In this discussion, we will go over the epidemiology, risk factors, pathophysiology, cancer nomenclature, staging, grading, treatment approach, and treatment goals of cancer.
Introduction to Cancer
Cancer is characterized by uncontrolled growth without any inhibition of abnormal cells. Cancerous cells also cannot perform the normal functions of regular cells. Over a period of replication without control, this leads to new growth (neoplasm) and death. This mass of abnormal tissues is referred to as a tumor.
There are two classes of tumors: benign and malignant.
Benign tumors are cancerous tissues enclosed in a fibrous shell. Due to this, they do not spread or metastasize to other areas of the body. Despite the lack of spreading, benign tumors can still cause problems in certain cases, which result in some dysfunction and symptoms. The biggest concern with benign tumors is that they may interfere with the surrounding tissues and impede the normal functions of the surrounding cells.
Malignant tumors are cancerous tissues that have the ability to invade other tissues either through the lymphatic system or the bloodstream. They are able to replace functioning cells with non-functioning cells. This leads to the death of the patients. The ability to spread to other areas of the body is referred to as metastasis.
History of Cancer Treatment
The oldest record is during the Ancient Egyptian time when fire drills were used to cauterize breasts.
In 1846, the first cancer surgery was performed to remove the tumor of the jaw.
In 1895, Beatson theorized that one organ could hold control over the secretion of another. He discovered that the removal of the ovary slows the growth of breast cancer. At the time, estrogen wasn’t discovered yet.
In 1909, Paul Ehrlich coined the term chemotherapy and used chemicals to treat syphilis (Salvarsan – a derivation of arsenic). He was searching for the “magic bullet,” which is the compound that killed only the target organism.
In 1946, Yale published a study that reported the use of nitrogen mustard in large tumor mass of the neck.
Cancer Epidemiology
According to the American Cancer Society, the incidence of cancer is on the rise, but the death rate is declining. This may be due to a reduction in smoking and advancement in medicine, leading to more early detection.
Despite this, there are still over 600,000 deaths due to cancer per year in the United States. 42% of which were avoidable.
The most common new cases are prostate and breast cancers, followed by lung and colon cancers. The most common cancer deaths are due to lung cancers, followed by prostate and breast cancers.
Cancer is the leading cause of death aside from cardiovascular-related deaths. About one in three individuals in the United States will develop cancer at some point in their lives.
About 80% of all cancers are diagnosed in those older than 55 years old. The prevalence is highest in non-hispanic blacks and non-hispanic whites. The mortality is highest in non-hispanic black.
Cancer Risk Factors
Cancer is multifactorial, and it can be very difficult to predict and control the risk factors.
There are known cancer-causing agents that cause cellular mutations, leading to cancer, but it is not certain what pushed these mutations to become cancerous. Nitrates are popular molecules included in many packaged meat that has been known to increase the risk of cancer. Poor diet is thought to be responsible for over 30-35% of cancers. Smoking and alcohol use has long been associated with cancers. These account for about 30% of cancers.
Genetics and hormones have been known to play a role in certain types of cancer as well as occupation exposure (2%) and environmental exposure (1%). Hormones are responsible for over 18-20% of cancer.
Long-term stress can also increase the risk of cancer over time. Medical factors, such as being immune-suppressed, increase the risk of cancer as well.
Lastly, some viruses, such as HPV and HIV, can create an opportunistic environment, allowing for cancer to occur more easily. Chronic infections from these viruses and other chronic inflammations account for about 18-20% of cancers.
Cancer Pathophysiology
The working theories behind the pathophysiology are the cellular change or mutation theories. Mutations can be a result of spontaneous errors, inherited mutations, or external agents.
Regardless of how mutations occur, the resulting changes are uniform in that they affect either the oncogenes or the tumor suppressors, leading to uncontrolled cell proliferation.
Oncogenes are genes that promote the formation of cancer cells. They are usually off. When they’re mutated, they become either constantly on, unregulated, or upregulated. Some of the common oncogenes that are mutated are the HER-2-Neu in breast and GI cancers, B-raf in melanoma, Bcr-Abl in leukemia, and EGFR in colon, head and neck, and lung cancers.
Tumor suppressors are genes that inhibit the formation of cancer cells. They are usually on. When they’re mutated, they become either constantly off or inactivated, thereby, allowing growth to occur unchecked. The most common tumor suppressor genes are p53 and BRCA. p53 is a transcription factor, and mutations in p53 may result in osteosarcoma. BRCA is a crucial player in DNA repair, and mutations in BRCA may result in breast or ovarian cancers.
Normally, tumor suppressors recognize errors or abnormal growth and work to fix the errors or push for apoptosis. In the case of cancer, there is either no DNA repair mechanism, lack of tumor suppressor, or the push for apoptosis fails. Over time, more mutations occur, leading to uncontrolled proliferation.
In malignancy, uncontrolled proliferation leads to a thickening of tissue, leading to dysplasia and affecting other surrounding tissues. After invading other areas, the cancerous cells become mixed with other tissues, and the tissues become indistinguishable. There are ways to reverse this process, but the further along the cancer is the harder it is. The malignant tumors will eventually metastasize into the basal lamina, and then into the capillary or lymphatic system. After this, the cancerous cells can be deposited at any other sites in the body. The most common sites are the liver, brain, and bone because the capillaries are very fine in these organs, making them easy spots for deposit.
In hematologic malignancies, there are three primary types of cancers: lymphatic leukemia, myelogenous leukemia, and myeloma. Lymphatic leukemias are leukemias that occur from the lymphoid stem cells and cells that differentiate from the lymphoid stem cell, such as T-cell and NK cells. Myelogenous leukemias are leukemias that occur from the myeloid stem cells and cells that differentiate from the myeloid stem cell, such as monocytes, eosinophils, neutrophils, platelets, and erythrocytes. Myelomas are the cancer of plasma cells, which technically differentiate from lymphoid stem cells.
Carcinoma in situ is a term used to describe cancer cells that have not metastasized to other areas yet but look abnormal under the microscope.
How Cancers Are Diagnosed
Many early detections occur during a routine screen or by chance. Without this, it can be hard to recognize cancer symptoms because symptoms can overlap with other illnesses. For example, bladder cancer symptoms may be mixed with UTI symptoms.
Imaging (CTI, MRI, ultrasound, or a scope) can be done to detect cancers. Most of the time, labs are not required, but in some cancers, labs can act as surrogate markers (not confirmatory markers like imaging).
A biopsy is needed to confirm the diagnosis. For solid tumors, fine needle aspiration, core needle biopsy, or open biopsy are typically done. For hematology malignancies, blood draw and bone marrow biopsy are typically performed.
In some cases, a PET scan or bone scan may be warranted. PET scans allow you to see areas of high metabolic activity.
Cancer Nomenclature
Cancer nomenclature can be confusing. Most malignant cancer names are derived from embryology.
- Carcinomas – cancers of the cells differentiated from the endoderm (the inner layer). This includes lung cells, thyroid cells, and pancreatic cells.
- Sarcomas – cancers of the cells differentiated from the mesoderm (the middle layer). This includes cardiac muscle, skeletal muscle, tubule cells of the kidney, smooth muscle in the gut, and all the leukemias (blood).
- Lymphomas – cancers of the lymphatic system
- Leukemias – cancers of the bone marrow
- Melanoma and Blastomas – cancers of the cells differentiated from the ectoderm (the outer layer). Blastomas are cancers of the neural tissues
Benign tumor nomenclature: Source prefix + “oma” (Fibroma)
Malignant tumor nomenclature: Source prefix + origins (Fibrosarcoma)
Staging Cancer
Staging the cancer is variable depending on practitioners and institutions. Solid tumors are generally staged using the TNM staging where T = tumor size (T1-T4), N = lymph node involvement (N1-N3), and M = malignancy or not (M0, M1). The higher the stage, the more advance the tumor.
For hematologic malignancies, since the “tumor” is already systemic, the staging is very different and is done based on lab, cell origin, and prognostic instead. The Rai or Binet staging is used for hematologic malignancies. The Rai staging has 5 different stages with stage 0 having the lowest risk with the highest mean survival, and stage 4 having the highest risk with the lowest median survival. The Binet staging has three stages: A, B, and C with A having the best prognosis and C having the worst prognosis.
Grading Cancer
Grading is different from staging. This is a pathological classification that is performed by looking at the biopsy.
The lower grade, the more differentiated the observed cells are. This means that these cells are more similar to the original tissues or the cell lines of origin. This is suggestive of a less aggressive cancer type.
The higher grade, the less differentiated the observed cells are. This means that these cells are more irregular. This is suggestive of a more aggressive cancer type.
Grading should only be used to determine the aggressiveness of cancer. An example of a grading scale is the Gleason score used in prostate cancer.
Treatment of Cancer
The most common curative treatment for solid tumors is surgery. Most solid tumors must be cut out to cure them. Typically, this is only seen in early-stage of cancers because once cancer spreads, it’s hard to cut all of the tissues out. Colon cancer may be a rare exception where a single-site incision of metastasis may be curative. During the surgery, we often see a removal of the sentinel lymph node as well. The sentinel lymph node is the first lymph node that lights up by the dye. If the dye doesn’t light up a lymph node, it usually means that cancer doesn’t have a lot of chance to metastasize.
The second common treatment for cancer is through radiation, which induces free radicals. This method is a delayed effect of 1-2 weeks after the start of the treatment. The downside of this treatment is the radiation must be passed through other tissues, which can cause adverse reactions. The severity of the reactions depends on the site and how much other tissues are exposed to the radiation. Typically, we see skin toxicity and skin breakdown. To minimize this, the radiation is hit from many different angles to minimize surrounding tissue exposure while maximizing the target organ exposure.
The third common treatment for cancer is systemic therapies. There are many methods of systemic therapies. Hormonal therapies have been used in the treatment of breast, ovarian, and prostate cancers. Cytotoxic chemotherapy is the use of chemicals to kill fast-growing or dividing cells and is used in many types of cancer. Targeted therapy involves agents like tyrosine kinase inhibitors and monoclonal antibodies, and is used for many types of cancers. Immunotherapy takes a different approach in trying to ramp up the immune system instead and is used often in the treatment of kidney cancer and melanoma.
Gompertzian Cell Growth demonstrated an increase in the doubling time and a decrease in growth fraction over time. This decrease is due to the increased blood supply demand as the tumor gets bigger. The cell kill hypothesis demonstrates the effect of chemotherapy where a zigzag downward trend can be observed as cancer cells are eradicated. Chemotherapy is given in cycles to allow the recovery of normal cells. The cycles are typically described as cycle X, day Y.
It is important to know the differences between dose intensity and dose density. Dose intensity describes the intensity of the chemotherapy dose, whether or not the patient receives a full dose or partial dose. Dose density is the timing of the dose where the higher dose frequency equates to a higher density.
Goals of Therapy
The goal of the therapy for most patients is curative. Usually, this would involve the use of combinations or cocktails of different agents. The benefit of duo or combination therapies is decreasing the likelihood of resistance.
For solid tumors, when chemotherapy is given before the surgery to shrink the tumor down for easier removal and less tissue removal, it is called neoadjuvant. When chemotherapy is given after the surgery for mopping up the tumors, it is called adjuvant.
For hematologic malignancies, reducing tumor burden is induction, adding a second regimen for greater effect is intensification, moping up is consolidation, and ensuring control of the cancer is maintenance.
The response rates range from cure (normal lifespan) to complete response (remove visual evidence of disease) to partial response (reduce disease burden) to stable disease (no growth) to progression (increase in size or new lesion).
Palliative cancer is considered in those individuals that cannot be cured. In these scenarios, chemotherapy is utilized to control or slow the progression of cancer. Radiation can be utilized to deliver spot radiation to help gain control of cancer.