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Patho 2 Fall 2011
―It has been estimated that approximately 35 billion cells divide each day in a healthy adult, and any of these divisions could produce a rogue cell population that continues to grow without constraint. Uncontrolled cell growth is called ―cancer‖. We make about 100 cancer cells per day but fortunately our immune system recognizes these cancer cells as foreign and immediately destroys the cells before they have the chance to develop into a malignant tumor.‖ Bancroft
Refers to all malignant neoplasms May arise from most organs Morbidity and mortality vary by type of CA Many are curable or treatable Ranks 2nd to CV disease as leading cause of death in US Affects all age groups Causes more deaths in children age 3 – 15 than any other disease
1 out of 3 Americans will develop cancer in their lifetime; 1 in 4 deaths in US is due to cancer Most common in all: Skin CA Men: prostate, lung, colorectal Women: Breast, lung, colorectal
Lung cancer is leading cause of CA death in US. Is resistant to treatment
Cancer cells first develop from mutation in a single cell. This cell grows without the control that characterizes normal cell growth. At a certain stage of development, the cancer cell fails to mature into the type of normal cell from which it originated . Cancer cells are capable of spreading from site of origin (metastasis)
Altered Cell Growth Neoplasia = new growth of cells. disorder of altered cell differentiation and growth Neoplasm = abnormal tissue which results .
. they continue to grow until they produce death. cancer cells undergo unrestrained growth and division. Some neoplasia’s grow fast and other grow slowly.Cell Proliferation Orderly process that provides body with means for replacing cells as needed Usually a balance between # cells dying and # cells proliferating Unlike normal cells. Without intervention.
Cell Differentiation Process by which proliferating cells are transformed into specialized cell types. the more likely it will lose it’s ability to reproduce and divide Stem cells remain incompletely differentiated throughout life . which determines cell function The more highly specialized a cell.
skin. liver cell --are partly differentiated—produce specialized cells (cell lines) when stimulated Well or fully-differentiated: neural. striated & cardiac muscle: cannot divide —have the structural and functional characteristics of a specific cell line Under genetic & environmental control .Cell Differentiation Groups of Cell types: Undifferentiated Stem cells: can be triggered to divide & reproduce several progenitor cells—> several cell lines Parent or progenitor: blood.
can be stimulated to divide Nondividing permanent cells. cardiac muscle . like neurons.Cell Cycle G0— resting phase.
cellsalive.htm . Has 4 major phases: G1 (Gap 1): cell prepares to make DNA S phase: DNA synthesis actually takes place G2: prepares for mitosis (cell division) M phase: mitosis occurs G0: resting phase (becomes mitotically dormant) http://www.Cell Cycle Cell cycle is sequence of events cell goes thru from one mitotic division to next.com/cell_cycle.
Defects in either of these can contribute to development of cancer (may cause genetic instability of cancer cells) . There are checkpoints in cell cycle which determine accuracy with which DNA is duplicated.Cell Cycle Entry into and progression thru stages are controlled by proteins called cyclins and their inhibitors.
vascular) . shape. arrangement Neoplasms have 2 tissue types: --Parenchymal (organ cells) --Stromal (supporting tissue—connective.Neoplasms Do not obey normal tissue growth laws: --Do not occur in response to appropriate stimulus --Continue to grow after the stimulus has ceased --Function independently of body’s needs: -faster growth rate -increase in size at expense of rest of body’s needs -great variation in cell size.
or metastasize May become encapsulated Less blood supply than malignant neoplasm Usually do not cause death unless interfere with vital functions because of their location Can cause alterations in body function thru abnormal alteration of hormones Benign Neoplasms . invade.Composed of well-differentiated cells that resemble cells of tissues of origin Slow growth rate Remain localized to site of origin without capacity to infiltrate.
Benign tumors--Fibroids .
Benign Uterine Tumor with Clearly Defined Edges .
irregular growth pattern. not distinct from surrounding tissue Invade adjacent cells rather than pushing aside Varying growth rates and do not die within normal timeframe More blood supply than normal tissue Hallmark Sign of malignancy: ability to metastasize or spread to distant sites See Porth Table for comparison of benign vs.Malignant Neoplasms = Cancer Atypical cell structure. no capsule formed. abnormal nucleus & chromosomes Lose differentiation or resemblance to origin cell--more anaplastic Not cohesive. malignant .
Naming Tumors Benign tumors: tissue name + ―-oma‖ Eg: osteoma = benign bone tumor Malignant tumors (cancers) Epithelial tissue: tissue name + ―carcinoma‖ Mesenchymal tissue: tissue name + ―sarcoma‖ ―Malignant _____oma‖ Eg: Adenocarcinoma = Cancer of glandular tissue .
lysis with enzymes Seeding of CA cells in body cavities Metastasis .Spread of Cancer Direct invasion & extension – local spread. mechanical.
CA may die.Metastasis Ability of CA cells to spread to distant sites Clumps of malignant cells break off & travel thru blood (hematogenic spread) or lymph (lymphatic spread) to new site – most are killed by body’s defense mechanisms In lymph nodes. or remain dormant . grow into mass.
What abilities would you need to survive in the tumor? What abilities would you need to metastasize? .Metastasis Cells in a primary tumor develop the ability to escape and travel in the blood Imagine you were a cancer cell.
Cancer Progression .
lungs. liver. brain Original tumor = primary neoplasm Metastatic site = secondary neoplasm (retains characteristics of primary tumor) .Metastasis Surviving CA cells leave lymph nodes & enter venous blood & are carried to major organs: bone.
Why? Doubling time (TD) = time to double total mass of CA cells GF and TD are very fast until tumor outgrows blood supply. So. then slows May be influenced by hormones . chemotherapeutic drugs are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction.Tumor Growth Growth Fraction (GF) = ratio of dividing cells / G0 cells A tissue with a large percentage of proliferating cells and few cells in G0 has a high growth fraction.
are active continuously & promote unregulated. breast. abnormal & disordered growth. Selected oncogenes have been associated with numerous cancer types Mutations in p53 gene have been implicated in development of lung. and colon cancer .Etiology of Cancer Genes that cancer cells contain – encode for cancer causing proteins Proto-oncogenes = Normal genes that regulate cell growth & differentiation & are active for only a short time in cell cycle Oncogenes = gene mutations which become cancer-causing genes.
chemical (many environmental and manmade substances) or biological (oncogenic viruses. immunodeficiency) carcinogens Is a monoclonal origin because a single cell is transformed into a cancer cell .Oncogenesis: Mechanism by which a normal cell is transformed into cancer cell by random genetic mutation or mutation induced by exposure to physical (radiation).
Tumor Supressor Genes Tumor Supressor genes =anti-oncogenes normally inhibit inappropriate cell growth--start senescence and crisis or cell death senescence = when cells stop dividing -.in response to growth inhibiting proteins like P53 crisis = when cells die Abnormal tumor suppressor genes are inherited or mutant genes Fail to inhibit inappropriate cell growth Mutation of TP53 gene is found in 50% of human cancers. codes for p53 protein which functions as a suppressor of tumor growth FHIT (fragile histidine triad protein) gene: tobacco smoke causes it to mutate – seen in small cell lung cancer .
or endogenous hormone Progression: process whereby tumor cells get malignant characteristics Metastasis: spread .Stages of Cancer Growth Initiation: exposure of cells (especially those actively synthesizing DNA) to enough carcinogens that alter cell's genomeirreversible mutation Promotion: induction of unregulated accelerated growth by some agent. chemical.
Mrs. Are they not all the same cells? . the tumor shrank by almost 75% Two years later the tumor was growing again. and this time it did not respond to the drug Last year she was diagnosed with metastases in her femur that has not responded to the drug either Mrs. T Has Liver Cancer … Her doctor did an initial molecular diagnosis and put her on targeted therapy. T wants to know why the cancer cells stopped responding.
Cervical Cancer .
leading to: Unchecked increase in # of cells Ability to invade body structures Ability to metastasize to distant locations Inappropriate cell life span .In Review… Cancer is error in DNA creates abnormal clonal cells which multiply and function inappropriately.
Risk Factors Heredity : < 5 % of all CA--MOST cancers are due to spontaneous genetic mutations Oncogenes: specific genes that CA cells contain-.may be inherited by autosomal dominant or autosomal recessive patterns Oncogenic viruses: viruses that may cause CA--alter genome of infected cell & cells it divides into Includes DNA and RNA viruses Cause CA by inserting viral genes into host's DNA which then replicates Herpesvirus cervical CA. HTLV-1 leukemia Oncogenic bacteria--H. Hepatitis B & C liver cancer. Epstein-Barr virus -> Burkitt’s lymphoma. Pylori--linked to gastric CA and lymphoma . human papillomavirus (HPV) skin & cervical CA.
cadmium.Chemical carcinogenesis: cause mutations Polycyclic aromatic hydrocarbons Food and drugs tobacco smoke CA of head & neck. pancreas. carcinogenic effect of cigarette smoke is enhanced in presence of alcohol Nitrosamines: develop from nitrites (a food additive) in presence of amines & nicotine gastric CA asbestos. nickel. bladder Plants: aflatoxin (mold) & betel nut liver CA Food preparation: smoked and charbroiled meats Alcohol: carcinogen promotor. chromium. benzene -> Lung & other CAs Nitrogen mustard & mustard gas leukemias & lymphomas Risk Factors Industrial Agents . lungs.
says immune system plays key role in detecting mutant / cancer cells and killing them Immunodeficiency states are associated with increased CA rates All immune cells can kill CA cells—NK (natural killer). T & B lymphocytes.Risk Factors Immune deficiency Immune surveillance hypothesis -. macrophages Tumor cells can evade immunosurveillance .
Risk Factors Hormones Role is unclear and controversial Excessive hormone use. may contribute to certain form of cancer while reducing risk of other forms Link may be due to ability of hormones to drive cell division of malignant phenotype . especially estrogen.
etc. Ultraviolet radiation Effects are usually additive and usually long delay between time of exposure and time of cancer detection . diagnostic or work exposure): skin cancer and leukemias.Risk Factors Radiation Ionizing radiation (from atomic bomb.
I: Indigestion / difficulty swallowing O: Obvious change in mole or wart N: Nagging cough or hoarseness .7 Warning Signs of Cancer C: Change in bowel / bladder habits A: A sore that doesn’t heal U: Unusual bleeding / discharge T: Thickening / lumps in breast. etc.
effusions or edema Cachexia: wt. anorexia. wounds. loss and muscle wasting.Clinical Manifestations Most body functions affected Initial S&S at primary site. weakness. bleeding. then systemic S/S due to disrupted tissue integrity: Pain. & anemia Cause is multifactorial .
Clinical Manifestations Paraneoplastic syndromes: Cancer cells can have effect on hormones Increased ADH SIADH Increased ACTH Cushing Syndrome Increased PTH Hypercalcemia .
Staging and Grading Grading = looking at cell histology & comparing to normal Stage I – IV Stage I – small localized cancers Stage II and III – locally advanced and/or with local lymph node involvement State IV – inoperable or metastatic Prognosis depends on type of cancer .
Staging and Grading Staging = based on clinical picture & spread of disease T = tumor size N = lymph nodes involved M = metastasis Lung cancer example Breast Cancer example .
Staging and Grading T = Tumor T0 – T4 (4 being most severe) N = Lymph nodes N0 – no lymph node involvement N3 – extensive node involvement M = Metastasis M0 – no metastasis M1 – metastases present .
Diagnostic tests Link to Web Path History and Physical Blood Tests (tumor antigens) Cytology (eg: Pap) Biopsy .
Diagnostic Test Tumor Markers – antigens expressed on surface of tumor cells or substances released from normal cells in response to presence of tumor Used for screening. establishing prognosis. dx. detecting recurrent disease Eg: PSA – prostate cancer screening . monitoring treatment.
Hepatic Adenoma .
Breast Cancer .
Liver metastases .