Principles of Cancer

Chapter 13

 PRINCIPLES OF CANCER

Introduction

• When cells in some area of body duplicate without control, the excess of tissue that develops called tumor or neoplasm. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the stimuli. Tumors may be cancerous and sometime fatal, or they may be quite harmless. A cancerous growth is called as malignant tumor or malignancy and noncancerous growth is called as benign growth. The study of tumor is called oncology. 

Epidemiology

• With the exception rare cases, cancer may be caused by inherited genetic defects and certain viruses. Specific cause is unknown. Several risk factors are associated with development of cancer. All types of cancers are common, in that, the cancer cells are abnormal and multiply out of control. However, there are often great differences between different types of cancer.

For example:

• Some grow and spread more quickly than others.

• Some are easier to treat than others, particularly if diagnosed at an early stage. 

• Some have a better outlook (prognosis) than others. For some types of cancer there is a very good chance of being cured. For some types of cancer, the outlook is poor. The incidence of cancer and cancer types are influenced by many factors such as age, sex, race, local environmental factors, diet, and genetics. Some respond much better than others to chemotherapy, radiotherapy, or other treatments. 

Classification of Cancer

• [I] Classification by Site of Origin

• By primary site of origin, cancers may be of specific types like

• Breast cancer

• Lung cancer

• Prostate cancer

• Liver cancer

• Renal cell carcinoma (kidney cancer),

• Oral cancer

• Brain cancer etc.

• [II] Classification by Tissue Types Based on tissue types of cancers may be classified into six major categories:

• 1. Carcinoma: 

• This type of cancer originates from the epithelial layer of cells that form the lining of external parts of the body or the internal linings of organs within the body.

• 2. Sarcoma:

• These cancers originate in connective and supportive tissues including muscles, bones, cartilage and fat. Bone cancer is one of the sarcomas termed as osteosarcoma. It affects the young most commonly. Sarcomas appear like the tissue in which they grow.

• Myeloma: 

• These originate in the plasma cells of bone marrow. Plasma cells are capable of producing various antibodies in response to infections. Myeloma is a type of blood cancer.

• 4. Leukemia: 

• This group of cancers are grouped within blood cancers. These cancers affect the bone marrow which is the site for blood cell production. When cancerous, the bone marrow begins to produce excessive immature white blood cells that fail to perform their usual actions and the patient is often prone to infection. Types of leukemia include:

• Acute myelocytic leukemia (AML) 

• Chronic myelocytic leukemia (CML) 

• Acute lymphatic, lymphocytic, or lymphoblastic leukemia (ALL)

• Chronic lymphatic, lymphocytic, or lymphoblastic leukemia (CLL) 

• Polycythemia Vera or erythema 

• 5. Lymphoma:

• These are cancers of the lymphatic system. Unlike the leukemias, which affect the blood and are called “liquid cancers”, lymphomas are “solid cancers”. These may affect lymph nodes at specific sites like stomach, brain, intestines etc. These lymphomas are referred to as extranidal lymphomas.

• 6. Mixed types:

•  These have two or more components of the cancer. Some of the examples include mixed mesodermal tumor, carcinosarcoma, Aden squamous carcinoma and teratocarcinoma. Blastomas are another type that involves embryonic tissues.

• Central nervous system cancers:

• Cancers that begin in brain tissue or the spinal cord are known as central nervous system cancers. Primary brain tumors develop in the brain. If the tumor began in another part of the body but spread to the brain, it is called a secondary brain tumor or brain metastases. The most common type of brain tumor develops from glial cells and is called glioma. 

• [III] Classification by Grade Cancers can also be classified according to grade. The abnormality of the cells with respect to surrounding normal tissues determines the grade of the cancer. Increasing abnormality increases the grade, from 1–4. 

Types of Staging

• Staging is done when a person is first diagnosed, before any treatment is given. The main types of staging are: 

• Clinical staging:

• This is an estimate of the extent of the cancer based on results of physical exams, imaging tests (x-rays, CT scans etc.), and tumor biopsies. For some cancers, the results of other tests, such as blood tests, also used in staging.  

• Pathologic staging:

• If surgery is being done, surgeon can also determine the pathologic stage (also called the surgical stag of the cancer. The pathologic stage relies on the results of the exams and tests mentioned before, as well as what is learned about the cancer during surgery. Often this is surgery to remove the cancer and nearby lymph nodes, but sometimes surgery may be done to just look at how much cancer is in the body and take out tissue samples.

Classification by Stage

• Cancer staging consists of determining the level of severity of the disease by means of clinical and complementary diagnostic tests. The aim is to detect the presence of visible metastases. 

• The most commonly used method uses classification in terms of tumor size (T), the degree of regional spread or node involvement (N), and distant metastasis (M). This is called the TNM staging. The TNM staging system for solid tumors was developed by the Union for International Cancer Control (UICC) most commonly used in oncology.

• T stands for the original (primary) tumor.

• N stands for nodes. It tells whether the cancer has spread to the nearby ly nodes.

• M stands for metastasis. It tells whether the cancer has spread to distant parts of the body.

• The following chart illustrates the different types of cancer according to the tissue in which they originated. Neoplastic Cell Characteristics.

• When a malignant tumor has the same name as a benign tumor, the word carcinoma or sarcoma is added to the end of the name to specify that it is cancerous. There are exceptions: lymphoma and melanoma are always cancerous; the word “malignant” is often added to them.

The Genesis of a Cancer Cell 

• Uncontrolled proliferation

• Dedifferentiation and loss of function

• Invasiveness

• Metastasis.

Uncontrolled proliferation:

• Normal cell division and tissue growth occurs by regulatory processes, but proliferation of cancer cell is not controlled by these processes and leads to uncontrolled proliferation which varies from type to type. Some cells slowly multiply and few fast multiply.

Dedifferentiation and loss of function:

• The multiplication of normal cells in a tissue begins with division of the undifferentiated stem cells giving rise to daughter cells. These daughter cells eventually differentiate to become the mature cells of the relevant tissue by achieving specific and characteristic physical forms, physiologic functions and chemical properties and ready to perform their programmed functions. One of the main characteristics of cancer cells is that they dedifferentiate to varying degrees. In general, poorly differentiated cancers multiply faster and carry a worse prognosis than well differentiated cancers.

Invasiveness:

• Change in factor that regulate cell adhesion and motility (process of invading responsible for rapid spread of cancer to secondary site, marked by a tendency to spread especially into healthy tissue; “invasive cancer cells”).

Metastasis:

• Migration of primary tumors to another site through blood vessels or lymphatics results in formation of secondary tumor.  

Etiology

• Cancer is caused by changes (mutations) to the DNA within cells. While the underlying causes for tumor growth can vary, the process by which they grow is the same. Normally, cells in body will naturally refresh themselves by dividing. This allows for dead cells to be disposed off naturally.

• Some cancer causes remain unknown while other cancers may develop from more than one known cause. Some may be developmentally influenced by a person’s genetic makeup. Many patients develop cancer due to a combination of these factors.

Host factor:

• Host factors are intrinsic to individual patient and include age, sex, genetic factor, psychological factor, immune suppression and chronic tissue trauma. Few cancers found in children commonly originate from embryonic tissues.

Environmental and lifestyle factor:

• Environmental and lifestyle factors include geographic location, cigarette smoking, nutrition and occupation. Certain cancers are more prevalent in some geographic locations. 

Infection:

• Some germs (viruses and bacteria) are associated to certain cancers. hepatitis B and hepatitis C virus is usually related to hepatocellular carcinoma and have an increased risk of developing cancer of liver. Another example is the link between human papillomavirus (HPV) and cervical cancer. Most women who develop cervical cancer have been infected with a strain of HPV at some point in their life.

• Radiation: Exposure to radioactive materials and nuclear fallout can increase the risk of leukemia and other cancers. Too much sun exposure and sunburn (radiation from UVA and UVB) increased risk of developing skin cancer.

Genetic factors:

• Genetic mutation is inherited from parents. This type of mutation accounts for a small percentage of cancers. Most gene mutations occur after birth and are not inherited. A number of forces can cause gene mutations, such as smoking, radiation, viruses, cancer causing chemicals (carcinogens), obesity, hormones, chronic inflammation and a lack of exercise. 

Obscure defects:

• Racial predilections (American women have breast cancer more often than Japanese women; Japanese men have stomach cancer far more often than American men). However, genetic factors are less conspicuous and more difficult to identify. There is probably a complex inter relationship between heredity, susceptibility and environmental carcinogenic stimuli in the causation of a number of cancers.

Age:

• Older persons have a greater tendency to develop neoplasm from lack of effective control mechanisms. This is due to an accumulation of damage to cells over time. Also, body’s defenses and resistance against abnormal cells may become less good as become older. For example, the ability to repair damaged cells and immune systems which may destroy abnormal cell may become less efficient with age. 

Pathophysiology 

• The rate of local tumor growth is dependent on cell cycle time and rate of angiogenesis or development of blood vessels within the tumor. Epithelial cell origin tumors have shorter cell cycle and grow rapidly than connective tissue origin. Tumor cannot enlarge beyond 1 or 2 mm in diameter, however, unless it develops its own blood supply. Angiogenic cytokines that promote vessel growth are apparently secreted by tumor cells as well as by inflammatory cells, such as macrophages, which infiltrate the area.  

Invasion and Metastasis:

• Cancers typically invade tissues adjacent to the site of origin (primary site) and may metastasize to distant (secondary or metastatic) sites by mechanical or lymphatic or hematogenous (blood-born) spread.

• Generally, cells are held together in tissues by adhesion molecules (cadherins) is an important means of intercellular signaling. Cells that become detached are normally destroyed by apoptosis. During the process of neoplastic transformation, cancer cells may lose the ability to express these molecules, promoting detachment; other genetic alteration permits survival in the detached state. 

• Attachment and proliferation of cancer cells at metastatic sites depend on several factors. Usually, cancer cells in blood become trapped within the first capillary bed downstream of their point of entry into the circulation. Blood leaving most organs first enters the capillary beds of the lungs, the most common site of metastasis. Blood from the intestine first encounter the capillary beds of the liver, and this is the second most common metastatic site. Cancer metastasis cannot always be predicted on this basis.

Symptoms 

• Symptoms depend on the type and location of the tumor. For example, lung tumors may cause coughing, shortness of breath, or chest pain. Tumors of the colon can cause weight loss, diarrhea, constipation, iron deficiency anemia, and blood in the stool. Some tumors may not cause any symptoms. In certain tumors, such as pancreatic cancer, symptoms often do not start until the disease has reached an advanced stage.

• Depending on cell type, origin, location of trauma, condition of host includes:

• Malnutrition due to cytokines produced by tumor, obstruction of GIT, anorexia, depression. 

• Pain due to nerve injury related to radiation or chemotherapy. 

• Infection due to immunosuppressant (barrier break down by cancer). 

Cancer Diagnosis 

• Like the symptoms, the signs of tumors vary based on their site and type. Some tumors are obvious, such as skin cancer. However, most cancers cannot be seen during an exam because they are deep inside the body. When a tumor is found, a biopsy is performed to determine if the tumor is noncancerous (benign) or cancerous (malignant). Depending on the location of the tumor, the biopsy may be a simple procedure or a serious operation.

Physical exam:

• Areas of body for lumps that may indicate a tumor. Physical exam includes looking for abnormalities, such as changes in skin color or enlargement of an organ that may indicate the presence of cancer. A mass may be palpable or visible.

Radiographic techniques:

• The use of plain films (x-rays) computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scans, mammography, and ultrasonography (US) may be very helpful to detect the tumor type, presence and location of mass lesions which also aid in staging and determination of therapy.

Laboratory analyses:

• Laboratory tests, such as urine and blood tests, may help to identify abnormalities that can be caused by cancer. For instance, in people with leukemia, a common blood test called complete blood count (CBC) may reveal an unusual number of white blood cells. Tumor markers in serum such as carcinoembryonic antigen (CEA), α-fetoprotein (AFP), or human chorionic gonadotropin (HCG) can be performed.

Genetic Testing:

• Genetic markers include chromosomal alterations (translocations, deletions, duplication etc.); specific gene defects; single nucleotide polymorphisms, and gene rearrangements. Detection of specific genes (such as BRCA-1 for breast cancer) may suggest an increased risk for some malignancies. 

Tissue Biopsy and Surgery:

• Methods that sample small pieces of tissue (biopsy) from a particular site, often via endoscopic techniques (such as colonoscopy, upper endoscopy, or bronchoscopy) can often yield a specific diagnosis of malignancy. It is also helpful to determine the stage and grade of the neoplasm.

Autopsy:

• The autopsy serves as a means of quality assurance for clinical diagnostic methods, as a way of confirming diagnoses helpful in establishing risks for family members, as a means for gathering statistics for decision making about how to approach diagnosis and treatment of neoplasm and to provide material for future research. 

Treatment 

Surgery:

• The goal of surgery is to remove the cancer or as much of the cancer as possible. The outcome of surgery also must be acceptable to the patient in terms of quality-of-life issues such as disfigurement or dysfunction. 

Chemotherapy:

• Chemotherapy uses drugs to kill cancer cells. The ideal chemotherapeutic agent would preferentially target cancer cells, by virtue of their genetic makeup, increased blood flow, or high oxygen consumption, while sparing normal cells. 

Radiation therapy:

•  Radiation therapy uses high-powered energy beams, such as X-rays to kill cancer cells.

Stem cell transplant:

• Stem cell transplant is also known as bone marrow transplant. A stem cell transplant can use own stem cells or stem cells from a donor. 

Biological therapy:

• Biological therapy uses body’s immune system to fight cancer. Cancer can survive unchecked in body because immune system does not recognize it as an intruder. Biological therapy can help immune system “see” the cancer and attack it. Biologic response modifiers are agents that boost immune system activity or antagonize tumor growth through the biologic effects. These agents may be isolated from human blood, or they may be produced by recombinant DNA technology. It includes antibodies and cytokines such as interferons, interleukins, tumor necrosis factor and colony stimulating factors. Hormone therapy: 

• Some types of cancer are felled by body’s hormones. Examples include breast cancer and prostate cancer. Removing those hormones from the body or blocking their effects may cause the cancer cells to stop growing. Gene therapy: Modes of gene therapy under investigation include the use of synthetic nucleotide strands to bind defective segments of cellular DNA or mRNA. Such binding prevents production of proteins involved in the molecular mechanism of neoplastic transformation.

Targeted drug therapy:

•  Targeted drug treatment focuses on specific abnormalities within cancer cells that allow them to survive.

Prevention

• Many cancers can either be prevented or the risk of developing cancers can be markedly reduced by avoiding its potential causes, public information campaign through media and warning labels (cigarette, tobacco, alcohol and drug abuse). Risk of cancerous (malignant) tumors may be reduced by: • Eating a healthy diet. 

•  Exercising regularly. 

•  Limiting alcohol. 

•  Maintaining a healthy weight.

•  Minimizing exposure to radiation and toxic chemicals. 

•  Not smoking or chewing tobacco. 

•  Reducing sun exposure, especially if burn easily.