Chapter 7: Neoplasia
Interferon-y
been approved for the treatment of hairy cell leukemia, AIDS related Kaposi sarcoma & chronic myelogenous leukemia & as a adjuvant therapy for patients at high risk for recurrent melanoma
Adenoma
benign epithelial neoplasm of glandular tissue
Papillomas
benign microscopic or macroscopic fingerlike projections that grow on any surface
Fibroma
benign tumor arising in fibrous tissue
Steps to Metastasize
A cancer cell must be able to 1) break loose from the primary tumor 2) invade the surrounding extra cellular matrix 3) gain access to a blood vessel 4) survive its passage in the bloodstream 5) emerge from the bloodstream at a favorable location 6) invade the surrounding tissue 7) begin to grow & establish a blood supply (angiogensis)
Major Chemical Carcinogens: Naturally Occurring Carcinogens
Aflatoxin B1 Griseofulvin Betel nuts
Major Chemical Carcinogens: Aromatic Amines & Azo Dyes
B-Naphthylamine Aniline dyes
Estimated Deaths
Lung & bronchus(28%) Lung & bronchus(26%) Prostate(10%) Breast(14%) Colon & rectum(9%) Colon & rectum(9%) Pancreas(6%) Pancreas(7%) Liver & bile duct(5 Ovary(5%) Leukemia(4%) Leukemia(4%) Esophagus(4%) Non-Hodgkin lymphoma3% Urinary bladder(4%) Uterine corpus(3%) Non-Hodgkin lymphoma(3%) Brain & other nervous sys2% Kidney & renal pelvis(3%) Liver & bile duct(2%)
Estimated New Cases
Prostate(28%) Breast(29%) Lung & bronchus(14%) Lung & bronchus(14%) Colon & rectum(9%) Colon & rectum(9%) Urinary bladder(6%) Uterine corpus(6%) Melanoma of the skin(5%) Thyroid(6%) Kidney & renal pelvis(5%) Non-Hodgkin lymphoma4% Non-Hodgkin lymphoma(4%) Melanoma of skin(4%) Leukemia(3%) Ovary(3%) Oral Cavity & pharynx(3%) Kidney & renal pelvis3% Pancreas(3%) Pancreas(3%)
TNM System
T for primary tumor N for regional lymph node M for metastasis T1, T2, T3, & T4 describe tumor size N0, N1, N2 & N3 lymph node involvement M0 or M1 the absence or presence of metastasis
Faulty Cell to Cell Communication
a feature that may contribute to the growth & survival of cancer cells, impaired cell to cell communication may interfere with formation of intracellular connections & responsiveness to membrane derived signals
Apoptosis
a form of programmed cell death that eliminates old cells, deoxyribonucleic acid (DNA) & damaged or unwanted cells
Polyp
a growth that projects from a mucosal (membrane that lines various cavities in the body & surrounds internal organs) surface such as the intestine
Epstein-Barr Virus
a member of the herpes virus family, has been implicated in the pathogenesis of several human cancers, including Burkitt Lymphoma a tumor of B lymphocytes in persons with normal immune function the EBV driven B-cell proliferation is readily controlled & the person becomes asymptomatic or experiences a self-limited episode of infectious mononucleosis
Neoplasm
a new & abnormal growth of tissue in some part of the body, especially as a characteristic of cancer (abnormal mass of tissue in which the uncontrolled proliferation of cells exceeds & is uncoordinated with that of the normal tissues)
RNA Viruses
a number of retroviruses (RNA viruses) cause cancer in animals, human T-cell leukemia virus-1 (HTLV-1) is the only known retrovirus to cause cancer in humans associated with a form of T-cell leukemia that is endemic in certain parts of Japan & some areas of the Carribbean & Africa & is found sporadically elsewhere including the United States & Europe similar to AIDS virus, HTLV-1 is attracted to the CD4+ T cells
Incidence & Types of Childhood Cancers Cont.
a number of tumors of infancy & early childhood are embryonal in origin, meaning that they exhibit features of organogenesis similar to that of embryonic development c/ of this characteristic, these tumors are frequently designated with the suffix "blastoma" ex: nephroblastoma Wilms tumor & neuroblastoma are particularly illustrative of this type of childhood tumor
Major Chemical Carcinogens: Miscellaneous (various) Agents
abestos chromium, nickel & other metals when volatilized(evaporate or disperse in vapor) & inhaled in industrial settings insecticides, fungicides polychlorinated biphenyls
Exogenous Hormones
act by producing a decrease in hormone receptors or by antihormone drugs (antiestrogens & antiandrogens) that bind to hormone receptors, making them inaccessible to hormone stimulation
All tumors
all tumors benign & malignant are composed of two types of tissues 1) parenchymal 2)connective tissue
Incidence & Types of Childhood Cancers
although most adult cancers are of epithelial cell origin(lung cancer, breast cancer, colorectal cancers) childhood cancers usually involve the hematopoietic system (leukemia), brain & other parts of the nervous system, soft tissues, kidneys & bone the incidence of childhood cancers is greatest during the first years of life, decreases during middle school & then increases during puberty & adolescence
Carcinogens
an agent capable of causing cancer
Microarray Technology
analyzing a large number of molecular changes in cancer cells to determine overall patterns of behavior that would not be available by conventional means, the technique uses "gene chips" that can perform miniature assays to detect & quantify the expression of large numbers of genes at the same times used for predicting prognosis & response to therapy examining tumor changes after therapy & classifying hereditary tumors
Major Chemical Carcinogens: Direct-Acting Alkylating Agents
anticancer drugs (ex: cyclophosphamide, cisplatin, busulfan)
Tumor Markers
antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor are used for screening, establishing prognosis, monitoring treatment, & detecting recurrent disease have limitations, nearly all markers can be elevated in benign conditions, & most are not elevated in the early stages of malignancy
Tumor Antigens
antigens: a toxin or other foreign substance that induces an immune response in the body especially the production of antibodies tumor antigens may be clinically useful as markers to indicate the presence, recurrence, or progressive growth of a cancer, response to treatment can also be evaluated based on an increase or decrease in tumor antigens
Interferons
appear to inhibit viral replication & also may be involved in inhibiting tumor protein synthesis prolonging the cell cycle & increasing the percentage of cells in the G0 phase stimulate NK cells & T-lymphcyte killer cells three major interferons: alpha (a), beta (b), & gamma (y)
Interleukins (ILs)
are cytokines that provide communication between cells by binding to receptor sites on the cell surface membranes of the target cells IL-2 has been the most widely used
Malignant Neoplasms
are less differentiated & have lost the ability to control both cell differentiation & proliferation immortal, unlimited life span, divide an infinite number of times composed of poorly differentiated or undifferentiated cells are described as being anaplastic, anaplasia literally means to form backward to an earlier dedfifferentiated state
Systemic Manifestations: Central Fatigue
arises in the central nervous system (CNS) & is often described as the difficulty in initiating or maintaining voluntary activities one hypothesis proposed to explain cancer-related fatigue is that cancer & cancer treatments result in dysregulation of brain serotonin (5-HT) levels or function evidence that proinflammatory cytokines can influence serotonin metabolism
Common Paraneoplastic Syndromes: Hematologic: Nonbacterial thrombolytic endocarditis
associated tumor type: advanced cancers
Common Paraneoplastic Syndromes: Dermatologic nigricans
associated tumor type: gastric carcinoma proposed mechanism: possibly caused by production of growth factors (epidermal) by tumor cells
Common Paraneoplastic Syndromes: Hematologic: Venous Thrombosis
associated tumor type: pancreatic, lung other cancers proposed mechanisms: production of procoagulation factors
Common Paraneoplastic Syndromes: Neurologic: Eaton-Lambert syndrome
associated tumor type: small cell lung cancer proposed mechanism: autoimmune production of antibodies to motor end-plate structures
Common Paraneoplastic Syndromes: Endocrinologic: Cushing Syndrome
associated tumor type: small cell lung cancer, bronchial carcinoid cancers proposed mechanisms: production & release of ACTH by tumor
Common Paraneoplastic Syndromes: Endocrinologic: Syndrome of inappropriate ADH
associated tumor type: small cell lung cancer, others proposed mechanisms: production & release of ADH by tumor
Common Paraneoplastic Syndromes: Endocrinologic: Hypercalcemia
associated tumor type: squamous cell cancers of the lung, head, neck, ovary proposed mechanisms: production & release of polypeptide factor with close relationship to PTH
Common Paraneoplastic Syndromes: Neurologic: Myasthenia gravis
associated tumor type: thymoma
Obesity cont.
associated with increased levels of sex hormones (androgens & estrogens) which act to stimulate cell proliferation, inhibit apoptosis, & therefore increase the chance of malignant cell transformation particularly of endometrial & breast tissue & possibly of other organs (prostate & colon cancer) related to a condition of chronic inflammation characterized by abnormal production of inflammatory cytokines that can contribute to the development of malignancies
Currently Approved Monoclonal Antibodies Bevacozumab (Avastin)
bevacozumab(avastin), a humanized IgG monoclonal antibody that targets vascular endometrial growth factor (VEGF) to inhibit blood vessel growth(angiogenesis) & is approved for treatment of colorectal, renal, lung, & breast cancer
Functional Features
c/ of their lack of differentiation, cancer cells tend to function on a more primitive level than normal cells, retaining only those functions that are essential for their survival & proliferation they may also acquire some new features & become quite different from normal cells
Local & Regional Manifestations
c/ tumor cells replace normally functioning parenchymal cells, the initial manifestations of cancer usually reflect the function of the primary site of involvement (ex. lung cancer initially produces impairment of respiratory functions, as the tumor grows & metastasizes other body structures become affected) cancer has no regard for normal anatomic boundaries as it grows, it invades & compresses adjacent structures
Cancer-Associated Genes
can be classified into two broad categories based on whether gene overactivity or underactivity increases the risk for cancer
Chemical Carcinogens
can be divided into two groups 1) direct-reacting agents, which do not require activation in the body to become carcinogenic 2) indirect-reacting agents called procarcinogens or initiators
Molecular & Cellular Pathways
can see where the cancer is coming from includes defects in DNA repair mechanisms, disorders in growth factor signaling pathways, evasion of apoptosis, development of sustained angiogenesis (development of new blood vessels) & evasion of metastasis genetic damage may be caused by the action of chemicals, radiation, or viruses, or it may be inherited in the germ line (pg.139 in the book)
Hematogenous Spread
cancer cells commonly invade capillaries & venules, whereas thicker walled arterioles & arteries are relatively resistant the liver & lung are the most frequent metastatic sites for hematogenous spread some tumors metastasize to distant & unrelated sites
Characteristics of Benign Neoplasms
cell characteristics: well-differentiated cells that resemble cells in the tissue of origin rate of growth: usually progressive & slow; may come to a standstill of regress mode of growth: grows by expansion without invading the surrounding tissues; usually encapsulated metastasis: does not spread by metastasis
Pleomorphism
cells & nuclei display variations in size & shape
Cell density-dependent inhibition
cells stop dividing after the cell population reaches a particular density this is sometimes referred to as contact inhibition since cells often stop growing when they come in contact with each other
Differences between Benign & Malignant Tumors
determined by: 1) the characteristics of the tumor cells 2) the rate of growth 3) location invasion 4) ability to metastasize(spread to other sites in the body of metastasis)
Fibrosarcoma
cancer of fibrous tissue
Systemic Manifestations: Fatigue & Sleep Disorders
cancer related fatigue is characterized by feelings of tiredness, weakness, & lack of energy & is distinct from the normal tiredness experienced by healthy individuals in that it is not relieved by rest or sleep occurs both as a consequence of the cancer itself & as a side effect of cancer treatment may be an early symptom of malignant disease & has been reported by as many as 40% of patients at the time of diagnosis
Childhood Cancers
cancer remains the leading cause of disease-related deaths among children between 1 to 14 years in the U.S
Immunologic Mechanisms: Immunotherapy
cancer treatment modality (a particular mode in which something exists or is experienced or expressed) designed to heighten the patient's general immune responses so as to increase tumor destruction
Long-Term Effects of Childhood Cancer Treatment: Second Malignancy
cancer treatment: radiation, chemotherapy(alkylating agents, epipodophylotoxins) risk: solid tumors, leukemia, lymphoma, brain tumors
Long-Term Effects of Childhood Cancer Treatment: Musculoskeletal & bone
cancer treatment: radiation, chemotherapy(alkylating agents, topoisomerase II inhibitors) amputation risk: disordered limb growth, disorders of ambulation & limb use
Long-Term Effects of Childhood Cancer Treatment: Cardiac
cancer treatment: radiation, chemotherapy(anthracyclines) risk: cardiomyopathy, conduction abnormalities, valve damage, pericarditis, left ventricular dysfunction
Long-Term Effects of Childhood Cancer Treatment: Hematologic & lymphatic systems
cancer treatment: radiation, chemotherapy(anthracyclines, alkylating agents, vinca alkyloids, antimetabolites) & corticosteriod medications risk: leukemia, lymphoma
Long-Term Effects of Childhood Cancer Treatment: Pulmonary
cancer treatment: radiation, chemotherapy(carmustine, lomustine, bleomycin) risk: reduction in lung volume with exercise intolerance, restrictive lung disease
Long-Term Effects of Childhood Cancer Treatment: Renal/urological
cancer treatment: radiation, chemotherapy(platinums, ifbsfamide & cyclophosphamide, cyclosporine A), nephrectomy risk: kidney hypertrophy or atrophy, renal insufficiency or failure, hydronephrosis
Long-Term Effects of Childhood Cancer Treatment: Endocrine
cancer treatment: radiation, chemotherapy,(alkylating agents) risk: pituitary, thyroid, & adrenal dysfunction; growth failure; ovarian & testicular failure, delayed secondary sex characteristics; obesity, infertility
Long-Term Effects of Childhood Cancer Treatment: Central Nervous System
cancer treatment: radiation, intrathecal(injected into subarachnoid or subdural space) chemotherapy risk: learning disabilities
American Joint Committee (AJC)
cancers are divided into stages 0 to IV incorporating the size of the primary lesions & the presence of nodal spread & distant metastasis
Host & Environmental Factors
cancers develop c/ of interactions among host & environmental factors among the host factors that have been linked to cancer are heredity, hormonal factors, obesity, & immunologic mechanisms environmental factors include chemical carcinogens, radiation & microorganisms
Human Herpesvirus 8 (HHV-8)
causes Kaposi sarcoma in persons with AIDS association between infection with the bacterium Heliobacter pylori & gastric adenocarcinoma & gastric lymphomas
Characteristics of Malignant Neoplasms
cell characteristics: cells are undifferentiated, with anaplasia & atypical structure that often bears little resemblance to cells in the tissue of origin rate of growth: variable & depends on level of differentiation; the more undifferentiated the cells, the more rapid the rate of growth mode of growth: grows by invasion, sending out processes that infiltrate the surrounding tissues metastasis: gains access to blood & lymph channels to metastasize to other areas of the body
Currently Approved Monoclonal Antibodies Cetuximab (Erbitux)
cetuximab(Erbitux) a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR) to inhibit tumor cell growth & is approved for treatment of colorectal cancer & squamous cell cancer of the head & neck
Chemotherapy Side Effects
chemotherapy drugs affect both cancer cells, & the rapidly proliferating cells of normal tissue, producing undesirable side effects: anorexia, nausea & vomiting are common problems associated with cancer chemotherapy alopecia or hair loss results from impaired proliferation of the hair follicles & is a side effect of a number of cancer drugs; it usually is temporary & the hair tends to regrow when treatment is stopped
Chemotherapy Side Effects Cont.
chemotherapy drugs are toxic to all cells special care is required when handling or administrating the drugs drugs, drug containers, & administration equipment require special disposal as hazardous waste
Chemotherapy Drugs
chemotherapy drugs that have similar structures & effects on cell function usually are grouped together & these drugs usually have similar side effect profiles combination chemotherapy has been found to be more effective than treatment with a single drug
Chemical Carcinogens: Cigarettes
cigarette smoke contains both procarcinogens & promoters it is directly associated with lung & laryngeal cancer & has been linked with cancers of the mouth, nasal cavities, pharynx, esophagus, pancreas, liver, kidney, uterus, cervix & bladder & myeloid leukemias
Effusions Cont.
complaints of abdominal discomfort, swelling & a feeling of heaviness & increase in abdominal girth (measure around the middle of something) which reflect the presence of peritoneal effusions or ascites (abdominal swelling caused by accumulation of fluid, most often related to liver disease) are the most common presenting symptoms in ovarian cancer occurring in up to 65% of women with the disease
Benign Neoplasms/Tumors
composed of well-differentiated cells that resemble the cells of the tissues of origin & are generally characterized by a slow, progressive rate of growth that may come to a standstill or regress loose ability to suppress the genetic program for cell proliferation but retained program for normal cell differentiation they grow by expansion & remain localized to their site of origin & do not have the capacity to infiltrate, invade or metastasize to distant sites
Benign Neoplasms
composed of well-differentiated cells that resemble the normal counterpart both in terms of structure & function but have lost the ability to control cell proliferation surrounded by fibrous capsule, provides sharp line of separation from normal tissue that facilitates surgical removal
Two Categories of Malignant Neoplasms: Solid Tumors
confined to a specific tissue or organ, as the growth of the primary solid tumor progresses, cells detach from the original tumor mass, invade the surrounding tissue & enter the blood & lymph system to spread to distant sites a process called metastasis
Genetic Instability
considered a hallmark of cancer, concept came after the realization that uncorrected mutations in normal cells are rare due to many cellular mechanisms to prevent them characteristics of genetic instability are alterations in growth regulatory genes & genes involved in cell cycle progression & arrest
Hormone & Antihormone Therapy
consists of administration of drugs designed to deprive the cancer cells of the hormonal signals that otherwise would stimulate them to divide surgery involves the removal of the organ responsible for the hormone production that is stimulating the target tissue(ex. ovaries in women & testes in men)
Cancer cells
differ from normal cells by being immortal, that is they have an unlimited life span
Monoclonal Antibodies
directed against tumor-specific antigens as well as signaling molecules directed to block major pathways central to tumor cell survival & proliferation whereas others are modified to deliver toxins, radioisotopes, cytokines or other cancer drugs
Targeted Therapy
drugs that selectively attack malignant cells while leaving normal cells unharmed first targeted therapies were the monoclonal antibodies presently being researched
Diagnosis: Childhood Cancer
early detection is imperative (minimizes the amount & duration of treatment) no early warning signs or screening tests for cancer in children prolonged fever, persistent lymphadenopathy, unexplained weight loss, growing masses(especially in association with weight loss), & abnormalities of central nervous system function should be viewed as warning signs of cancer in children involves many methods that are used in adults
Radiation: Ultraviolet Radiation
emits relatively low-energy rays that do not deeply penetrate the skin, the evidence supporting the role of ultraviolet radiation in the cause of skin cancer includes skin cancer that develops primarily on the areas of skin more frequently exposed to sunlight(ex. the head & neck, arms, hands, & legs), a higher incidence in light-complexioned individuals who lack the ultraviolet filtering skin pigment melanin, & the fact that the intensity of ultraviolet exposure is directly related to skin cancer
Chemo Drugs: Cell Cycle Specific
exert their action during a specific phase of the cell cycle for example, methotrexate an antimetabolite acts by interfering with DNA synthesis & thereby interrupts the S phase of the cell cycle
Chemo Drugs: Cell Cycle- Nonspecific
exert their effects throughout all phases of the cell cycle, the alkylating agents which are cell cycle nonspecific, act by disrupting DNA when cells are in the resting state as well as when they are dividing
Radiation Therapy: Ways of Administration
external beam (Teletherapy) sealed radioactive sources placed close to the tumor(Brachytherapy) oral or injection administration of radioisotopes(systemic therapy)
Cancer Treatment
falls into 3 categories: curative, control & palliative (relieving pain) most common: surgery, radiation, chemotherapy, hormonal therapy & biotherapy
Direct & Indirect Acting Initiators
form highly reactive species (such as free radicals) that bind with residues on DNA, RNA or cellular proteins they then prompt cell mutation or disrupt protein synthesis in a way that alters cell replication & interferes with cell regulatory controls the carcinogenicity of some chemicals is augmented(being made greater in size or value) by agents called promoters that by themselves have little of no cancer causing ability
Major Chemical Carcinogens: Nitrosamines & Amides
formed in gastrointestinal tract from nitro-stable amines & nitrates used in preserving processed meats & other foods
Connective tissue
forms the supporting tissue framework or stroma(supportive tissue of an epithelial organ, tumor gonad etc consisting of connective tissues & blood vessels)
Malignant Neoplasms/Tumor
grow rapidly, invade & infiltrate nearby tissue, & spread to other parts of the body lack a well-defined capsule & their margins are not clearly separated from the normal surrounding tissue c/ of their rapid growth they may compress blood vessels & outgrow their blood supply, causing ischemia(decrease blood flow) & tissue injury some malignancies secrete hormones & cytokines, liberate enzymes & toxins & induce inflammatory response that injures normal tissue as well as the tumor
Local & Regional Manifestations Cont.
growing tumors may also compress & erode blood vessels causing ulceration & necrosis along with frank bleeding & sometimes hemorrhage
Chemical Carcinogens: Alcohol Consumption
heavy or regular alcohol consumption is associated with a variety of cancers. the 1st & most toxic metabolite of ethanol is acetaldehyde a known carcinogen that interferes with DNA synthesis & repair & that causes point mutations in some cells the carcinogenic effect of cigarette smoke can be enhanced by consumption of alcohol; persons who smoke & drink considerable amounts of alcohol are at increased risk for development of cancer of the oral cavity, larynx, & esophagus
Hormones
hormones have received considerable research attention with respect to cancer of the breast, ovary, & endometrium in women & of the prostate & testis in men may reside with the ability of hormones to drive the cell division of a malignant phenotype
Anoikis
if normal epithelial cells become detached, they often undergo a type of apoptosis known as anoikis due to not having a home, cancer cells often survive in microenvironments different from those of the normal cells
Systemic Manifestations: Paraneoplastic Syndromes
in addition to signs & symptoms at the sites of primary & metastastic disease, cancer can produce manifestations in sites that are not directly affected by the disease some of these manifestations are caused by the elaboration of hormones by cancer cells & others result from the production of circulating factors that produce hematopoietic, neurologic & dermatologic syndromes, these syndromes are most commonly associated with lung, breast, & hematologic malignancies
Epstein- Barr Virus Cont.
in regions of the world where Burkitt lymphoma is endemic, such as parts of East Africa, concurrent malaria or other infections cause impaired immune function, allowing sustained B-lymphocyte proliferation Epstein-Barr virus is also associated with B-cell lymphomas in immuno-suppressed individuals such as those with AIDS or with drug-suppressed immune systems (individuals with transplanted organs)
Chemical Carcinogens: Chewing Tobacco
increases the risk of cancers of the oral cavity & esophagus
Initiation
initial mutation occurs involves the exposure of cells to doses of a carcinogenic agent that induce malignant transformation the carcinogenic agents can be chemical, physical, or biologic & they produce irreversible changes in the genome of a previously normal cell c/ the effects of initiating agents are irreversible multiple divided doses may achieve the same effects as single exposures of the same comparable dose or small amounts of highly carcinogenic substances cells most susceptible to mutagenic alterations are those actively synthesizing DNA
Cytokines
interferons & interleukins
Two Categories of Malignant Neoplasms: Hematologic Cancers
involve cells normally found within the blood & lymph, making them disseminated (spread/disperse) diseases from the beginning
Epigenetic Mechanisms
involve changes in the patterns of gene expression without a change in the DNA may silence genes such as tumor-suppressor genes so that even if the gene is present, it is not expressed & a cancer-suppressing protein is not made one such mechanism of epigenetic silencing is by the methylation (process by which methyl groups are added to DNA) of the promoter region of the gene, a change that prevents transcription & causes gene inactivity
Treatment: Childhood Cancer
involves appropriate multidisciplinary & multimodal therapy as well as evaluation for recurrent disease & late effects of the disease & therapies used in its treatments chemotherapy is more widely used c/ children better tolerate the acute adverse effects & in general pediatric tumors are more responsive to chemotherapy than adult cancers radiation therapy is used sparingly in children c/ they are more vulnerable to the late adverse effects, adequate pain management is critical
Grading of Tumors
involves microscopic examination of cancer cells to determine their level of differentiation & the number of mitoses on a scale ranging from grade I to IV grade I neoplasms are well differentiated & grade IV are poorly differentiated & display marked anaplasia
Promotion
involves the induction of unregulated accelerated growth in already initiated cells by various chemicals & growth factors promotion is reversible if the promoter substance is removed, cells that have been irreversibly initiated may be promoted even after long latency periods, the latency period varies with the type of agent, the dosage, & the characteristics of the target cells many chemical carcinogens are called complete carcinogens c/ they can initiate & promote neoplastic transformation
Tissue Biopsy
involves the removal of a tissue specimen for microscopic study, it is of critical importance in designing the treatment plan should cancer cells be found
Biotherapy
involves the use of immunotherapy & biologic response modifiers as a means of changing a person's immune response & modifying tumor cell biology it involves the use of monoclonal antibodies, cytokines & adjuvants (applied after initial treatment for cancer)
Immunohistochemistry
involves the use of monoclonal antibodies to facilitate the identification of cell products or surface markers, for example certain anaplastic carcinomas, malignant lymphomas, melanomas, & sarcomas look very similar under microscope but must be accurately identified c/ their treatment & prognosis are different often help to identify the tumor source
Radiation: (dose dependent) Ionizing Radiation
ionizing radiation in carcinogenesis have been well documented in atomic bomb survivors, in patients diagnostically exposed & in industrial workers, scientists, & physicians who were exposed during employment, malignant epitheliomas of the skin & leukemia were significantly elevated in these populations
Cytologic, Histologic & Gene- Profiling Methods
laboratory methods used to examine tissues & cells several sampling approaches are available including cytologic smears, tissue biopsies & needle aspiration
Tumor-Suppressor Genes
less active, create an environment in which cancer is promoted mutations inhibit or decrease- gene underactivity inhibit cell activity mutations inhibit or decrease
Malignant Tumors Spread By:
lymph channels (lymphatic spread) or blood vessels(hematogenous spread) lymphatic spread is more typical of carcinomas, whereas hematogenous spread is favored by sarcomas
Adenocarcinoma
malignancies that originate from glandlike structures
Chondrosarcoma
malignant tumor composed of chondrocytes
Sarcomas
malignant tumors of mesenchymal origin
Systemic Manifestations: Anorexia & Cachexia
many cancers associated with weight loss & wasting of body fat & muscle tissue, accompanied by profound weakness, anorexia, & anemia (cancer anorexia-cachexia syndrome) most common in in children & elderly people persons with this syndrome respond less well to chemotherapy & have more side effects
Systemic Manifestations: Anemia
may be related to the blood loss, iron deficiency hemolysis, impaired red cell production, or treatment effects tumors decrease erythropoietin synthesis resulting in a decrease in erythrocyte production cancer related anemia is associated with reduced treatment effectiveness, increased mortality, increased transfusion requirements, & reduced performance & quality of life often treated with iron supplementation & recombinant human erythropoietin (rHuEPO, epoetin alfa)
Anaplasia
mean to form backward to an earlier dedifferentiated state, highly anaplastic cancer cells, whatever their tissue of origin, begin to resemble undifferentiated or embryonic cells more than they do their tissue of origin (THE LOSS OF CELL DIFFERENTIATION IN CANCEROUS TISSUE)
Oncogenesis
mechanisms & genes that regulate repair of damaged DNA
Metastatic Spread
metastasis is used to describe the development of a secondary tumor in a location distant from the primary tumor cells in a primary tumor develop the ability to escape, travel & survive in the blood, exit the blood, & develop a secondary tumor
Chemical Carcinogens: Dietary Intake
most known dietary carcinogens occur either naturally in plants (ex. aflatoxins: any of a class of toxic compounds that are produced by certain molds found in food & can cause liver damage & cancer) are produced during food preparation the polycyclic aromatic hydrocarbons are of particular interest c/ they are produced during several types of food preparation including frying foods in animal fat that has been reused multiple times, grilling or charcoal-broiling meats & smoking meats & fish
Tumor Antigens
most tumor cells have molecular configurations that can be specifically recognized by immune cells or antibodies these configurations are therefore called tumor antigens, some tumor antigens are found only on tumor cells whereas others are found on both tumor cells & normal cells however, quantitative & qualitative differences in the tumor antigens permit the immune system to distinguish tumor from normal cells
Genetic Amplification
multiple copies of certain genes may cause overexpression with higher than normal levels of proteins that increase cell proliferation
p53 gene
named after molecular weight of the protein it encodes, is the most common target for genetic alteration in human cancers mutations in p53 gene can occur in every type of cancer including lung, breast, & colon cancer - the 3 leading causes of cancer death
Cancer-Associated Genes: Proto-Oncogenes
normal genes that become cancer-causing genes if mutated encode for normal cell proteins such as growth factors, growth receptors, transcription factors that promote cell growth, cell cycle proteins (cyclins or cyclin-dependent proteins) & inhibitors of apoptosis
Obesity
obesity is a risk factor for certain types of cancer, including breast, endometrial, & prostate cancer associated with insulin resistance & increased production of pancreatic insulin, both of which can have a carcinogenic effect
Chemical Carcinogens: Exposure to Chemicals
occupational exposure to industrial chemicals is another significant risk factor for cancer these include polycyclic aromatic hydrocarbons (chemicals released from burning coal, oil, gasoline, trash, tobacco, wood etc) which are metabolized in the liver
Tumor Growth
one of the reasons cancerous tumors often seem to grow so rapidly relates to the size of the cell pool that is actively engaged in cycling, cancer cells do not die on schedule & growth factors prevent cells from exiting the cell cycle & entering G0 or noncycling phase
Viral & Microbial Agents:
only four DNA viruses have been implicated in human cancers: 1) human papilloma virus (HPV) 2) Epstein-Barr virus (EBV) 3) Hepatitis B viruss (HBV) 4) human herpesvirus 8 (HHV-8)
Systemic Manifestations: Peripheral Fatigue
origin in the neuromuscular junction & muscles results from the inability of the peripheral neuromuscular apparatus to perform a task in response to central stimulation mechanisms implicated in peripheral fatigue include a lack of adenosine triphosphate (ATP) & the buildup of metabolic by-products such as lactic acid
Squamous Cell Carcinoma
originate from squamous cells
Papanicolaou Smear
pap smear is a cytologic method that consists of a microscopic examination of a properly prepared slide by a cytotechnologist or pathologist for the purpose of detecting the presence of abnormal cells is widely used as a screening test for cervial cancer, it can be performed on other body secretions, including nipple drainage, pleural or peritoneal fluid & gastric washings
Hormone & Antihormone Therapy Cont.
pharmacologic suppression of circulating hormone levels can be effected through pituitary desensitization(diminish) as with the administration of androgens or through the administration of gonadotropin-releasing hormone(GnRH) analogs that act at the level of the hypothalamus to inhibit gonadotropin production & release
Chemical Carcinogens: Nitrosamines
powerful carcinogens are formed in foods that are smoked, salted, cured, or pickled using nitrites or nitrates as preservatives cancer of the colon has been associated with high dietary intake of fat & red meat & a low intake of dietary fiber
Differentiation
process of specialization whereby new cells acquire the structural, microscopic, & functional characteristics of the cells they replace
Proliferation
process of the cell division, is an inherent adaptive mechanism for cell replacement when old cells die or additional cells are needed
Progression
process whereby tumor cells acquire malignant phenotypic changes these changes may promote the cell's ability to proliferate autonomously, invade, or metastasize, they may also destabilize its karyotype (test to identify & evaluate the size, shape, & number of chromosomes in a sample of body cells)
Cancer-Associated Genes: Oncogenes
proto-oncogenes mutate to oncogenes (encode for abnormal cells) insertions, deletions, translocations-> increased or activated ex. Philadephia chromosomes, HER-2/neu
Interferon-a
used to treat some solid tumors (renal cell carcinoma, colorectal cancer, carcinoid tumors, ovarian cancer) & hematologic neoplasms (B-cell & T-cell lymphomas, cutaneous T-cell lymphoma, & multiple myeloma)
Radiation Therapy Cont.
rapidly proliferating & poorly differentiated cells of a cancerous tumor are more likely to be injured by radiation therapy than are the more slowly proliferating cells of normal tissue radiation is injurious to all rapidly proliferating cells, including those of the bone marrow, & the mucosal lining of the gastrointestinal tract results in many of the common adverse effects of radiation therapy including infection, bleeding, & anemia due to loss of blood cells, & nausea & vomiting due to loss of gastrointestinal tract cells
Chemokines
recent evidence indicates chemoattractant cytokines called chemokines that regulate the trafficking of leukocytes(WBCs) & other cell types under a variety of inflammatory & noninflammatory conditions may play a critical role in cancer invasion & metastasis
Differentiation
refers to the extent to which the parenchymal(specific organ versus supportive tissue) cells of a tumor resemble their normal forbearers morphologically(study of form & structure of organisms) & functionally
Genomic Instability
results in gross chromosomal abnormalities, benign tumors usually have a normal number of chromosomes, by contrast malignant cells often display a feature called aneuploid (have abnormal number of chromosomes)
Currently Approved Monoclonal Antibodies Rituximab (Rituxan)
rituximab (Rituxan), a chimeric IgG monoclonal antibody that targets the CD20 antigen on B cells & is used in the treatment of nonHodgkin lymphoma;
Screening
screening can be achieved through observation ( skin, mouth, external genitalia) palpation (breast, thyroid, rectum, & anus, prostate, lymph nodes) laboratory tests & procedures (pap smear, colonoscopy, mammography)
p53 gene cont.
sometimes called the "guardian of the genome" the p53 gene acts as a molecular police officer that prevents the propagation of genetically damaged cells, the p53 gene normally senses DNA damage & assists in DNA repair causing arrest of the cell cycle in G1 & inducing DNA repair or initiating apoptosis in a cell that cannot be repaired
Tumor Markers Specific Proteins: Monoclonal immunoglobulin
source: abnormal immunoglobulin produced by neoplastic cells associated cancers: multiple myeloma
Tumor Markers Oncofetal Antigens: Carcinoembryonic antigen (CEA)
source: embryonic tissues in gut, pancreas, & liver associated cancers: colorectal cancer & cancers of the pancreas, lung, & stomach
Tumor Markers Oncofetal Antigens: a-Fetoprotein (AFP)
source: fetal yolk sac & gastrointestinal structures early in fetal life associated cancers: primary liver cancers; germ cell cancer of the testis
Tumor Markers Hormones: Human chorionic gonadotropin (hCG)
source: hormone normally produced by placenta associated cancers: gestational trophoblastic tumors; germ cell cancer of testis
Tumor Markers Hormones: Calcitonin
source: hormone produced by thyroid parafollicular cells associated cancers: thyroid cancer
Tumor Markers Hormones: Catecholamines (epinephrine, norepinephrine) & metabolites
source: hormones produced by chromaffin cells of the adrenal gland associated cancers: pheochromocytoma & related tumors
Tumor Markers Cluster of Differentiation: CD antigens
source: present on leukocytes associated cancers: used to determine the type & level of differentiation of leukocytes involved in different types of leukemia & lymphoma
Tumor Markers Mucins & other Glycoproteins: CA-19-9
source: produced by alimentary tract epithelium associated cancers: cancer of the pancreas & colon
Tumor Markers Mucins & other Glycoproteins: CA-125
source: produced by mullerian (upper portions of the vagina ex.uterus, fallopian tubes) cells of ovary associated cancers: ovarian cancer
Tumor Markers Specific Proteins: Prostate-specific antigen (PSA)
source: produced by the epithelial cells lining the acini & ducts of the prostate associated cancers: prostate cancer
Parenchymal
specific functional cells of an organ or tissue, made up of the transformed neoplastic cells of a tumor, determines its behavior & its component for which the tumor is named
Hepatitis B virus (HBV) & Hepatitis C
strong epidemiologic evidence linking chronic HBV & hepatitis C virus (HCV) infection with hepatocellular carcinoma has been estimated that 70% to 85% of hepatocellular cancers worldwide are due to infection with HBV or HCV it seems probable that oncogenic effects are multifactorial with immunologically mediated chronic inflammation leading to persistent liver damage, regeneration & genomic damage
Anchorage Independence
studies in culture show that normal cells with the exception of hematopoietic cells(give rise to all the other blood cells) will not grow & proliferate unless they are attached to a solid surface such as extracellular matrix
Adjuvants
substances such as Bacillus Calmette-Guerin (BCG) that nonspecifically stimulate or indirectly augument(make something greater) the immune system an attenuated(unnaturally thin) strain of the bacterium that causes bovine tuberculosis are used to treat noninvasive bladder cancer after surgical ablation(surgical removal of body tissue) it is assumed that BCG acts locally to stimulate an immune response thereby decreasing the relapse rate
Immunologic Mechanisms: Immune Surveillance Hypothesis
suggest that the development of cancer might be associated with impairment or decline in the surveillance capacity of the immune system increases in cancer incidence have been observed in people with immunodeficiency diseases & in those with organ transplant who are receiving immunosuppressant drugs, the incidence of cancer is also increased in the elderly in whom there is a known decrease in immune activity
Immunologic Mechanisms: Immune Surveillance
suggest that the immune system plays a central role in protection against the development of tumors cancer-host interactions as a mechanism of cancer development, immunologic mechanisms provide a means for the detection, classification & prognostic evaluation of cancers & a potential method of treatment
Cancer Treatment: Chemotherapy Side Affects
suppress bone marrow function & formation of blood cells anemia- hypoxia neutropenia- increased risk of developing serious infections thromnocytopenia- increased risk for bleeding treatment hematopoietic growth factors erythropoietin- stimulates RBC production (granulocyte colony stimulation factor G-CSF) IL-11- stimulates platelet production
Tumor-Suppressor Genes Cont.
tend to behave normally until there is a deletion, inactivation or silencing of both maternal & paternal gene best known tumor-suppressor genes p53 & RB
RB gene
the RB gene was isolated in studies involving a malignant tumor of the eye known as retinoblastoma the tumor occurs in a heredity & sporadic form & becomes evident in early life pg. 138 in book
Immunologic Mechanisms: Kaposi Sarcoma
the association of Kaposi sarcoma with acquired immunodeficiency syndrome(AIDS) further emphasizes the role of the immune system in preventing malignant cell proliferation
Etiology of Cancer
the cause of causes of cancer can be viewed from two perspectives: 1) the genetic & molecular mechanisms that characterize the transformation of normal cells into cancer cells 2) the external & more contextual (surrounding words) factors such as age, heredity, & environmental agents that contribute to its development & progression.
Genetic & Molecular Basis of Cancer Cont.
the cellular microenvironment that involves the extracellular matrix & a complex milieu(a person's social environment) of cytokines, growth factors, & other cell types is also recognized as an important contributor to cancer development & its growth & progression
Local & Regional Manifestations: Effusions
the development of effusions (fluid) in the pleural, pericardial or peritoneal spaces may be the presenting sign of some tumors direct involvement of the serous surface seems to be the most significant inciting factor, although many other mechanisms such as obstruction of lymphatic flow may play a role most persons with pleural effusions are symptomatic at presentation with chest pain, shortness of breath, & cough
Lymphatic Spread
the first evidence of dispersed disease is the presence of tumor cells in the lymph nodes that drain the tumor area when metastasis occurs by the way of the lymphatic channels, the tumor cells lodge first in the initial lymph node that receives drainage from the tumor site once in lymph node, the cells may die c/ of the lack of a proper environment, remain dormant for unknown reasons or grow into a visible mass
HER-2/neu
the human epidermal growth factor receptor-2 (HER-2/neu) genes is amplified in up to 30% of breast cancers & indicates a tumor that is aggressive with a poor prognosis one of the agents used in treatment of HER-2/neu overexpressing breast cancers is trastuzumab(Herceptin) a monoclonal antibody that selectively binds to HER-2, thereby inhibiting the proliferation of tumor cells that overexpress HER-2
Survivors of Childhood Cancers
the number of children who survive childhood cancer is continuing to increase, radiation & chemotherapy may produce late consequences such as impaired growth, neurologic dysfunction(cognitive difficulties) , hormonal dysfunction(growth hormone & delayed sexual maturation in both boys & girls), cardiomyopathy, pulmonary fibrosis & risk for 2nd malignancies cranial irradiation may result in premature menarche(menstruation) in girls
Philadelphia Chromosomes
the outcome of the translocation in chronic myeloid(relating to bone marrow or spinal cord) leukemia is the appearance of Philadelphia chromosome involving chromosomes 9 & 22 & the formation of an abnormal fusion protein that promotes cell proliferation
Genetic & Molecular Basis of Cancer
the pathogenesis(the manner of development of a disease) of most cancers is thought to originate from genetic damage or mutation with occurring changes that transform a normally functioning cell into a cancer cell epigenetic factors that involve silencing of a gene or genes may also be involved
Tumor Cell Transformation
the process by which carcinogenic agents cause normal cells to become cancer cells is hypothesized to be a multistep mechanism that can be divided into three stages: initiation, promotion, & progression
Tumor Growth: Rate of Growth
the rate of growth in normal & cancerous tissue depends on 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
Tumor Growth Cont.
the ratio of dividing cells to resting cells in a tissue mass is called the growth fraction the doubling time is the length of time it takes for the total mass of cells in a tumor to double, as the growth fraction increases, the doubling time decreases
Seeding of Cancer Cells
the seeding of cancer cells into body cavities occurs when a tumor erodes & sheds cells into these spaces the seeding of cancers is often a concern during the surgical removal of cancers, where it is possible to accidentally introduce free cancer cells into a body cavity such as the peritoneal cavity
Radiation
the type of cancer that developed depended on the dose of radiation, the sex of the person & the age at which exposure occurred the length of time between exposure & the onset of cancer is related to the age of the individual
Invasion
the word cancer is derived from the latin word meaning crablike c/ cancers grow & spread by sending crablike projections into the surrounding tissues, unlike benign tumors which grow by expansion & usually are surrounded by a capsule, cancer spreads by direct invasion into surrounding tissues, seeding of cancer cells in body cavities & metastatic spread
The Human Papilloma Virus (HPV)
there are over 70 genetically different types of HPV, some types (ex. types 1, 2, 4, 7) have been shown to cause benign squamous papillomas (ex. warts) by contrast, high risk HPVs ( types 18 &16) are implicated in the pathogenesis of squamous cell carcinoma of the cervix & anogenital (anus & genitals) region cervical cancer can be viewed as a sexually transmitted disease caused by transmission of HPV
Biology of Childhood
there is probably no one cause of childhood cancer interaction between genetic susceptibility & environmental exposures
Tumor Markers Cont.
they are not in themselves specific enough to permit a diagnosis of a malignancy, but once a malignancy has been diagnosed & shown to be associated with elevated levels of a tumor marker, the marker can be used to assess progress of the disease the greatest value of tumor markers is in monitoring therapy in people with widespread cancer
Systemic Manifestations: Paraneoplastic Syndromes Cont.
three most common endocrine syndromes associated with cancer are the syndrome of inappropriate antidiuretic hormone (ADH) secretion, cushing syndrome due to ectopic adrenocorticotroptic hormone & hypercalcemia also can be caused by osteolytic (bone spurs, breaks up bone & calcium goes into your blood stream) processes induced by cancer such as multiple myeloma or bony metastases from other cancers
Major Chemical Carcinogens: Polycyclic & Heterocyclic Aromatic Hydrocarbons
tobacco combustion (cigarette smoke) animal fat in broiled & smoked meats benzo(a)pyrene vinyl chloride
Angiogenesis
tumor cells as well as other cells in the microenvironment secrete factors that enable the development of new blood vessels within the tumor known as angiogenesis
Heredity
two tumor suppressor genes called BRCA1 (breast carcinoma 1) & BRCA 2 (breast carcinoma 2) have been implicated in a genetic susceptibility to breast cancer & RB(retinoblastomas) which are inherited & carriers of the mutant RB suppressor gene
Chemotherapy
unlike surgery & radiation chemotherapy is a systemic treatment that enables drugs to reach the site of the tumor as well as distant sites most cancer drugs are more toxic to rapidly proliferating cells than to those incapable of replication or in phase G0 of the cell cycle c/ of their mechanism of action, they are more effective against tumors with a high growth fraction
Radiation Therapy
used as the primary treatment as preoperative or postoperative treatment with chemotherapy or along with chemotherapy & surgery, it can be used as a palliative treatment to reduce symptoms in persons with advanced cancers can immediately kill cells, delay or halt cell cycle progression, or at dose levels commonly used in radiation therapy cause damage to cell nucleus resulting in cell death after replication
Surgery
used for diagnosis, staging of cancer, tumor removal, & palliation( relief of symptoms) when a cure cannot be achieved if the tumor is small & has well defined margins, the entire tumor often can be removed, if however the tumor is large or involves vital tissues, surgical removal may be difficult if not impossible
Lymphatic Spread: Sentinel Node
used to describe the initial lymph node to which the primary tumor drains extent of disease may be determined through lymphatic mapping & sentinel lymph node biopsy, this is done by injecting a radioactive tracer & blue dye into the tumor to determine the first lymph node in the route of lymph drainage from the cancer, once the sentinel lymph node is identified, it is examined to determine the presence or absence of cancer cells
Carcinoma
used to designate a malignant (infectious) tumor of epithelial tissue origin
Clinical Staging
uses methods to determine the extent & spread of the disease useful in determining the choice of treatment for individual patients, estimating prognosis & comparing the results of different treatment regimens two methods of staging is the TNM system & American Joint Committee (AJC)
Neoplasia
which is cancer (a disorder of altered cell differentiation & growth) a disease in which abnormal cells divide uncontrollably & destroy body tissue
