ilya Ilyich Metchnikov (1845-1916).

Metchnikov was born in Ukraine, then a Russian governate. Fascinated by nature since childhood, he was first schooled in zoology but ultimately earned a Nobel Prize—along with Paul Erlich—for his pioneering work in immunology (1908), a field of science he cofounded. He is also considered a founder of gerontology—he coined the term--the study of aging. (Metchnikov’s ideas about aging are worth separate treatment.) To round out his seminal achievements, Metchnikov was the first to recognize the role of the gut microbiome—and Lactic acid bacteria in particular—in health and disease. He advocated that everyone consume yogurt once a day, based on research he conducted on Bulgarians. This prescient insight would not be further developed until almost a century later.

I will focus on Metchnikov’s immunological work. It began with his zoological studies. While examining a larval starfish under a microscope, he noticed that some of the cells inside were moving. He had an inkling that the moving cells were sentinels of some kind. To test his surmise, he poked the starfish larva with a citrus thorn, just penetrating the outer layer. Within hours the mobile cells surrounded the puncture site. He recognized that these mobile cells were white blood cells of some kind. From this he boldly hypothesized that these same white blood cells could provide a defense against other threats to the larva, including bacterial infection by consuming bacteria. Essentially, Metchnikov thought that those mobile white blood cells engulfed bacteria and ate them up.

A colleague with whom he discussed the idea suggested the term phagocyte (Greek for eat cell) for any cell that could operate in this manner, a process that came to be known as phagocytosis. Metchnikov’s hypothesis that white blood cells could engulf and destroy bacteria was not well-received by microbiologists of that day, including Louis Pasteur, the most widely celebrated scientist of his time, and the director of the institute in which Metchnikov conducted his research. Fortunately he had one eminent supporter in Rudolph Virchow (Often called “The Pope of Medicine” and The Father of Modern Pathology”), who published Metchnikov’s idea in his own journal. (Virchow also championed the work of Paul Langerhans.)

The phagocytic white blood cells were later called macrophages, the other guise of Langerhans cells. The macrophage, the form identified by Metchnikov, and dendritic cell, the form identified by Langerhans, are equally Langerhans cells. How they manifest themselves depends on circumstances, the state of the tissue niche in which they find themselves. The tissue niche for Langerhans cells is the epidermis, the outermost cell layers of most organs, orifices and skin.

For many threats, Langerhans cells are the first line of immune defense. Ultraviolet radiation, for example. Sunburns activate the macrophage in Langerhans cells, which consume the cells killed by the sun. But it is the microbial invaders—viral, bacterial and fungal-- that provoke the full arsenal of Langerhans cell defenses.

When not provoked Langerhans cells are mostly in the macrophage state. It is in this state that Langerhans cells sometimes misbehave in a way that is both autoimmune and cancerous. Autoimmune because they eat cells that aren’t supposed to be eaten, cells that aren’t foreign invaders but rather members of the same (self) team. Cancerous because they proliferate too much, and worse, go to places where they don’t belong. It’s called Langerhans Cell Histiocytosis.

Fortunately, it is only rarely that Langerhans cells misbehave in these ways. There are .07-8.9 per million cases diagnosed per year. It is one of the few cancers more common in children than adults. More than 60% of the cases occur in children under two years of age. For those over 15 year of age the chances that your Langerhans cells will turn on you are literally one in a million. I guess that makes me special. Special in the same way that getting struck by lightning makes you special. Special in a way that nobody wants to be special.

It's therefore unsurprising that few oncologists or immunologists are familiar with the disease. My dermatologist, who first noticed a lesion, had never seen the like. Oncologists have generally heard of it but those who know enough about it to provide insight and treatment are few and far between. Fortunately, for me, a friend of mine (Jeff Oxendine), through a friend of his, was able to connect me with a doctor at UCSF, Dr. Jerry Lee, who was one of those few, probably in the world, who could be called an expert on LCH. His first question was “how did you find me?”

Localized LCH that originates in the skin epidermis has a very high 5-year survival rate. But Langerhans cells, when in the dendritic mode, have a propensity to disperse beyond their native niche. The first step in my treatment was to determine if my cancer had originated in the skin, or was, rather, seeded from elsewhere. The elswheres include some significant organs, among them, lung, liver and brain. The ruling out of candidate sources involved PET scans MRIs and sonograms, all of which came up negative. But there was still one more possible source that remained to be ruled out, the pituitary gland, a pea sized structure at the base of the brain. The functional importance of the pituitary gland is out of proportion to its small size. My own postdoctoral research was related to one aspect of pituitary function, the regulation of sex the steroids, testosterone and estrogen.

But the role of the pituitary as an endocrine organ extends well beyond the regulation of sex steroids. It is often called the “master (endocrine) gland”. Other essential functions for which the pituitary is an apex regulator include, metabolism—through regulation of the thyroid gland, the stress response, through regulation of the adrenal glands, water levels through regulation of reabsorption in the kidneys, childbirth and lactation, through the release of oxytocin, which causes the uterus to contract and the mammary glands to release milk, respectively.

I wasn’t worried about the last two, but everything else was on the table.