LESSON 1.2 WORKBOOK - Tufts University1.0+Workbook+Lesson+1.… · LESSON 1.2 WORKBOOK How has our...

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W o r k b o o kLesson 1.2

DEFINITIONS OF TERMS

For a complete list of defined terms, see the Glossary.

MC Questions:

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1. What treatment for tumors persisted for the longest time?

.a Surgery;

.b Bloodletting;

.c Herbal potions;

.d None of the above.

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Cancer in ancient times: an imbalance of humors?

While Hippocrates first named cancer, it has been described as far back as 2600 BC. The Egyptian physician Imhotep kept detailed records of many of his patients, commenting on one case - a woman with ‘swellings on the breast’ that her tumors could be “compared to the unripe hemat fruit, which is hard and cool to the touch’. Imhotep was not optimistic about possible treatments stating starkly: “There is none.” Even at that time, it was well understood to be a serious diagnosis.

The Greeks understanding of human physiology was strongly influenced by their preoccupation with engineering, particularly fluid dynamics. Hippocrates believed that the human body is composed of four major fluids, he called ‘humors’ each with characteristics of the four elements the Greeks had described:

■ Blood was thought to have characteristics of air.

■ Lymph was thought to have characteristics of water.

■ ‘Yellow bile’ was thought to have characteristics of fire.

■ ‘Black bile’ was thought to have characteristics of earth.

LESSON 1.2 WORKBOOKHow has our understanding of cancer changed over time?

Cancer has been recognized as a disease since ancient times, but how we have described it and sought to treat it has been influenced by the prevailing interpretation of how our physiology operates. This lesson describes the technical breakthroughs that shaped our understanding of cancer as a disease and shows how, surprisingly, old ideas have become new again.

http://sites.tufts.edu/greatdiseases/student/glossary/

LESSON READINGS

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Inflammation – the body’s immediate immune response to

infections. Typically produces redness, fever, and itchiness.

Pus – a yellowish-white fluid con-sisting of dead cells, live immune

cells, and debris.

Pustule – a swelling of tissue filled with pus. Can be located

anywhere on body.

Tubercule – Like a pustule, but more often in found in lungs.

Jaundice – yellowing of the skin, often associated with liver

disease.

MC Questions:

2. Which of the following humors was believed to be imbalanced in cancer?

.a Black Bile;

.b Blood;

.c Lymph;

.d Yellow Bile.

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3. Which of the following was a major achievement by Galen?

.a Accurate description of human anatomy;

.b Realizing that cancer had an actual cause;

.c Discovery of black bile;

.d All of the above.

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The Greeks believed that disease occurs when one humor is in excess over another. The forces influencing humor balance were unclear although highly likely to be supernatural. To the Greeks then, treating disease meant rebalancing the humors – for example by preventative blood-letting and using laxatives. The notion that a disease, like cancer, may have a specific physiological cause, simply did not fit into their world-view.

As time passed, and with the advent of Christianity, the notion that the Gods were responsible for disease became less persuasive. Galen of Pergamon, a 2nd century A.D. philosopher, surgeon, and physician felt that linking observable physiological symptoms to the humors would provide more scope for treatment.

■ He suggested that the redness and fever of inflammation were linked accumulation of blood.

■ He suggested that the pus in pustules and tubercules was linked to accumulation of lymph.

■ He suggested that the yellowing of skin in jaundice was linked to accumulation of yellow bile.

■ He suggested that the tumors found in cancer was linked to accumulation of black bile.

One obvious flaw in Galen’s idea was that no fluid ‘humor’ with characteristics of black bile has been detected in tumors (which are generally solid). While Galen considered cancer an incurable disease, as did Imhotep and Hippocrates before him, he nevertheless felt that tumors must have a natural cause and therefore should be preventable. His solution was to bleed the patient to the humors and prevent accumu-lation of the elusive black bile, which in turn should prevent tumors forming.

Galen’s theory of black bile dominated medicine for over a thousand years, effectively short circuiting rational study into disease and how they could be treated. This was particularly true for cancer, since the ‘black bile’ theory was already without basis. Lack of rational study didn’t prevent remedies being proposed (and used) however. Among the most notable included: boar’s tooth, fox lungs, rasped ivory, ground white-coral, hulled castor and tincture of lead.

Figure 1: Galen of Pergamon was the first person to describe a way to treat cancer.

LESSON READINGS

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MC Questions:

4. Why did Galen dominate the field of medicine for over a thousand years?

.a He offered the best explanation possible at the time;

.b Cultural taboos of handling corpses prevented learning about human anatomy;

.c Galen’s work was readily available;

.d All of the above.

5. Which of the following humors was Vesalius able to identify through his research? (Circle all correct.)

.a Black bile.

.b Blood.

.c Lymph.

.d Yellow Bile.

6. True or False: Breast tumors are a type of ‘moveable’ tumor.

.a True.

.b False.

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Moveable tumor – type of tumor described by John Hunter, now

known as a “solid” tumor. These tumors could be felt and moved

when touched.

Galen made a second contribution to the study of disease: a deep appreciation for the importance of understanding anatomy. In this he was thwarted by the cultural taboos around handling corpses that had persisted as a legacy of Roman times and that prevented him from working on human cadavers. He attempted to get around these proscriptions by vivisecting animals and his meticulous work persisted as the go-to studies in anatomy until the Renaissance, which ushered in a new ethos of understanding the world through empirical research and observation. Galen’s work began to be re-assessed.

Cancer moving forward: from humors to tumors

Andreas Vesalius seized the possibilities that arose when the taboos about human dissection finally crumbled. His seminal work, the seven-volume De humani corporis fabrica (On the fabric of the human body) published in the 16th century challenged Galen ‘drawing for drawing’ - clearly demonstrating the major differences between humans and the dogs Galen had drawn. This was the first book to provide a detailed road map of the human body, and Vesalius’s sketches of the circulatory system were quickly used to identify the sites that should be bled to squeeze humors out of afflicted areas. Vesalius succeeded in transforming preventative blood letting from an inefficient, ineffective treatment, to an efficient, ineffective treatment!

By mapping the circulatory and lymphatic systems Vesalius was able to pin down the physiological basis for blood and lymph. ‘Yellow bile’ he located in the liver. But despite his best efforts ‘black bile’ remained elusive. “If there is no black bile in the body” he wondered “How are tumors formed?”

This was clearly an unsolvable conundrum and interest moved away from how tumors form to what could be done about them. By the 1760s, dissections had become commonplace, and surgery was starting to be more successful. The Scottish surgeon John Hunter pioneered the surgical removal of ‘moveable’ tumors. These tumors, located just below the skin, were solid and moved when touched. The notion that solid tumors could be removed finally squelched the idea that they formed from accumulation of black bile. But if they weren’t made of humors, what were they made from?

Figure 2: Andreas Vesalius wrote a seminal work on human anatomy and was first to disprove the black bile theory of cancer.

LESSON READINGS

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MC Questions:

7. Which of the following did not cause a paradigm change in our understanding of cancer? (Circle all that apply)

.a Galen’s black bile theory.

.b John Hunter’s moveable tumor theory.

.c Van Leeuwenhoek’s discovery of cells.

.d Virchow’s cellular model of cancer.

8. If a tumor originated in the lung and then metastasized to the bone, what would the primary cancer be?

.a Lung cancer.

.b Bone cancer.

.c Both a & b.

.d None of the above.

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Primary tumor – the original organ in which a cancer is identi-

fied.

Secondary cancer – other organs in which a cancer forms after it has undergone metasta-

sis.

Recurrence – the return of cancer in either the primary organ

or secondary organs.

Radical surgery – the complete removal of an organ including

surrounding tissue that supports the organ in the effort to com-

pletely remove all cancer cells.

Antonie van Leeuwenhoek (who was the first to look down a microscope at a flea, as we saw in the Infectious Disease module) made the landmark discovery that our bodies are composed of billions of cells. While his idea also gained general acceptance during the 17th century, the logical connection between van Leeuwenhoek’s and Turner’s work – that solid tumors were also formed from cells – was not made until the 19th century, by Rudolph Virchow. In 1858, Virchow proposed that, “Omnis cellula e cellula” (Every cell originates from another cell) implying that tumors too were actually a large mass of cells that had originated from other cells but were now behaving abnormally.

Cancer now: from tumors back to humors?

The notion that tumors arise from the same cells that form the rest of the human body was a paradigm-shifting discovery. Far from being a supernatural phenomenon, Cancer had a solid physiological cause: These cells had become abnormal. Surely it was now a problem with a simple answer? If abnormal cells were the cause of cancer as a disease, then removing or killing the abnormal cancer cells should cure the disease.

By the 1800s, surgery had improved to the point that it could effectively remove many tumors. However, a sizeable percentage of people who had had their tumors removed would see their cancer recur. Surgeons assumed that the surgery had simply left some cancer cells behind. In 1882, William Halsted, a surgeon at Johns Hopkins Hospital introduced radical surgery for removing breast tumors. In this case the term “radical” comes from the Latin radix, radicalis, meaning “root”. Halstead wanted to root out every abnormal cell that could cause the tumors to recur.

Figure 3: Antoine van Leeuwenhoek proposed that our bodies were composed of 'cells', and not 'fluids', so cancers were cell-based.

Figure 4: Rudolph Virchow believed that cancer cells came from normal cells.

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LESSON READINGSMC Questions:

9. Which of the following paradigm changing descriptions of disease are relevant to cancer ? (Circle all correct.)

.a Galen’s black bile theory.

.b John Hunter’s moveable tumor theory.

.c Virchow’s cellular model.

.d Stephen Paget’s seed and fertile soil theory.

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10. True or false: The seed and fertile soil hypothesis attempts to explain why secondary cancers don’t appear in every organ.

.a True.

.b False.

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Metastasis – the spread of ma-lignant tumor cells to other parts of the body through blood/lymph

vessels. (noun)

Metastasize – the spreading of malignant tumor cells to other

parts of the body. (verb)

'Seed and fertile soil' theory – a theory by Stephen Paget that proposed that tumors only form

when they are in the appropriate environment for their growth.

Halsted felt that removing as much tissue as possible would solve the problem. He performed surgeries removing the entire breast, as well as chest muscles, and lymph nodes in the arm-pit. These radical surger-ies were extremely disfiguring to the extent that many women were left unable to stand upright because the muscles that controlled posture had been removed. These heroic efforts did indeed control recurrence at the primary site, however they failed to solve a second, even more insidious problem. In many cases when tumors recurred they appeared in secondary sites a distance from the primary tumor. Following breast removal secondary cancers in the lungs and bone were not unusual. Doctors and surgeons were flummoxed.

The British surgeon Campbell de Morgan, proposed the logical, but nonetheless provocative idea that once a tumor had formed in a primary organ it might acquire the ability to migrate to other tissues. The notion of cancer cells traveling in blood was not unknown – blood cancers were being studied. But de Morgan noticed that after solid tumors had been detected in a primary organ they were often also found in the lymph nodes surrounding the organ. This migration of the tumors was described as 'metastasis', from the Greek for “next place”.

Primary tumors seemed to have distinct preferences for where they migrate to. The surgeon Stephen Paget proposed the theory that the abnormal cells in tumors can act like ‘seeds’ and seek ‘fertile soil’. Not all organs are fertile soil for each tumor. Paget’s ‘seed and fertile soil’ theory was revived as a basis for study in the 1980s, when the importance of metastasis in cancer mortality was finally appreciated.

Our evolving understanding of physiology has driven how we have thought about. We once thought our body is a system of fluids, and we now realize it is a community of cells. We once thought cancer was a judgment of the Gods, now we know it comes down to cells behaving in anti-socially. But we can also argue that our understanding of cancer has come full circle – from humor to tumor and now back to humor — even if it's the circulatory and lymph systems rather than black bile.

Figure 5: Radical surgery of the breast removes the entire breast, muscle, and lymph nodes in the arm pit.

STUDENT RESPONSES

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Remember to identify your sources

Give two examples of how the black bile hypothesis is similar to our current understanding of cancer as a disease, and two examples of how the black bile hypothesis is different.

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TERMS

For a complete list of defined terms, see the Glossary.

TERM DEFINITION

Inflammation The body’s immediate immune response to infections. Typically produces redness, fever, and itchiness.

Jaundice Yellowing of the skin, often associated with liver disease.

Metastasis The spread of malignant tumor cells to other parts of the body through blood/lymph vessels. (noun)

Metastasize The spreading of malignant tumor cells to other parts of the body. (verb)

Moveable tumor Type of tumor described by John Hunter, now known as a ‘solid’ tumor. These tumors could be felt and moved when touched.

Primary cancer The original organ in which a cancer is identified.

Pus A yellowish-white fluid consisting of dead cells, live immune cells, and debris.

Pustule A swelling of tissue filled with pus. Can be located anywhere on body.

Radical surgery The complete removal of an organ including surrounding tissue that supports the organ in the effort to completely remove all cancer cells.

Recurrence The return of cancer in either the primary organ or secondary organs.

Secondary cancer Other organs in which a cancer forms after it has undergone metastasis.

'Seed and fertile soil' theory

A theory by Stephen Paget proposing that tumors only form when they are in the appropriate environment for their growth.

Tubercule A swelling of tissue filled with immune cells. Like a pustule, but more often in found in lungs.

http://sites.tufts.edu/greatdiseases/student/glossary/

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