6010 Modules 13 & 14 Study Guide PDF

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N6010 MODULES 13 & 14 (LAST ONE YAY) Molly, Caroline, Allie, Julia, Cliff

Pathology of Cancer INTRODUCTION 1) Identify the most prevalent cancer found in men, women, and children.

MALES ● Prostate cancer (21%), ● lung (13%) ● colorectal (9%) cancers FEMALES ● breast (30%), ● lung (12%), ● Colorectal and rectum (8%) CHILDREN ● Brain and other nervous system tumors ● Leukemia ● fast growing and have metastasized before a diagnosis is made ● Boys are affected more than girls. Cancer Terminology ●

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Tumor ○ Any abnormal mass in or on a part of the body. The term is usually applied to an abnormal growth of tissue, which may be benign or malignant. Cancer ○ Diseases in which abnormal cells divide without control and are able to invade other tissues ○ Not just one disease but many diseases

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Over 100 different types of cancer

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Identify naming classification and nomenclature based on which type of cancers arise from which types of tissues.

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Malignant tumors & benign tumors are named according to the tissues from which they arise. Such as a lipoma, which would be a fatty tumor, ○ malignant name would be a liposarcoma; and leiomyoma versus and leiomyosarcoma. And then adenoma versus adenocarcinoma ○ ● ○ Tumor Grading ■ Measure of a tumors appearance and architectural structure ■ Grade 1: ● Tumor cells and tissue looks most like healthy cells and tissue. These are called welldifferentiated tumors and are considered low grade. ■ Grade 2: ● The cells and tissue are somewhat abnormal and are called moderately differentiated. These are intermediate grade tumors. ■ Grade 3: ● Cancer cells and tissue look very abnormal. These cancers are considered poorly differentiated, since they no longer have an architectural structure or pattern. Grade 3 tumors are considered high grade. ■ Grade 4:

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These undifferentiated cancers have the most abnormal looking cells. These are the highest grade and typically grow and spread faster than lower grade tumors. ■ There are unique grading systems for certain types of cancers including: ● Nottingham grading system (breast) ● Gleason grading system (prostate) ● Fuhrman grading system (kidney) Solid Tumor Staging ○ Involves the size of the tumor, degree to which it has invaded, and the extent to which it has spread (varies by organ site) ○ Stage 1 ■ Confined to its organ of origin ○ Stage 2 ■ Locally invasive ○ Stage 3 ■ Regional structures ○ Stage 4 ■ Distant sites ○ Specific cancer staging systems ■ World Health Organization (WHO) ■ American Joint Committee on Cancer (AJCC)

3)

Examine cell differentiation.

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Cancer cells are immortal ○ Their lifespan is not limited to a certain number of divisions and they will continue to replicate and survive if they have access to enough nutrients. Contact inhibition ○ a process of where cell growth stops as cells come in contact with each other and this occurs in normal cells. Contact inhibition is a powerful anticancer mechanism that is lost in cancer cells and leads to uncontrolled proliferation and solid tumor formation While normal cells “stay put”, cancer cells break apart and migrate or metastasize to distant locations in the body. Cancer cells continue to create blood supply to get nutrients. With advanced cancer the cells become more differentiated and less like the mother cell.

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4)

Examine differences between malignant and benign tumor. ○

Malignant tumors ■ Carcinoma ● Begins in the skin or in tissues that line or cover internal organs (epithelial tumors) ○ Adenocarcinoma ○ Basal cell carcinoma ○ Transitional cell carcinoma ■ Sarcoma ● Begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue ○ Chondrosarcoma-bladder cancer ○ Osteosarcoma- typically primary bone tumors. ■ Carcinoma in situ (CIS)

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Pre-invasive epithelial malignant tumors of glandular or squamous cell origin that have not broken through the basement membrane or invaded the surrounding stroma Often seen in the cervix, skin, oral cavity, esophagus, bronchus, stomach, breast, and endometrium Three things can happen to carcinoma in situ tumor: ○ Can remain stable for a long time. ○ Can progress to invasive and metastatic cancers. ○ Can regress and disappear.

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Benign tumors ○ Named according to the tissues from which they arise, often include the suffix “-oma” ■ Lipoma (vs. liposarcoma) ■ Leiomyoma (vs. leiomyosarcoma) ■ Adenoma (vs. adenocarcinoma) ○ Note: “-oma” can also be malignant

5)

Examine characteristics of cancerous cells including cell size, shape and arrangement.

See chart below

6) Identify general solid tumor staging (Do not memorize WHO TNM system shown in lecture handout). This is a general format for staging solid tumors. However, each type of cancer (breast, lung, etc.) has its own unique and specific method of staging where the overall stage of the tumor (stage I through IV) is determined by the combination of T, N, and M descriptors: Solid tumor staging: Involves the size of the tumor, degree to which it has invaded, and the extent to which it has spread (varies by organ site) Stage 1: Confined to organ of origin Stage 2: Locally invasive Stage 3: Regional Stage 4: Distant Sites In the TNM system: T: Size and extent of the main tumor. The main tumor is usually called the primary tumor. N: Number of nearby lymph nodes that have cancer. M: Whether the cancer has metastasized. BIOLOGY OF CANCER CELLS 1) Examine the concept of apoptosis. The total number of cells composing the human body is determined not only by the rate of proliferation of cells but also by the rate of cell loss. Excess cells, and those that are aged or have sustained damage that impairs normal functioning, are eliminated to prevent accumulation of abnormal numbers of cells. The mechanism for regulating the removal of excess and impaired cells is known as apoptosis. Also referred to as cell suicide or programmed cell death, apoptosis is an orderly process during which internal cellular structures are progressively dismantled, the impaired cell shrinks and then is destroyed. The loss of apoptotic control allows cancer cells to survive longer and gives more time for the accumulation of mutations which can increase invasiveness during tumor progression, stimulate angiogenesis, deregulate cell proliferation and interfere with differentiation. 2)

Examine concept of chromosome translocation as it refers to gene mutation to oncogenes.

Chromosome translocations are large changes in chromosome structure in which a piece of one chromosome is translocated to another chromosome. Translocations can activate oncogenes in one of two distinct mechanisms. First, a translocation can cause excess and inappropriate production of a proliferation factor (ex Burkitt Lymphoma). Second, chromosome translocations can lead to production of novel proteins with growth promoting properties. Chromosomal translocations are considered as the primary cause for many cancers For example, The Philadelphia chromosome is found in more than 90 percent of patients with chronic myelogenous leukemia. The translocation involves the fusion of a proto-oncogene called c-ABL, which is located on chromosome 9, to a site on chromosome 22 known as a breakpoint cluster region (BCR). BCR and the c-ABL gene produce a hybrid oncogene, BCR- ABL, which produces a mutant protein that promotes cellular proliferation. 3)

Examine the concept of loss of heterozygosity or “Two Hit” hypothesis specifically as it pertains to tumor suppressor genes.

Whereas oncogenes are activated in cancers, tumor suppressors must be inactivated to allow cancer to occur. A single genetic event can activate an oncogene because it can act in a dominant manner in the cell; however, each individual has two copies of each tumor suppressor gene, one from each parent. Both copies must be inactivated therefore, two mutations are necessary.

Because inactivation of tumor suppressor genes requires at least two mutations (one in each allele), a single mutation in the germline cells (eggs or sperm) results in the transmission of cancer-causing genes from one generation to the next, producing families with a high risk for specific cancers. These inherited mutations that predispose to cancer are almost invariably in tumorsuppressor genes because only a single additional mutation is needed to inactivate completely the tumor suppression gene. I got this off the internet. I thought it was good. I also included his car analogy below.

First let’s define loss-of-function mutations and gain-of-function mutations. Remember that each cell has two copies of the same gene, one from each parent. ● Loss-of-function mutations describe mutated genes that produce proteins that have been being partially or completely inactivated. A loss-of-function mutation is masked if a normal copy of the gene is present. ● Gain-of-function mutations changes the protein made by the now mutated gene such that it has a different and abnormal function. In most cases, gain of function mutations in just one copy of a particular proto-oncogene are enough to make that gene a true oncogene. ● On the other hand, and in a good way, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. Many hereditary cancers show up more frequently and earlier because a patient starts out with a “one hit” where a TSG from the affected parent has already been inactivated. Even after “one

hit”, the single remaining wild-type (“normal”) tumor suppressor allele may be able to provide enough of the normal TSG protein to halt or, at least, slow the oncogene’s ability to cause growth, replication, and migration of cancer cells

A normal TSG are like the brakes on a car that keeps an oncogene from growing and dividing. Even if you have an active oncogene, the TSG normally will halt or drastically reduce the mutated cell’s ability to grow and divide. However, if you lose 1 TSG through mutation or you were only born with 1 the risk of cancer spreading is increased. Finally, with the 2nd “hit”, the car has lost its brakes and the mutated cells are free to grow and divide.

TUMOR PROGRESSION AND METASTASIS

1) Examine the mechanisms that allow local invasion of cancer cells occur. Invasion, or local spread, is a prerequisite for metastasis. In its earliest stages local invasion may occur by direct tumor extension. Eventually, however, cells migrate away from the primary tumor and invade the surrounding tissue. Invasion is a multistep process that includes diminished cell to cell adhesion, digestion of the surrounding extracellular matrix, and increased motility of individual cancer cells.

A tumor can directly invade organs that are close by. ● ● ● ● ●

Local invasion occurs when cancer cells continue to replicate indefinitely. This constant increase in tumor size may displace or stretch surrounding tissue. In addition, cancer cells have the ability to produce and release lytic enzymes such as protease that degrade the extracellular matrix of normal tissues. Intravasation: the invasion of cancer cells through the basal membrane into a blood or lymphatic vessel. Extravasation: cancer cells exiting the capillaries and entering organs Many cancers have known organs they typically spread to such as breast cancer. Breast cancer tumors will spread to the lungs, bones, the liver, and can go to the brain. Prostate cancer patients will often have bone-only metastasis where no other organs or tissues are affected

2) Examine the concept of metastasis including how cancer spreads to distant areas of the body. ● Genetic changes are the basis of cancer ● Metastasis - the spreading of cancer cells from the site of the original tumor to distant tissues and organs through the body ○ Is a complex process that requires cells to have many new abilities, including the ability to invade, survive, and proliferate in a new environment ■ Invasion consists of loss of cell-to-cell contact, degradation of the ECM, and migration of tumor cells to the vascular or lymphatic systems ■ Stromal cells (particularly TAMs or tumor-activated macrophage) are essential ○ Most common pathway for metastasis is through both blood and the lymphatic system - metastatic cancer cells must be able to withstand the physiologic stresses of traveling through these systems ■ Cancer often spreads first to regional lymph nodes through the lymphatic system and then to distant organs and tissues through the bloodstream. This is why you’ll see lymph node sampling performed with almost every surgery that is oncology related because of the preference for the tumor cells to travel through the blood and lymphatic system. ■ After moving into the area, to survive, cancer cells must attach to specific receptors in the new environment. By a not fully understood process called Epithelial-mesenchymal transition (EMT), many epithelial-like characteristics(polarity, adhesion to basement membrane) are lost = migratory capacity increases, and resistance to apoptosis increases, and dedifferentiation to a stem cell-like state favors growth in foreign microenvironments and the establishment of metastatic disease. ● Normal human cells can only divide a limited number of times - natural defense against abnormal proliferation ○ Telomeres: are repetitive sequences of non-coding DNA that protect the chromosome from damage ■ Each cell division shortens the telomere ■ The cell can no longer divide when the telomere is too short ○ Telomerase: an enzyme that normally maintains telomere length during development ■ Is only active during embryonic and fetal development

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However, with the inactivation of certain TSGs (p53 and retinoblastoma protein), continues to be active, effectively making the cancer cells immortal ■ P53 - controls the expression of many genes that repair DNA damage, suppression of cellular proliferation during genomic repair, and initiation of apoptosis ■ Retinoblastoma protein - is an inheritable mutation that greatly increases risks for particular cancers ○ Cancer cell immortality: Tumor suppressor gene (TSG) inactivation keeps telomerase activated ■ Malignant tumors will continue to grow and divide at the expense of surrounding healthy tissue. Angiogenesis (neovascularization) is the development of new capillaries from pre-existing vessels ○ Is a major component of wound healing ○ Tumor growth is dependent upon new blood vessel growth to supply their nutrient demands ○ With loss of the TSGs like, p53 and Retinoblastoma protein (pRb), the body is unable to inhibit angiogenesis induction by signaling proteins like vascular endothelial growth factor (VEGF). ■ VEGFs stimulate angiogenesis ○ Advanced cancers can secrete angiogenic factors like VGEF to facilitate feeding of the tumor Inflammation is another important factor in the development of cancer. ○ Cells with malignant phenotypes appear to take advantage of the inflammatory response process, especially the portion that initiates and directs the healing process. ○ Successful tumors appear capable of manipulating cells of the inflammatory response from a rejection response toward the phenotypes assoc w/ wound healing and tissue regeneration → a process that includes induction of damaged tissue of cellular proliferation, neovascularization, and local immune suppression. ○ These activities benefit cancer progression, as well as increase resistance to chemotherapeutic agents. ○ Organs susceptible to the oncogenic effects of chronic inflammation: ■ GI tract ● Chronic H. pylori infection increases risk for gastric adenocarcinoma ○ Although most H. pylori infections are asymptomatic, prolonged chronic inflammation can lead to increased gastric acid secretion, atrophic gastritis, and duodenal ulcers, that can, in a small fraction of individuals, progress to dysplastic changes and finally gastric adenocarcinoma. ● Reflux esophagitis (Barrett’s esophagus): esophageal adenocarcinoma ■ COPD - lung carcinoma ● COPD is an independent risk factor for lung carcinoma, particularly for squamous cell carcinoma. ■ Bladder inflammation (indwelling catheter) - bladder carcinoma ■ Chronic pancreatitis - pancreatic carcinoma ■ Prostate ■ Thyroid gland

3) Identify the environmental-lifestyle risk factors that increase the risks of developing cancer. ● Tobacco use most important risk factor for cancer → especially cigarette smoking ○ Multipotent carcinogenic mixture ■ NOTE: both cigars, E-cigarettes, and even smokeless tobacco all have increased risks of cancer and are not a safe alternative ○ Tobacco smoking is linked to cancers of the lung, mouth, lips, nasal cavity and sinuses, larynx, pharynx, esophagus, pancreas, kidney, lower urinary tract, uterus, cervix, colon and rectum, liver, and acute myeloid leukemia. ■ E-cigarettes = increased risk of lung adenocarcinoma, larynx, liver, and kidney cancers. ■ Smokeless tobacco = increases risk of cancers of the mouth and lips. ○ Environmental tobacco smoke (secondhand smoke) increases the risk for lung cancer. ■ 100,000 infant deaths by SIDS or complications from LBW or other conditions were as a result of parental smoking, particularly from the mother. ■ More than 7000 chemicals have been identified in tobacco smoke exhaled by the smoker. ● Ionizing radiation ○ Includes exposure to XRYs, radioisotopes, and other radioactive sources ○ Randomly damages tissues, cells, and chromosomes - damage may lead to oncogene activation, tumor-suppressor genes deactivation, cell transformation, chromosomal aberrations, and DNA damage ■ Cells of the skin and GI tract & Immune system cells ○ Leads to thyroid cancers, leukemias, lymphomas ● UV radiation

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Principal source is sunlight Leads to basal cell carcinoma, squamous cell carcinoma, and melanoma

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Toxic, mutagenic, and carcinogenic chemicals in food such as those produced in the cooking of fat, meat, or proteins increase the risk for cancers. Consuming kiwi fruits, cooked carrots, or supplemental coenzyme Q10 improves DNA repair and decrease the risk of cancer NOTE: Cancer risks in older adults may depend as much on diet in early life as on current eating practices. In addition, studies targeting diet and disease associations are difficult to carry out because it can be hard to accurately measure specific nutrients, food types, and dietary patterns.

Diet

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Obesity ○ Increases the risk of 11 cancers including colon, breast, pancreatic, and endometrial cancers ○ Correlates with BMI → the greater the BMI the greater the risk for cancer Physical activity ○ Decreases the risk of cancer by not only decreasing obesity, decreasing inflammation, and improving immune function; but it also decreases insulin and insulin- like growth factors and circulating sex/metabolic hormones, both of which are known to increase the risk of certain cancer. ○ Physical activity reduces the risk for breast, colon, and endometrial cancers, independent of weight changes. ○ After a cancer diagnosis, physical activity is associated with improved cancer-specific and overall survival with early-stage breast, prostate, and colorectal cancers. Alcohol consumption ○ Classified as a human carcinogen ○ No “safe limit” known and the effect is from ethanol regardless of what type of drink ○ Oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver cancers

CLINICAL MANIFESTATIONS OF CANCER 1) Examine cancer pain including causes of pain in different types of cancer. ● PAIN "It’s whatever the experiencing pt says it is, existing whenever and wherever the pt says it does.” ○ May correlate with the stage of cancer ○ Pain intensity influenced by fear, anxiety, sleep loss, fatigue, and overall physical deterioration