I. INTRODUCTION

In 1850, 1 out of 200 people died of cancer. In 1997, cancer was the cause of 1 out of 4 to 5 deaths. Does this increase mean that we are now in the midst of a cancer epidemic? No! It simply reflects the fact that people now live longer. In 1850, people commonly died of infectious diseases and accidents at a relatively early age.

There has been a dramatic rise in the incidence of lung cancer since 1940. Prior to this time, lung cancer was quite a rare disease. This rise is due to smoking of cigarettes, which became fashionable around the time of World War I. The number of deaths due to lung cancer is now leveling off or even falling for men, but it is still rising for women. This delayed increase reflects the fact that smoking became popular among women later than it did for men. Incidence of lung cancer in women began to rise only in the 1960’s. The number of deaths from lung cancer in women now surpasses the number due to breast cancer, although the incidence of breast cancer is much higher.

The incidence of stomach cancer in the US is decreasing for both men and women. One explanation that has been proposed is that refrigeration produces fewer carcinogens than less modern methods of food preservation, such as smoking. There has also been a decrease in deaths from uterine cancer due to widespread use of the Pap smear for screening.

The most common cancer for both men and women is skin cancer. However, skin cancers rarely lead to death. The exception is melanoma, which is the rarest of the skin cancers. However, melanoma is undergoing a marked increase in incidence, perhaps because more people live in sunny climates, and people tend to spend more time exposed to the sun. Sun exposure in the early years of life is a big risk factor for melanoma. The incidence is high in Australia, where exposure to the sun is great for many people.  The cancers that most frequently cause death are those of colon, prostate, breast, and lung.

II. DEFINITION

The term cancer is a general one that refers to any malignant tumor. The term carcinoma refers specifically to cancers arising from epithelial cells.

A good definition of cancer is that it is a new growth that is purposeless and uncontrolled. Feedback mechanisms that ordinarily operate to control the growth of cells are not operational in cancers.

Some growths are excessive and purposeless but not out of control. Therefore, these growths are not considered cancers. Examples include keloids (excessive formation of scar tissue) and goiter (enlargement of the thyroid, apparently purposeless, but not without limit – growth eventually stops). In a cancer, there is no control; the cells just keep on growing.

Remember from your first lecture that cells can also increase in number (hyperplasia) or size (hypertrophy) to adapt to unfavorable conditions. However, these changes are under control and have a purpose. Examples of hypertrophy include enlargement of skeletal muscle cells in weight lifters and enlargement of cardiac muscle in people with heart failure. Examples of hyperplasia include polycythemia (increase in number of red blood cells) in people who live at high altitude and goiter (enlargement of the thyroid) in people who have a deficiency in dietary iodine.

In contrast, there is a partial loss of control in dysplasia. Dysplastic cells have microscopic abnormalities; their differentiation and maturation are not normal. Thus, there are organizational changes, and there may be some increase in cell number as well. Often, dysplasia is partly or completely reversible if whatever caused it (e.g., an irritant) is removed. High grade dysplasia refers to more severe changes that involve a greater percentage of the tissue in question.

In metaplasia, one type of mature, differentiated cell is replaced by another. Note that the differentiated cells themselves do not change to a different type. Rather, there are undifferentiated, immature stem cells present in many tissues. In metaplasia, these stem cells differentiate along a pathway other than the usual one. This new type of differentiated cell gradually replaces what is normally present. Metaplasia initially is an adaptive, protective response, and it is usually reversible. There is still a regular organization of the cells, BUT metaplasia is often a step along the road to cancer. Examples of metaplasia include replacement of columnar epithelium by squamous epithelium in the respiratory tract of smokers and replacement of squamous epithelium with columnar epithelium in the esophagus of patients with reflux. Metaplasia can also occur in the cervical epithelium due to irritation or infection.

Normal tissue can progress directly to neoplasia (tumor), but it can also progress from metaplasia to dysplasia to neoplasia or from dysplasia to neoplasia. Tumors of supporting structures (connective tissue, bone, fat, vasculature) usually do not go through a dysplastic step. Likewise, malignant melanoma does not always arise from a change in a pre-existing mole. Obviously, there is less chance for early detection if there is no dysplastic stage. The term neoplasm literally means "new growth" and refers to any tumor, whether benign or malignant. Neoplasia means that there is abnormal differentiation of cells, a marked increase in cell number, and a complete loss of growth control. The degrees to which organization is lost and cytological abnormalities are seen are variable. The more a tumor looks like the normal cells from which it arose, the better differentiated it is. Poorly differentiated tumor cells are termed anaplastic. A highly anaplastic appearance usually indicates that a tumor is malignant and aggressive.

Malignant tumors are distinguished from benign ones by their ability to infiltrate into surrounding tissues and form distant metastases. Benign tumors may push on adjacent structures, but they do not infiltrate and invade. Malignant tumors tend to have an irregular, "crab-like" shape (which is the origin of the term cancer) and usually have more cytological abnormalities than benign tumors. Benign tumors tend to be more uniform in shape and to have a sharp demarcation from surrounding tissues. However, even benign tumors can kill if they are located in a critical place (e.g., the heart, the confined space of the skull). On the other hand, some malignant tumors may have an extremely slow course of development, even if they metastasize. One example of a slowly progressing malignant tumor is papillary carcinoma of the thyroid.

Carcinoma in situ refers to a neoplasm of epithelial origin. It has many features of cancer, but it has not yet breached the basement membrane that underlies the epithelium of origin. Therefore, it cannot yet metastasize through the blood or lymph. This term can only apply to tumors of epithelial surfaces. The most common tumors (lung, breast, colon) arise from epithelial surfaces. This is due to the fact that these epithelial surfaces are exposed to carcinogens in the external environment (although breast is an obvious exception). Also, epithelial cells are constantly replicating, which, as we shall see, is a risk factor for development of cancer.

III. NOMENCLATURE

Tumors are classified according to the tissue from which they arose and whether they are malignant or benign. Benign tumors arising from squamous epithelium are called papillomas; those that arise from glandular or ductal epithelium are called adenomas. Malignant tumors arising from epithelium are called carcinomas. Benign tumors arising from mesenchymal tissue are named according to the specific type of tissue with the suffix "-oma" attached. Examples are angioma (a benign tumor of blood vessels), lipoma (a benign tumor of fat cells), chondroma (a benign tumor of cartilage), and osteoma (a benign tumor of bone). Malignant tumors of mesenchymal tissue are named similarly, but with the suffix "-sarcoma," e.g., angiosarcoma, liposarcoma, chondrosarcoma, and osteosarcoma. Warning: There are exceptions to this otherwise logical scheme. Lymphomas are malignant tumors of lymphocytes, although the name would imply that they are benign. Likewise, hepatoma, mesothelioma, and melanoma are malignant tumors of the liver, lining of the chest cavity, and melanocytes in the skin, respectively.

Also note that there can be different types of cancers within a single organ. For example, there are several types of lung cancers arising from different types of cells. Oat cell carcinoma (also known as small-cell carcinoma) is very aggressive. The most slowly growing lung cancer is adenocarcinoma. There are also lung squamous cell carcinomas and undifferentiated large-cell carcinomas.

IV. GRADING AND STAGING

The grade of a tumor refers to how similar or dissimilar to the parent tissue it appears when examined microscopically. Grade is important for determining therapy, as high grade tumors in general are more aggressive than those of lower grade. However, there are exceptions: oat cell carcinomas of the lung do not always appear to be of high grade, but the prognosis is very bad.

The stage of a tumor refers to its size and how far it has spread. The "TNM" classification system is often used for staging. "T" refers to the size of the tumor, "N" to spread to regional lymph nodes (how many and how distant), and "M" to the presence of distant metastases. Both staging and grading are important for determining prognosis and treatment.

Tumor cells can spread to distant sites (metastasize) by several different means. They can travel into lymph nodes in the region, which is very common, particularly with carcinomas. They can gain access to blood vessels, especially veins, and spread through the blood. Often, blood-borne tumor cells end up in the lung, because that is where venous blood goes. Either carcinomas or sarcomas can metastasize through the blood. Lastly, tumor cells can break off and "seed" onto surfaces lining body cavities. Examples include spread of lung carcinomas to the pleura and ovarian carcinoma spreading throughout the pelvic cavity. Generally, cells from tumors tend not to implant on other epithelial surfaces, but rather seed onto mesothelial surfaces.

Often, patterns of metastasis are predictable. For example, breast carcinomas usually spread first to the axillary lymph nodes. Colon carcinoma tends to spread to regional lymph nodes and then to the liver through the portal circulation. A sarcoma in the leg often metastasizes through the venous circulation to the lung. Some of these patterns are clearly based on vascular drainage, but there is also selective metastasis. Some lung adenocarcinomas tend to metastasize preferentially to the brain. The tumor cells probably spread to many places, but they find favorable conditions for their growth only in the brain.

V. CHARACTERISTICS OF TUMOR CELLS

The adult body is composed of three classes of cells: 1) cells that never divide (e.g., neurons, muscle cells); 2) cells that will divide if stimulated (e.g., liver cells); and 3) cells that are constantly dying and being replaced in the normal course of events (e.g., linings of lung, gut, breast ducts, prostate, blood). These latter cells are at the highest risk for being "transformed" into a malignant state, since every cell division is a chance for a mistake that affects growth control to occur. In your body, cells are dividing at the rate of 2 x 10⁶ per second, or 25 x 10¹² per day! Tumors of the heart and skeletal muscle are very rare, because these cells do not divide. Tumors of the bone usually occur in children, because their bone cells are still dividing.

The cell cycle is divided into different phases. Cells make the decision whether or not to divide in the so-called G1 phase of the cell cycle. Tumors arise when a cell continues to divide when it should not, leading to continuous and out-of-control cell division.

Most tumors are clonal, meaning that they are derived from a single cell. A single cell that has lost its normal growth regulatory mechanisms can kill you! Specific genetic markers have been used to experimentally demonstrate the clonal nature of tumors.

Tumor cells behave differently from normal cells when they are grown in the laboratory. Normal cells form a single layer of cells (monolayer) that stops growing when the cells contact one another (contact inhibition). Tumor cells will continue to divide and pile up on one another. They also are immortalized, meaning that they can be cultured in the laboratory indefinitely; normal cells have a finite life-span in culture. Normal cells need to be attached to a surface to grow in culture; tumor cells do not require attachment.

Many malignant tumor cells have chromosomal abnormalities. The first example to be discovered is the so-called Philadelphia chromosome, which is found in chronic myelogenous leukemia cells. Not every abnormal chromosome causes a tumor, but most tumors probably have a genetic or chromosomal abnormality. These chromosomal abnormalities may cause deletion of genes that are important in growth control or they may cause rearrangement of genes, so that expression of crucial genes is no longer properly controlled. It is presumed that these chromosomal abnormalities cause formation of tumors, but it is possible that they result from the abnormal differentiation and growth of the cells.

Tumors must be nourished. Tumors secrete substances that cause the ingrowth of new vessels (a process called angiogenesis) to ensure a good supply of blood and nutrients. Recently, there has been a lot in the news about treatment of tumors with drugs that block angiogenesis and thus starve the tumors. (Editorial note: clinical trials of some of these anti-angiogenic agents are scheduled to begin by the end of 1998.)

Some tumors display specific antigens on the surfaces of their cells. These antigens may be ones that are normally seen only in the fetus, while others may be seen in the adult but are present on the tumor cells in increased amounts. Blood tests have been developed to detect some of these antigens (e.g., prostate-specific antigen or PSA; carcinoembryonic antigen or CEA; a-fetoprotein). For the most part, these have not turned out to be very useful for screening purposes, although they may be of help in following the success of therapy. These antigens themselves may have therapeutic potential, since antibodies directed against them would theoretically kill tumor cells more specifically than current chemotherapeutic agents.

In paraneoplastic or paraendocrine syndromes, tumors inappropriately produce hormones that affect blood chemistry, metabolism, etc. For example, some lung cancers can cause enlargement of the breasts in men. This situation can arise because all genetic information is present in every cell. Normally, expression of many genes is suppressed in any particular cell. However, in tumor cells, inappropriate genes can be turned on again inappropriately.

VI. CAUSES OF CANCER

A. How carcinogens are identified

One way to uncover causes of cancer is through epidemiological studies. Such studies can be retrospective (looking back into the past), prospective (in which subjects are followed over time), or sporadic (which is not usually very useful).

There are many problems inherent in carrying out good epidemiological studies to determine causes of cancer. These include:

• Difficulty of finding appropriate control subjects
• Difficulty of controlling for variables like age
• Presence of complicating co-factors, e.g., smoking
• Long latent periods between cause and development of disease (there may be decades between exposure and appearance of tumor)
• Lack of specific endpoints, meaning most types of tumors have more than one cause. A notable exception is mesothelioma, a malignant (despite its name) tumor that is almost always caused by exposure to asbestos. But smoking can cause tumors in the bladder (because carcinogens are secreted in the urine) as well as in the lung, and not all lung tumors are due to smoking.
• "Healthy worker effect": surveys in the workplace may miss the sick population because they are no longer working.
• Intercurrent death: subjects might have developed cancer but die of some other cause first.

Although "clusters" of cancer cases frequently make the news, these clusters often turn out to be not so unlikely on a statistical basis. Usually, these clusters are not very useful for identifying causes of cancer.

Some cancers show particular geographical distributions that give clues to their causation. For example, there is a high incidence of stomach cancer in Japan. When Japanese people move to the US, the incidence decreases. This points to a dietary or environmental cause. Conversely, women in Japan have a relatively low incidence ot breast cancer, which increases when they move to the US.  Burkitt’s lymphoma, which occurs mainly in Africa, has been found to be caused by virus (Epstein-Barr Virus, which is also linked to nasopharyngeal cancers in the Orient).

Testing of potentially carcinogenic substances in animals usually just confirms what we already know from epidemiological studies in humans. Only one or two substances were first shown to be carcinogenic in animals. Animal studies have many limitations:

• They confirm known carcinogens but rarely predict new ones.
• Different species may react in different ways. A lot of chemicals are not toxic until they are metabolized, and animals and men do not have identical metabolic pathways.
• Animals can develop tumors spontaneously, which complicates analysis.
• The short life span of animals means that unrealistically high doses of suspected carcinogens must be given to produce effects. (However, it is not true that if you give enough of anything to a mouse, it will get a tumor.)
• There is lack of important cofactors (e.g., most mice don’t smoke!)
• There is a relatively high rate of false negatives (~10%), which may reflect the different responses of different species.

Another screening test for carcinogens is the Ames test. In the Ames test, substances are screened to see if they cause mutations in bacteria. The test assumes that all carcinogens are also mutagens (i.e., cause genetic damage). But the opposite is not always true, i.e., not all mutagens are carcinogens. The test also ignores many important factors, including route of exposure, distribution of substances in the body, metabolic activation and deactivation of substances, and co-factors. Note that bacteria do not get tumors!

Often, it is possible to predict whether a given substance is carcinogenic based on its chemical structure. If it shares many structural features with known carcinogens, it may well also be a carcinogen.

It is not known whether there is a "safe dose" of carcinogens, that is, a threshold below which a given factor will not cause cancer. However, if a carcinogen is reduced to a low enough level, the latent period between exposure and disease will probably be so long that the level can be considered safe.

B. Specific carcinogens

Carcinogens can be physical, chemical, hormonal, or viral in nature.

1. Physical causes of cancer include :

• Ionizing radiation: can cause many types of tumors, e.g., leukemia, breast cancer
• Ultraviolet light: exposure to sunlight damages DNA. Normally, the body repairs this damage, but sometimes the repair mechanism fails and tumors result. People suffering from xeroderma pigmentosum have a genetic deficiency in the DNA repair mechanism and get skin cancers in childhood unless they are rigorously shielded from exposure to the sun.
• Electromagnetic radiation: has received a lot of attention as a cause of cancer, but the risks of exposure remain unknown.

2. Chemicals and hormones

The first chemical, occupational carcinogen was described by Sir Percival Pott in 1775. In England, small boys were commonly employed to clean chimneys. Personal hygiene was not what it is today, and soot would accumulate in the scrotal area of these boys, leading to carcinomas of the skin of the scrotum.

It has been estimated that 30% of cancers are due to tobacco and 35% to diet. Another 15% may be due to preventable exposure to environmental factors. In all, some 80% of cancers may be due to life style and are therefore potentially preventable.

Some medical drugs may cause cancers. Sometimes chemotherapy will lead to another tumor, as can radiation therapy. Diethylstilbestrol (DES) used to be given to pregnant women to prevent miscarriage. Daughters of these women are at increased risk for developing vaginal clear cell carcinoma. Whether estrogen replacement therapy leads to increased risk of developing certain cancers is a matter of controversy. 

Some naturally occurring substances may be carcinogenic. Some fungi produce substances called aflatoxins. Aflatoxins may be carcinogenic, although whether they are harmful to humans is an unresolved question. Aflatoxins have been found in foods such as peanut butter.

3. Viruses

It has long been known that viruses cause tumors in animals. More recently, their involvement in human cancers also has been confirmed.

Viruses associated with tumors:

• Hepatitis B virus: infection may lead to hepatocellular carcinoma.

• Human papillomavirus: Some types cause common warts, which can be considered to be benign tumors. Other types have been associated with cancers: HPV is the cause of most or all cervical carcinomas.

• Epstein Barr virus: In the US, EBV usually causes infectious mononucleosis, but it has rarely been associated with nasopharyngeal cancers. Nasopharyngeal cancers associated with EBV are more common in the Orient, and EBV is associated with the childhood cancer called Burkitt’s lymphoma in Africa.

• Human T cell leukemia virus: relatively rare in the US.

The first three of these viruses have DNA genomes, whereas HTLV is an RNA virus (retrovirus). The DNA genome of DNA viruses can directly incorporate into the host cell genome, where it can cause transformation (malignant changes). RNA viruses have an enzyme called reverse transcriptase that makes DNA from viral RNA. This DNA can then incorporate into the host cell’s genetic material and cause transformation. Many transforming viruses have genetic material that is similar to that of their host cells. It is thought that they may have acquired these genes from the host cells during their evolution. When these genes are reintroduced back into the host cells in the wrong place, proper control mechanisms may not operate. The genes may then be expressed in an unregulated fashion, leading to transformation.

C. Oncogenes and tumor suppressor genes

Genes that promote tumor formation when unregulated are called oncogenes. Oncogenes can be introduced by viruses or can be present in our own cells. The normal cellular forms of oncogenes are called proto-oncogenes. These proto-oncogenes are necessary for the normal growth of cells. Control of growth can be lost if a proto-oncogene is mutated so that its gene product functions in an inappropriate manner or if its product is made in excessive amounts. Oncogenes are usually given three-letter names, e.g., myc, erb, ras.

Other genes important in tumor formation are called tumor suppressor genes. An example is p53, a gene that is a "master control switch" regulating cell division. When p53 becomes mutated and fails to exert proper control, unregulated growth of the cell may lead to a tumor. Mutations in genes such as p53 may explain why some cancers tend to run in families. Another tumor suppressor gene is involved in retinoblastoma, a tumor of the eye that usually occurs in children. Children who develop retinoblastoma usually inherit a defective copy of the retinoblastoma gene from one of their parents. If a mutation occurs that destroys the function of their remaining normal retinoblastoma gene, the disease will develop. In addition to this inherited form of the disease, there is also a "sporadic" form that strikes at random. The sporadic form is rarer, since it requires that mutations occur in both copies of an individual’s retinoblastoma gene. In the inherited form, one copy is already defective. Therefore, only one random mutation (in the remaining copy of the gene) needs to occur to cause disease. In the hereditary form, note that children are not born with the tumor; they are born with an increased risk of developing it.

It may be useful to think of the growth of cells being controlled by "on" switches (proto-oncogenes) and "off" switches (tumor suppressor genes). Tumors can result from either acquisition of new on switches (oncogenes) or loss of needed off switches. Normal growth of cells results from a balanced interplay between substances that promote proliferation (the products of proto-oncogenes) and those that suppress it (the products of tumor suppressor genes). The balance may be thrown off (by carcinogens and/or genetic predisposition) when oncogenes that promote excessive growth are activated or when tumor suppressor genes that inhibit growth are destroyed. In either case, a tumor could result. Remember that tumors are clonal – only one cell needs to be thrown out of whack for a tumor to arise.

It is thought that progression of tumors is step-wise and involves more than one change in the cell (the so-called multi-hit hypothesis). A normal cell is first altered in a process called initiation. This apparently (but not truly) normal cell is then transformed into a neoplastic cell in a process termed promotion.  Luckily, we have built-in protective mechanisms that can be overcome only by repeated exposures to carcinogenic agents or by a single exposure to a very strong insult (such as massive radiation).

VII. MISCELLANEOUS ISSUES

Early detection has proven useful for a limited number of cancers. Use of the Pap smear to screen for cervical carcinomas is the biggest success story, and mammography also appears beneficial. It is not yet know whether routine use of colonoscopy will improve the outcome for colon cancer. For some tumors, however, by the time they are detectable, it is already too late. A good example is lung cancer. When a lung tumor is seen by sputum analysis or X-ray, the ultimate outcome is already inevitable. The patient is just aware of his or her death sentence sooner.

Another issue is that patients may find the number of options for treatment of tumors overwhelming. This is especially true for breast cancer.