physiology exam 2 neoplasia-cancer

anaplasia genetic instablility growth factor independence cell cohesiveness and adhesion anchorage dependence cell-to-cell communication unlimited life span antigen expression production of enzyme, hormones, other substances cytoskeletal changes or abnormalities seeding metastasis sentinel node growth fraction doubling time

2.3: Cancer Cell Characteristics As discussed previously, cancer cells exhibit abnormal and rapid proliferation as well as a loss of differentiation. However, cancer cells possess numerous other characteristics as well. Anaplasia, meaning "to form backward," is the term that describes the loss of cell differentiation in cancerous tissue. These undifferentiated cancer cells display many morphological changes. The cells and nuclei both have variations in size and shape, a condition called pleomorphism. The chromatin is coarse and clumped, the nucleoli are often larger than normal and contain an abnormal number of chromosomes. Due to the high rate of proliferation, there is often a greater number of cells in mitosis. Highly anaplastic cells resemble undifferentiated or embryonic cells, rather than the tissue of origin. In order to classify and track these changes, a 'grading' system was developed. The cytologic/histologic grading of tumors is based on the degree of differentiation and the number of proliferating cells. The closer the tumor cells resemble comparable normal tissue cells, both morphologically and functionally, the lower the grade. On a scale from I to IV, grade I neoplasms are well differentiated, while grade IV are poorly differentiated/anaplastic. Genetic instability is considered a hallmark of cancer. Under normal conditions, cells are protected from genetic errors because of the many cellular mechanisms in place to prevent them. In contrast, the dysregulated nature of cancer often leads to a high frequency of genetic errors and therefore an increase in its genetic instability. Consequently, these attributes promote the development and progression of cancer. Included are aneuploidy (chromosomes are lost or gained); intrachromosomal instability (insertions, deletions, and amplifications); microsatellite instability (short, repetitive sequences of DNA); and point mutations (specific, usually affecting only a single nucleotide). Growth factor independence describes how cancer cells can proliferate even in the absence of growth factors. Under standard conditions, cells cannot grow in cell culture without the addition of growth factors. Cancer cells, however, can rapidly divide without the binding of growth factor to its receptor. Complicating matters is that some cancer cells may produce their own growth factors. Still others have abnormal receptors or signaling proteins that may activate growth signaling pathways in the cells. Cell density-dependent inhibition, the cessation of growth after cells reach a certain density, is often lost in cancer cells. The process is also referred to as contact inhibition because cells usually stop growing when they come into contact with each other. For example, during the process of wound healing, contact inhibition causes tissue growth to stop at the point where the edges of the wound come together. However, cancer cells grow rampantly without regard for adjacent tissue and in a similar instance, the cells would continue growing even after the edges of the wound came together. Cell cohesiveness and adhesion are lost, meaning cells do not stick together. This, in turn, permits the surface cells of the tumor to shed into the surrounding body fluids or secretions. Anchorage dependence is lost in cancer cells. In order to live and grow, normal epithelial cells must be anchored to neighboring cells or the underlying matrix. If they become detached, they undergo a type of apoptosis called anoikis, which is Greek for "homeless." Cancer cells, however, can remain viable and multiply without normal attachments to other cells or the extracellular matrix. Cell-to-cell communication is diminished in cancer cells. This interferes with intercellular connections and the responsiveness to membrane-derived signals. For example, some types of cancer have altered gap junction proteins, which negatively impacts cell-to-cell communication. Unlimited life span. A normal cell harvested from the body and grown in a lab-based culture can only divide a limited number of times. As the cells eventually become old, they fail to divide further. Cancer cells, however, tend to divide an infinite number of times, thereby achieving immortality. While telomeres, the protective 'end-caps' on chromosomes, typically shorten with each cell division, most cancer cells keep high levels of telomerase, an enzyme that prevents telomere shortening. As such, older and consequently more error prone cells continue to replicate, giving rise to cell populations of increasing levels of dysfunction. Antigen expression. Cancer cells contain several cell surface molecules or antigens that are immunologically different from its normal tissue counterpart. Cancer cells often revert to embryonic patterns of gene expression and therefore produce antigens far different from the cells of the original tissue. For this reason, tumor antigens are useful clinically as identification markers. As such, the presence of abnormal markers can be used to indicate the presence, recurrence, or progressive growth of a cancer. Production of enzymes, hormones, and other substances. Unlike the tissues of origin that either do not produce or produces in much smaller amounts, cancer cells have the capacity to overcome these restrictions. Further, they can also secrete hormones or enzymes that promote metastasis. Cytoskeletal changes or abnormalities. In cancerous cells, this includes abnormal intermediate filament types or changes in actin filaments and microtubules. Such changes enhance their ability for invasion and metastasis. A summary of normal cells versus cancer cells can be found in Table 2.3 below. Table 2.3 Cell Characteristics: Normal vs Cancer Cells CharacteristicsNormal CellsCancer CellsGrowthRegulatedUnregulatedDifferentiationHighLowGenetic stabilityStableUnstableGrowth factor dependenceDependentIndependentDensity-dependentHighLow inhibitionCell-to-cell adhesionHighLowAnchorage dependenceHighLowCell-to-cell communicationHighLowCell life spanLimitedUnlimitedAntigen expressionAbsentMay be presentSubstance production (proteases, hormones)NormalAbnormalCytoskeletal composition and arrangementNormalAbnormal Cancer Growth and Spread As previously discussed, benign tumors grow by expansion, usually in a capsule. Cancer, however, spreads by direct invasion and extension, seeding, and metastasis. The word cancer is Latin for "crablike," because cancer spreads in crablike projections. Since there is no good line of demarcation separating the good tissue from the bad, surgical removal is often challenging. For this reason, a surgeon will remove margins beyond the tumor, so the pathologist can verify that cancer-free margins are indeed present. If cancer-free margins are not detected in the dissected sample, this strongly indicates not all of the tumor was removed. Seeding of cancer cells describes the process of how shed tumor cells enter circulation and move into similar or different body cavities. Most often seeding occurs into the peritoneal cavity, as typically seen with ovarian cancer. If seeding occurs in these spaces, fluid accumulation usually follows (e.g. ascites, pleural effusion). Seeding into other areas of the body can also be a complication following the removal of cancerous cells. As the cells are disturbed during removal, the cancerous cells may migrate, having been disturbed/shed during surgery, into new body cavities. The term metastasis describes when a secondary tumor develops in a location distant from the primary tumor. As the secondary tumor usually retains many of the characteristics of the primary tumor, this makes it possible to determine the site of the primary tumor. In the disease process, some tumors metastasize early while others occur later. Interestingly, sometimes the secondary tumor is found before the primary is detected. For example, malignant kidney tumors may be asymptomatic and go undetected until a metastatic lesion is found in the lung. Metastasis occurs via the lymph channels and blood vessels. The first evidence of disease may be found in the lymph nodes that drain the tumor area. The sentinel node is the first lymph node to which the primary tumor drains. Notably, breast cancer spreads by way of the lymph nodes. The extent of disease may be determined through lymphatic mapping and sentinel lymph node biopsy. A radioactive tracer and/or blue dye is injected into the tumor to determine the first lymph node. This lymph node is then examined for the presence of cancer cells. When cancer spreads hematologically (via blood vessels), the cells enter the venous system that drains the site of the primary neoplasm. Venous blood from the GI tract, spleen, and pancreas flows through the portal vein to the liver. As such, the liver becomes a common site for the metastatic spread of cancers that originate in these organs. Some tumors metastasize to distant and unrelated sites, probably due to suitable environments for growth, as with prostate cancer spreading to bone. As shown in Figure 2.3, the multistep process of metastasis occurs as follows: a cancer cell is shed from the primary tumor, it then invades the surrounding extracellular matrix where it gains access to a blood vessel. If the cancerous cells survive its passage in the bloodstream, it must emerge at a favorable location, invade the surrounding tissue, begin to grow, and importantly, establish a blood supply. When the tumor reaches the distant site, it must establish a blood supply (along with growth factors) in order to continue to grow. The development of new blood vessels within the tumor is termed angiogenesis. Figure 2.3 Mechanisms of tumor metastasis. When cells establish an adequate blood supply, the rate of tissue growth in both normal and cancerous tissue depends on the following three factors: (1) the number of cells that are actively dividing or moving through the cell cycle; (2) the duration of the cell cycle; (3) the number of cells that are being lost relative to the number of new cells being produced. Interestingly, recent studies indicate cancer cells go through the cell cycle at approximately the same rate as normal cells. However, because cancer cells have a prolonged lifespan and seldom enter G0, there is a greater percentage of cancer cells actively dividing relative to normal cells. There are two key terms associated with cancer growth rates: (1) growth fraction and (2) doubling time. Growth fraction is the ratio of dividing cells to resting cells. Doubling time is the length of time it takes for the total mass of cells in a tumor to double. Thus, as the growth fraction increases (more cells are dividing), doubling time decreases (more cells dividing can double in size faster). In normal adult tissues, the equilibrium between cell death and cell renewal is maintained. However, cancer cells tend to continue to divide until their blood supply and nutrients are gone. This undeterred growth necessitates a tumor is identified as soon as possible. Thankfully, current screening imaging can now detect tumors as small as 0.2 cm.

neoplasm neoplasia proliferation differentiation apoptosis proto-oncongenes tumor suppressor genes cellcycle g1 sphase g2 checkpoints mphase cell proliferation cell differentiation progenitor (parent cells) stem cells self-renewal potency pluripotent multipotent unipotent stem embryonic stem cells adult stem cells

Cancer is the unregulated growth of abnormal cells. Most often, cancer cells showcase patterns of altered cell differentiation and growth. This process is termed neoplasia, meaning "new growth." The new growth itself is referred to as a neoplasm. Whereas normal tissue growth responds with hypertrophy and hyperplasia, a neoplasm's growth lacks normal regulatory controls over cell growth and division. Neoplasms serve no purpose, do not respond to appropriate cellular signaling stimuli, and continue to grow primarily at the host's expense. Proliferation, a process of cell division, is an adaptive process for new cell growth to replace old cells or when additional cells are needed. Neoplasms tend to have genetic abnormalities that cause excessive and uncontrolled proliferation that is unregulated by normal growth-regulating stimuli. Differentiation is the process by which cells become more specialized with each mitotic division. Apoptosis eliminates senescent (old), damaged, or unwanted cells through a process of controlled cell death. Both the beginning (proliferation) and end stages (apoptosis) of a cell lifecycle are carefully regulated. Proto-oncogenesencode proteins that signal for the cell to proliferate through a tightly regulated process. Conversely, tumor suppressor genes encode proteins that inhibit cell growth and signal (when necessary) for apoptosis. For instance, should a particular cell growth become unregulated, which if left unregulated could lead to tumor formation, the tumor suppressor genes will initiate apoptotic events to eliminate the potential tumor cells. As each type of gene regulates either the initiation of cell growth (proto-oncogenes) or cell death (tumor suppressor genes), dysregulation in either can lead to unregulated growths and ultimately cancer. The cell cycle is the process by which a cell duplicates its genetic information and divides between two genetically identical daughter cells, as shown in Figure 2.1. The cell cycle is divided into four phases: G1, S, G2, and M. G1 (gap 1): DNA synthesis stops while the cell enlarges and both RNA and protein synthesis begins S phase: DNA synthesis occurs, producing two separate sets of chromosomes, one for each daughter cell. G2 (gap 2): DNA synthesis again stops while RNA/protein synthesis continues. These first three phases are referred to as interphase. Located at the end of each of these phases (G1, S-phase, and G2) are cell cycle checkpoints. Checkpoints are a means of molecular surveillance used to ensure the cell is ready to proceed to the next phase. If not, the cycle is halted and allowed to complete its replication or even repair any DNA damage (when detected), thereby ensuring all the genetic information is passed on correctly M phase: consists of mitosis (dividing up the DNA) and cytoplasmic division. Continually dividing cells, like the skin's squamous epithelium, continue to cycle from one mitotic division to the next, while some cells go into a resting state known as G0. A resting phase (G0) may occur when nutrients or growth factors are unavailable or when highly specialized cells first leave the cell cycle. Cells in G0 may then re-enter the cell cycle when nutrients become available, or the cell receives stimuli via growth factors, hormones, or other signals that trigger cell growth, such as blood loss or tissue injury. Notably, highly specialized and terminally differentiated cells, like neurons, may permanently stay in G0. Cell proliferation is the process of increasing cell numbers by mitotic cell division. In normal tissues, the number of new cells being produced is equivalent to the number of cells dying or being shed. Thus, tissue/organ structure and function are maintained. However, in most cases of cancer, the equilibrium of new vs old (or removed) cells becomes unregulated and unbalanced. When considering cell proliferation, human cells fall within one of two major categories: gametes (ovum and sperm) and somatic (non-reproductive) cells. Gametes are haploid, having only one set of chromosomes from one parent. They are designed for sexual fusion. After fusion, a diploid cell containing both sets of chromosomes is formed. These are the somatic cells that proceed to form the rest of the body. Of the 200 various cells that proliferate, they can be divided into three large groups: (1) well-differentiated neurons and cells of skeletal and cardiac muscles that rarely divide and reproduce; (2) progenitor or parent cells that continue to divide and reproduce, such as blood, skin, and liver cells; (3) undifferentiated stem cells that can enter the cell cycle and produce large numbers of progenitor cells if needed. The cells vary greatly in their rates of reproduction. White blood cells and cells that line the GI tract live only several days and therefore must be replaced continuously. In most tissues, cell reproduction is increased when tissue is either injured or lost. For instance, injuries that induce bleeding results in the stimulation and reproduction of blood-forming cells in the bone marrow. Cell differentiation refers to the process by which cells become more specialized in both their structure and function. The resulting adult cell has a specific set of characteristics relative to its composition, function, and turnover (lifespan) rates. As an example, generalized blood-forming cells in the bone marrow differentiate into specialized adult red blood cells programmed to develop into concave disks and serve as an oxygen transport for about three months. The various cell types of the body all originate from the fertilized ovum. Specific genes and patterns of gene expression, along with numerous forms of chemical and environmental stimuli all factor into how cells differentiate into various tissue and organ types. Importantly, the rate of cellular reproduction and differentiation must be precisely controlled in prenatal and postnatal life so that both mechanisms stop once the appropriate numbers, and types, of cells are formed. Moreover, as differentiation progresses, the process within each developing cell type must also be tightly regulated. As cells become more and more specialized they lose the ability to develop the structural and functional characteristics of other cell types. This ensures the integrity and composition of developing organs is maintained and free from differing (and unwanted) cells types. For example, as cells are differentiating into specialized cardiac tissue, the pathway must be 'locked in' as to avoid differentiating into non-cardiac cell types. Indeed, catastrophic events would ensue if half of the cells destined to be cardiac (heart) cells suddenly began differentiating into renal (kidney) cells. When specialized cells are unable to divide, these cell populations rely on progenitor or parent cells of the same lineage that are still able to divide. Such cells are not yet fully differentiated to the same extent as mature specialized cells and yet are differentiated enough to give rise to daughter cells of the same lineage. Stem cells, unlike progenitor cells, remain incompletely differentiated and dormant until they are needed. When needed, they begin to divide, producing not only other stem cells, but also cells capable of carrying out the functions of the needed differentiated cell. When a stem cell divides, one daughter cell retains the stem cell characteristics, while the other daughter cell becomes a progenitor cell until it reaches a state of terminal differentiation. Figure 2.2 outlines the basic mechanism of stem cell-mediated cell replacement. Two important properties that stem cells possess are (1) self-renewal and (2) potency. Self-renewal means the stem cell can undergo numerous mitotic divisions while maintaining an undifferentiated state. Potency describes the differentiation potential of stem cells. Pluripotent stem cells, often referred to as 'master cells,' can potentially differentiate into any cell type. Multipotent stem cells can differentiate into only a few select types. Unipotent stem cells are restricted to a single cell type but can maintain self-renewal. The two types of stem cells are classified as either (1) embryonic or (2) adult stem cells. Embryonic stem cells play a major role in the developing embryo, giving rise to the three main germ layers (endoderm, mesoderm, and ectoderm) which in turn develop into all the organ systems of the body. Adult stem cells have significant roles in homeostasis, contributing to tissue regeneration and replacement of cells lost to apoptosis.

clinical manifestations, dx and treatment

Clinical Manifestations Cancer affects almost every part of the body. Although cancer may only affect the area surrounding the primary tumor initially, if it grows and spreads, other body structures frequently become impacted as well. Treatment options can be challenging, as the side effects of the cancer treatment are often as bad as the symptoms themselves. As such, pain often becomes a primary concern for many facing the disease. As the types, locations, and effects of cancer are diverse, the following should be considered as a very general overview of the potential clinical manifestations. Tissue. Cancer disrupts the integrity of tissues. As such, bleeding results when blood vessels become compressed or eroded, causing ulceration and necrosis. Bleeding is sometimes the first sign of cancer, as seen in colorectal cancer. In other instances, cancer may present as a growth or sore that does not heal. Fluid. The development of unusual amounts of fluid in the pleural, pericardial, or peritoneal spaces can be an initial sign of some cancers. Lung, breast, and lymphomas often present with pleural effusions. During such occurrences, people may develop chest pain, shortness of breath, or cough. Ovarian cancer can present with fluid in the peritoneal cavity, evidenced by abdominal discomfort or swelling. Wasting. Many cancers are associated with weight loss and wasting of body fat and muscle tissue. They also can cause weakness, anorexia, and anemia. This wasting syndrome is called cancer anorexia-cachexia syndrome. Decreased eating and lack of appetite are common, but the extent of weight loss and protein wasting goes beyond reduced food intake alone. It occurs mainly with solid tumors, except in cases of breast cancer. Wasting is a significant cause of morbidity and mortality, especially in people with advanced disease. Fatigue. Two frequent side effects of cancer are fatigue and sleep disturbances. People report feeling tired, weak, and lacking energy. Symptoms can also remain for months' post-treatment. It occurs both as a result of the cancer itself, and as a side effect of the cancer treatment. Anemia. Possibly due to the effects of the treatment, or because of blood loss, hemolysis, or impaired red blood cell production, an insufficient level of healthy blood cells is commonly seen in people with cancer. Cancer-related anemia can also cause less effective treatments, increased mortality, increased blood transfusions, and decreased performance and quality of life. Cancer-related anemia can be treated with recombinant human erythropoietin. Unrelated. Cancer can also produce symptoms in sites not directly affected by the disease. These manifestations are termed paraneoplastic syndromes. Some are caused by hormones secreted by the cancer cells. Others produce hematopoietic, neurologic, and dermatologic syndromes. These syndromes can occasionally be seen with lung, breast, and hematologic malignancies. Three common endocrine syndromes are the syndrome of inappropriate ADH secretion, Cushing syndrome due to ectopic ACTH production, and hypercalcemia. Paraneoplastic syndromes may be the first clue that a person has cancer and should be worked up appropriately. Treatment involves concurrent treatment of the underlying cancer, as well as suppression of the mediator causing the syndrome. Diagnostics Screening is an important secondary prevention strategy for early detection of cancer. Screening is done through the following ways: Observation: skin, mouth, external genitalia Palpation: breast, thyroid, rectum and anus, prostate, lymph nodes Laboratory tests and procedures: Pap smear, colonoscopy, mammography The above procedures are cost effective tests that have been shown to improve outcomes. After all, the sooner cancer is detected, the better the outcome. For instance, there is now a screening test for lung cancer: a 20-pack per year smoker (or more) and age 50 or older can be screened with an annual low dose chest CT scan. In contrast, not all forms of cancer can be screened as a screening test for pancreatic cancer unfortunately still does not exist. The methods used to diagnose and stage cancer are based on the location and type of cancer suspected. Blood tests for tumor markers, cytologic studies and tissue biopsy, endoscopic examinations, ultrasonography, x-ray studies, MRI, computed tomography (CT), and positron emission tomography (PET) scans are ways in which cancer can be diagnosed. Tumor markers present in two main ways (1) as antigens expressed on the surface of tumor cells or (2) as substances released from normal cells in response to the presence of a tumor. Additional markers include hormones and enzymes that become overexpressed because of cancer, or oncofetal proteins that are produced during fetal development and reappear later in life from benign or malignant neoplasms. Collectively, these tumor markers are used for establishing prognosis, monitoring treatment, and detecting recurrent disease. As perhaps the most well-known marker, the prostate specific antigen (PSA) becomes elevated in prostate cancer and can be easily screened via a blood test. However, it should be noted the use of tumor markers does have its limitations. Under benign conditions, most tumor markers can be elevated, whereas most markers are not elevated in the early stages of malignancy. Given their lack of specificity, most tumor markers (with the exception of the PSA test) are limited in their ability to accurately screen or diagnosis a tumor. Instead, once antigen levels can become associated with a given malignancy, these markers become quite valuable in accessing the response to therapy or recurrence of cancer. For instance, if a particular marker is associated with a tumor, and is correspondingly measuring at high levels, then once treatment begins, over the course of treatment, if it works, the levels of this particular marker should decrease, indicating the reduction/elimination of the malignancy. Conversely, when a cancer has been eliminated, the associated marker can be monitored. Over time, if the levels of the marker begin to rise, this may indicate a recurrence of the cancer. Histologic and cytologic studies are laboratory methodologies used to examine the structural, compositional, and functional characteristics of tissues and cells. There are many approaches to this, including cytologic smears, tissue biopsies, and needle aspiration. The Papanicolaou (Pap) test is a method used to detect cancer cells, in which the pathologist examines a prepared slide for abnormal cells. Most commonly used for cervical cancer screening, it can also be used on other bodily secretions, including pleural or peritoneal fluid, nipple drainage, and gastric and anal washings. Tissue biopsy involves the removal of a tissue specimen for microscopic study and is an essential procedure in diagnosing the correct cancer and histology. Biopsies can be obtained in a variety of ways, including via a needle, endoscopic methods (bronchoscopy or cystoscopy), or laparoscopic methods. Excisional biopsy removes part or all of the tumor through a surgical excision. Fine-needle aspiration involves drawing up (removing) cells and fluid with a small-bore needle and syringe (or vacuum). This is commonly done in the thyroid, breast, and lymph nodes. Immunohistochemistry uses antibodies which recognize and bind to specific cell products or surface markers to correctly identify the desired antigen(s). For example, consider how certain anaplastic carcinomas, melanomas, sarcomas, and malignant lymphomas, can all appear very similar under the microscope. As their respective prognosis and corresponding treatment options are very different, accurately identifying the cancer is extremely important. Immunohistochemistry can also be helpful in determining the site of origin of metastatic tumors by determining which tissues, or even organs, in the surrounding area contain the same antigens. It can also detect molecules that have prognostic or therapeutic significance, like the detection of estrogen receptors on breast cancer cells, which then guides the specific treatment regimen needed (anti-estrogen therapy). Microarray technology uses "gene chips" that can simultaneously perform hundreds or even thousands of miniature assays to detect and quantify the expression levels of a large number of genes. It analyzes the large number of molecular changes present in cancer cells in order to determine (overall) patterns of behavior. DNA arrays are currently being used to guide clinical decisions, such as for determining the best course of treatment in breast cancer patients. Cancer classification is accomplished using a combination of the above tests, all in an effort to better characterize and identify the type of cancer cells present in a patient. The classifications used are based on established standards within the medical community. The two main strategies for classifying cancers are (1) grading and (2) staging. Grading is based on the cellular characteristics of the tumor and the degree of abnormalities present. Tumor grading involves the microscopic examination of cancer cells to determine their level of differentiation. Cancers are classified as grades I, II, III, or IV, where each numerical grade designation coincides with a specific set of associated characteristics. Staging is the assessment of the clinical spread of the disease. The staging of cancer is classified, similar to grading designations, as stages I, II, III, or IV, with stage IV being the most widespread, often to distant parts of the body. Staging of cancer may also require surgery to determine tumor size and lymph node involvement. A more sophisticated and detailed staging system, the TNM system of the American Joint Committee on Cancer (AJCC), is used by cancer facilities. It classifies the disease into stages using three tumor components (Tumor, Nodes, and Metastasis) as shown in Table 2.5: Table 2.5 TNM Classification System TNM Classification System T (Tumor)Tx Tumor cannot be adequately assessedT0 No evidence of primary tumorTis Carcinoma in situT1-4 Progressive increase in tumor size or involvement N (Nodes) Nx Regional lymph nodes cannot be assessedN0 No evidence of regional node metastasisN1-3 Increasing involvement of regional lymph nodes M (Metastasis)Mx Not assessedM0 No distant metastasisM1 Distant metastasis present, specify sites T is the size and local spread of the primary tumor. N is the involvement of the regional lymph nodes. M is the extent of the metastatic involvement. Treatment The goals of cancer treatment methods are classified into three categories: curative, control, and palliative. The most common ways to achieve these are by (1) surgery, (2) radiation therapy, (3) chemotherapy, (4) hormonal therapy, and (5) biotherapy. Cancer treatment involves a carefully managed and executed plan, often combining the expertise of a wide range of medical specialists. Surgery is a multifactorial process, now being used not only to remove cancer but is also beneficial for diagnosing, staging, and palliation (relief of symptoms when a cure is not possible). As there are many factors, the type of surgery frequently depends on the extent of disease, location, structures involved, tumor growth rate and invasiveness, surgical risk to the patient, and the quality of life the patient will have post-surgery. Surgery is often the first treatment for solid tumors. If the tumor is small with well-defined margins, it can be removed completely. However, if the tumor is large or has grown into vital areas, surgery may be difficult. Additionally, surgery can be used in combination with chemotherapy or radiation therapy for certain cancers (see below). Further, it can be used to treat oncologic emergencies like a GI hemorrhage, or it can be used prophylactically in families with a high risk for developing cancer (e.g. prophylactic bilateral mastectomy in women with a strong family history of breast cancer). Radiation therapy can be used as the primary method of treatment, or as an adjuvant treatment with surgery, chemotherapy, or both. It can be used palliatively to reduce symptoms of bone pain metastasis, for example. Radiation can also treat oncologic emergencies like superior vena cava syndrome, spinal cord compression, or bronchial obstruction. Radiation therapy uses high-energy particles or waves to destroy or damage cancer cells. The use of radiation leads to the creation of free radicals, which damage cell structures. Radiation can interrupt the cell cycle process, kill cells or damage DNA in the cells. Notably, radiation injures allproliferating cells that are in the radiation field. However, normal tissue that is exposed is usually able to recover from the damage more readily than cancerous tissue. The most common side effect from radiation is skin irritation. It can suppress bone marrow function and cause a decrease in leukocytes, platelets, and red blood cells if a bone marrow space is in the radiation field. Chemotherapy may be used alone or in combination with surgery and/or radiation. Chemotherapy is a systemic treatment that uses drugs to reach the tumor site, as well as other distant sites. It is the main treatment for most hematologic and some solid tumors, as well as a palliative option if curative therapy simply is not possible. Cancer chemotherapeutic drugs act in several ways. They prevent cell growth and replication by halting protein, DNA, and RNA synthesis while simultaneously inhibiting enzyme production and cell mitosis. Chemotherapeutic drugs are especially effective at treating tumors that contain rapidly dividing cells. As an unfortunate side-effect, normal tissue is damaged as well in the process of killing the cancerous cells. Chemotherapy drugs are classified according to their site and mechanism of action. The two major categories are direct DNA-interacting (alkylating agents, antitumor antibiotics, topoisomerase inhibitors) and indirect DNA-interacting (antimetabolites, mitotic spindle inhibitors) agents. Other drugs include hormonal and molecularly targeted agents. These drugs can be cell-cycle specific or cell-cycle nonspecific. For instance, methotrexate is a cell-cycle specific drug because it interferes with DNA synthesis by specifically disrupting the S phase of the cell cycle. Conversely, alkylating agents are considered cell-cycle nonspecific because they act by disrupting DNA when cells are both resting and dividing. Because these drugs work through different mechanisms of action, they are often combined when treating cancer. Many chemotherapeutic drugs cause a reduction in all three blood cell types (RBC, WBC, and platelets) due to bone marrow suppression. This can lead to neutropenia (risk for infections), anemia (causing fatigue), and thrombocytopenia (risk for bleeding). The administration of hematopoietic growth factors is helpful to combat this. Anorexia, nausea, and vomiting are common side effects. Oral and intravenous antiemetics are very effective in combating those effects. Alopecia, or hair loss, results from the impaired proliferation of the hair follicles during treatment. It is usually temporary and grows back when treatment is stopped. Hormonal therapy consists of drugs designed to disrupt the hormonal environment of cancer cells. The goal is to deprive the cancer cells of the hormonal signals that otherwise would stimulate the cells to divide. The breast, prostate, and endometrium are all responsive to hormone therapy. Other areas like renal, liver, ovarian, and pancreatic cancers have recently been treated with hormone therapy as well. If surgery is necessitated, it is first done to remove the organ responsible for producing the hormone responsible for overstimulating the target tissue or tumor (e.g. oophorectomy in women or orchiectomy in men). Drug therapy then suppresses the circulating hormone levels and/or alters the existing hormone receptors so that they fail to respond to the hormone. Hormone receptor function can be altered by removing the receptors or by effectively turning them off. For instance, an exogenous hormone can be administered to decrease the number of hormone receptors, or an anti-hormone drug can be given that binds to hormone receptors without stimulating or activating them, thereby effectively blocking any future signaling. Examples of these include the antiestrogens (tamoxifen, fulvestrant) and antiandrogens (flutamide, bicalutamide, nilutamide). Biotherapy uses immunotherapy and biologic response modifiers to change the person's own immune response to cancer. It includes the use of monoclonal antibodies, cytokines, and adjuvants. Monoclonal antibodies (mAbs) are highly specific antibodies made from cloned cells. IgG is the most commonly used immunoglobulin. For a mAb to work as a cancer treatment, a specific target antigen should be present on cancer cells only. Some mAbs are capable of blocking major pathways central to tumor cell survival and proliferation. Others are modified to deliver toxins, radioisotopes, cytokines, or other cancer drugs. Currently approved mAbs include rituximab (IgG that targets CD20 antigen on B cells to treat non-Hodgkin lymphoma); bevacizumab (targets vascular endothelial growth factor to inhibit blood vessel growth in colorectal, lung, renal and breast cancer); and cetuximab (targets epidermal growth factor receptor to inhibit tumor cell growth and used to treat colorectal cancer and squamous cell cancer of head and neck).

etiology

External Factors The process by which carcinogenic (cancer-causing) agents cause normal cells to become cancerous is thought to be a multistep process divided into three stages: (1) initiation, (2) promotion, and (3) progression (Figure 2.5). Initiation involves the exposure of cells to a carcinogenic agent that makes them vulnerable to cancer transformation. These agents can be physical, chemical, or biologic and cause irreversible alterations to the cellular genome. Since they are irreversible, repeated small exposures may achieve the same effects as a single exposure of the same total amount. Importantly, the cells most susceptible to mutagenic changes are those actively synthesizing DNA. Figure 2.5 Process of initiation, promotion, and progression in the clonal evolution of malignant tumors. Promotion allows for the abundant growth of cells, usually triggered by multiple growth factors or chemicals. Notably, the result is reversible if the promoter substance is removed. Promotion can occur at any time, as initiated cells may be promoted even after long latency periods. The latency period varies with the type of agent, dosage, and characteristics of the target cells. Progression is the final step that occurs when tumor cells become malignant. As stated previously, malignant cells show heightened levels of invasiveness, the ability to spread (metastasis), grow virtually unregulated (autonomous), and often have an increase in genomic alterations. As previously stated, cancer is not a single disease with a single, isolated event. Cancer occurs due to interactions among multiple risk factors or because of repeated exposures to a single carcinogenic agent. Risk factors linked to cancer include heredity, obesity, hormonal factors, immunologic mechanisms, and environmental agents such as chemicals, radiation, and cancer-causing viruses. Heredity has been linked to about 50 types of cancer in families. Breast cancer is seen more frequently in women whose grandmothers, mothers, aunts, or sisters have also had breast cancer. Two tumor suppressor genes, BRCA1 and BRCA2 (breast carcinoma 1 & 2), are linked to an increased risk of breast and ovarian cancer. Carriers of the BRCA mutation have a lifetime risk (if they live to age 85) of 80% for developing breast cancer. The lifetime risk of ovarian cancer is 40-60% with BRCA1, and 10-20% in BRCA2 mutations. These genes also increase the risk of prostate, pancreatic, colon, and other cancers. Other cancers have an autosomal dominant inheritance link. The inherited mutation is usually a point mutation occurring in a single allele of a tumor suppressor gene. People who inherit these carry one mutant gene and one normal gene. For cancer to develop, the normal gene must be inactivated, usually through a non-inherited (somatic) mutation. For example, a retinoblastoma is a rare childhood tumor of the retina that follows this pattern. Familial adenomatous polyposis of the colon is another example. In people who inherit this gene, hundreds of adenomatous colon polyps develop, some of which have the potential to become cancerous. Obesity. Recent research has shown a strong link between obesity and cancer, including breast, endometrial, and prostate. The process is multifactorial and involves several metabolic and immunologic mechanisms. Obesity is associated with insulin resistance and increased production of pancreatic insulin, both of which can have a carcinogenic effect. It is associated with increased levels of sex hormones, androgens, and estrogens. These stimulate cell proliferation, inhibit apoptosis, and increase the chance of malignant cell transformation, especially of the endometrial and breast tissue. Lastly, obesity has been related to chronic inflammation, which can lead to the development of malignancies. Hormones. The link between hormones and the development of cancer is unclear, but research strongly suggests a close association, especially with cancer of the breast, ovary, endometrium, and prostate. It has been suggested that hormones play a role in promoting the cell division of a malignant phenotype. This has come under concern lately with the administration of hormones for therapeutic purposes. Immune Mechanisms. A decline or impairment in the surveillance capacity of the immune system has been associated with cancer. Immunologic mechanisms provide a means for the detection, classification, and prognostic evaluation of cancers and as a method of treatment. Immunotherapy is a cancer treatment designed to raise the general immune responses in order to increase tumor destruction. Thus, as the immune system is heightened it may detect and destroy tumors more efficiently. As a proof of concept, there is a higher rate of cancer in people with immunodeficiency diseases, and those on immunosuppressant drugs due to organ transplants. Kaposi sarcoma is a prime example of a cancer developing in those with acquired immunodeficiency syndrome (AIDS). Most tumor cells have molecular determinants that can be specifically recognized by immune cells or by antibodies, called tumor antigens. As such, the immune system has the potential to rid the body of cancer cells. Protective mechanisms include T lymphocytes, B lymphocytes and the antibodies they produce, macrophages, and natural killer (NK) cells. The T-cell is perhaps one of the most important mechanisms for controlling the growth of antigenic tumor cells. The two subsets of T cells involved in the detection of cancerous cells include the CD4+ helper T cells and CD8+cytotoxic T cells, which signal the presence of and then eliminate cancer cells, respectively. A carcinogen is an agent capable of causing cancer. Chemical carcinogens include the following: (1) direct-reacting agents, which are carcinogenic and active as soon as it enters the body; and (2) indirect-reacting agents, called procarcinogens or initiators, which must be first metabolized before becoming active. Both direct and indirect agents form highly reactive species (like free radicals) that bind to DNA, RNA, or cellular proteins. The result is a disruption that can have numerous downstream effects in the metabolic, structural, replicative and regulatory pathways within the cell. As described above, promoters may also enhance the carcinogenicity of some chemicals. Lifestyle risk factors, such as smoking, dietary factors, and alcohol consumption, are associated with these chemical carcinogens. Cigarette smoke contains both procarcinogens and promoters and is the cause of lung and laryngeal cancer, as well as many others (mouth, esophagus, pancreas, liver, kidney, uterus, bladder, etc). Chewing tobacco, or tobacco products in general, increases the risk of oral cavity and esophageal cancer. Tobacco use is the cause of about 30% of all cancer deaths and 87% of lung cancer deaths in the United States. Secondhand smoke kills about 3,400 nonsmoking adults per day. The US Environmental Protection Agency has classified environmental tobacco smoke as a "group A" carcinogen. There is also strong evidence that chemicals in our diet increase the likelihood of cancer. While some dietary carcinogens occur naturally in plants (aflatoxins), others are used in the preparation or preservation of food. For instance, when foods are fried in fat that has been reused multiple times, due to the extreme heat, benzo[a] pyrene (and other polycyclic hydrocarbons) are converted to carcinogens. The polycyclic aromatic hydrocarbons are among the most potent and can be found in many common places. They are produced from animal fat when charcoal-broiling meats, are present in smoked meats and fish, and are also present in tobacco smoke. Nitrosamines are formed in foods that are smoked, salted, cured, or pickled using nitrites or nitrates as preservatives. The effects of nitrosamines, however, may be reduced by antioxidants such as vitamin C found in fruits and vegetables. Colon cancer is associated with high dietary fat and red meat intake and low dietary fiber intake, as well as obesity and low physical activity. Alcohol is also linked to many types of cancer. The most toxic metabolite of ethanol is acetaldehyde, which can cause point mutations in some cells. It can also alter DNA methylation and interfere with retinoid metabolism, which is important in antioxidant mechanisms. Alcohol consumption also enhances the carcinogenic effects of cigarette smoke. People who smoke and drink considerable amounts of alcohol are at increased risk for developing cancer of the oral cavity, larynx, and esophagus. The effects of carcinogenic agents are usually dose-dependent. Meaning, the larger the dose or the longer the duration of exposure, the greater the risk of cancer. Some chemical carcinogens may be promoted by viruses or radiation exposure. As it can take anywhere from 5 to 30 years for cancer to develop, it is often difficult to recognize the association between an agent and its effects. However, a known example was the use of diethylstilbestrol, a synthetic form of estrogen, that was used from the 1940s to 1970 to prevent miscarriages. Unfortunately, it was not until the late 1960s that many cases of vaginal adenosis and adenocarcinoma in young women were found to be the result of their exposure in utero to this drug. Table 2.4 summarizes the chemical and environmental agents known to be carcinogenic in humans. Table 2.4 Chemical and Environmental Human Carcinogens Polycyclic Hydrocarbons: soots, tars, and oils; cigarette smoke Industrial Agents: aniline and azo dyes; arsenic compounds; asbestos; B-naphthylamine; benzene, benzo[a]pyrene; carbon tetrachloride; insecticides, fungicides; nickel and chromium compounds; polychlorinated biphenyls; vinyl chlorideFood and Drugs: smoked foods; nitrosamines; high fat/low fiber diet; alcohol; aflatoxin B; diethylstilbestrol; anticancer drugs (alkylating agents, cyclophosphamide, chlorambucil, nitrosourea) Ionizing radiation and its effects in cancer development are well documented, particularly with the atomic bomb survivors. High rates of malignant epitheliomas of the skin and leukemia were diagnosed. Sadly, between 1950 to 1970, the death rate from leukemia alone climbed to 30 times the normal rate in the exposed population groups in Hiroshima and Nagasaki. Studies showed the type of cancer that developed depended on the dose of radiation, the person's gender, and the age at which exposure occurred. In addition to leukemia, there was increased rates of breast, lung, stomach, thyroid, salivary gland, gastrointestinal and lymphoid tissue cancer. The younger the exposure, the sooner the cancer developed. For example, children exposed in utero to ionizing radiation have an increased risk for developing leukemia and childhood tumors about 2-3 years after birth. The latency period extends to 5-10 years if exposure occurred after birth, and to 20 years for some solid tumors. Ultraviolet radiation in sunlight and its link to skin cancer has been reported for more than 100 years. Skin cancer develops in the areas more frequently exposed to sunlight, like the head, neck, arms, hands, and legs. People with a light complexion and less melanin in their skin to help filter out the ultraviolet rays, have a higher incidence. The intensity of the exposure is directly related to the incidence of skin cancer. Higher rates are seen in Australia and the American Southwest. The effects of ultraviolet radiation are additive, and there is typically a long delay between the time of exposure and cancer detection. Other studies suggest that intense, episodic exposure to sunlight, especially during childhood, is more likely to cause melanoma, than prolonged low-intensity exposure. Viruses and Cancer An oncogenic virus is any virus that has been shown to cause cancer. As viruses integrate their own viral genome into the host cell genome, this not only disrupts the cells chromosomal DNA, it also causes the cell to produce viral proteins. Together, these foreign events have the potential to promote oncogenesis. In fact, four DNA viruses have been linked to cancer in humans. These are the (1) human papillomavirus (HPV), (2) Epstein-Barr virus (EBV), (3) human herpesvirus-8 (HHV-8) and (4) hepatitis B virus (HBV). HPV consists of over 100 genetically different types. While some cause benign warts, others have been shown to cause skin cancers (squamous cell carcinoma) associated with the regions surrounding the cervix, anus, and genitals. HPV types 16 and 18 are strongly associated with cervical cancer, and to a lesser extent, types 31, 33, 35, and 51, with an incident rate of approximately 85%. Additionally, at least 20% of oropharyngeal cancers are associated with high-risk HPV. Cervical cancer can be viewed as a sexually transmitted disease, caused by the transmission of HPV. As such, vaccines were developed and are now offered to protect against these specific subtypes in both young men and women. EBV, a herpesvirus that primarily targets B cells, has been noted to play a role in the pathogenesis of four human cancers: Burkitt lymphoma, nasopharyngeal cancer, B-cell lymphomas in immunosuppressed people, and in some cases of Hodgkin lymphoma. Under normal, healthy circumstances EBV-driven B cell proliferation is quickly controlled. Although an infected individual may experience infectious mononucleosis (mono), they will usually recover without any further complications. However, in regions of the world where Burkitt lymphoma (impairments in B cells) is pervasive, having malaria or another infection simultaneously can cause further impaired immune function, and sustained B-lymphocyte proliferation. HHV-8 is associated with Kaposi sarcoma (KS) and is in the same family of viruses as EBV. Kaposi sarcoma is a malignancy that develops from the endothelial cells that line small blood vessels throughout the body, causing small patches of abnormal skin to develop. KS most frequently occurs in people who are immunosuppressed. In fact, KS was one of the first opportunistic cancers associated with AIDS and is still the most frequent malignancy related to HIV infection. HBV is the causative agent in the development of hepatitis B, whereby ~15-25% of infected individuals progress into chronic liver damage, cirrhosis, and ultimately liver cancer (hepatocellular carcinoma). Roughly 70-85% of hepatocellular cancers worldwide are due to infection with HBV or by the closely-related variant hepatitis C (HCV). While the exact mechanism is unknown, the occurrence of cancer is likely the result of prolonged HBV-induced liver damage and regeneration.

oncology tumor benign neoplasms malignant solid tumors metastasis hematologic cancers adenoma osteoma papilloma carcinoma adenocarcinoma sarcoma polp carcinoma in situ

Oncology comes from the Greek word onkos, which means "swelling." Oncology is thus the study or science of neoplasms. A clinical oncologist provides care in the clinical setting to diagnose and treat neoplasms. Although neoplasm is the proper term, the term tumor is commonly used to refer to a cancerous mass of cells. However, a tumor can be caused by several conditions, like inflammation and trauma. In contrast, neoplasms refer to the new cell growths and are classified as either (1) benign or (2) malignant. Benign neoplasms are well-differentiated cells, resemble the cells of tissues of origin, and have a slow, progressive rate of growth. They grow by expansion and remain localized to their site of origin, not capable of metastasizing. They develop a rim of connective tissue around the tumor called a fibrous capsule, which aids in surgical removal. Benign tumors are less of a threat unless they interfere with vital functions. For example, a benign brain tumor can cause death by compressing surrounding brain structures. Although not often life-threatening, the potential to interfere with general functions is possible. Benign tumors can compress blood vessels or nerves, or even abnormally produce hormones. Malignant neoplasms invade and destroy tissue. They grow rapidly, spread to other parts of the body, often via the circulatory or lymphatic systems, and lack well-defined margins. They can compress blood vessels and outgrow their blood supply, causing ischemia and tissue injury. Some secrete hormones, liberate toxins, or elicit an inflammatory response. Many others secrete vascular endothelial cell growth factor (VEGF). This increases blood supply to the tumor and facilitates more rapid growth. There are two broad categories of malignant neoplasms: solid tumors and hematologic cancers. Solid tumors are initially confined to a specific tissue or organ. As growth continues, cells detach, invade the surrounding tissue, and enter the blood and lymph systems to spread to other sites. This process is called metastasis. Hematologic cancers involve cells found in the blood and lymph systems; therefore, they are already spread throughout the body. Benign and malignant neoplasms are distinguished by the following traits: (1) cell characteristics, (2) rate of growth, (3) manner of growth, (4) capacity to invade and metastasize to other parts of the body, and (5) potential for causing death. These characteristics are summarized in Table 2.1 below. Adenoma is a benign tumor of glandular epithelial tissues. Osteoma is a benign tumor of bone tissue. Papilloma is a benign finger-like projection that grows on any surface. Carcinoma is a malignant tumor of epithelial tissue origin. Adenocarcinoma is a malignant tumor of glandular epithelial tissues Sarcoma is a malignant tumor of mesenchymal (multipotent) origin. A polyp is a growth that projects from a mucosal surface, such as the intestine. A polyp can be benign or malignant. Carcinoma in situ is a localized pre-invasive lesion. These can typically be surgically removed or treated, and recurrence is less likely. Breast ductal carcinoma in situ is one example, in which the cells have not crossed the basement membrane. Carcinoma in situ of the cervix is essentially 100% curable.