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Neoplasia Patho

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

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, cancer cells undergo unrestrained growth and division. Without intervention, they continue to grow until they produce death. Some neoplasias grow fast and other grow slowly.

Cell Differentiation
Process by which proliferating cells are transformed into specialized cell types, which determines cell function The more highly specialized a cell, the more likely it will lose its ability to reproduce and divide Stem cells remain incompletely differentiated throughout life

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, skin, liver cell --are partly differentiatedproduce 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 Cycle
G0 resting phase; can be stimulated to divide Nondividing permanent cells, like neurons, cardiac muscle

Cell Cycle
Cell cycle is sequence of events cell goes thru from one mitotic division to next. 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)

Cell Cycle
Entry into and progression thru stages are controlled by proteins called cyclins and their inhibitors. There are checkpoints in cell cycle which determine accuracy with which DNA is duplicated. Defects in either of these can contribute to development of cancer (may cause genetic instability of cancer cells)

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 bodys needs: -faster growth rate -increase in size at expense of rest of bodys needs -great variation in cell size, shape, arrangement

Neoplasms have 2 tissue types:

--Parenchymal (organ cells) --Stromal (supporting tissueconnective, vascular)

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, invade, 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

Benign tumors--Fibroids

Benign Uterine Tumor with Clearly Defined Edges

Malignant Neoplasms = Cancer

Atypical cell structure; abnormal nucleus & chromosomes Lose differentiation or resemblance to origin cell--more anaplastic Not cohesive, irregular growth pattern, no capsule formed, 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

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

Spread of Cancer
Direct invasion & extension local spread, mechanical, lysis with enzymes Seeding of CA cells in body cavities 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 bodys defense mechanisms In lymph nodes, CA may die, grow into mass, or remain dormant

Cells in a primary tumor develop the ability to escape and travel in the blood Imagine you were a cancer cell. What abilities would you need to survive in the tumor? What abilities would you need to metastasize?

Cancer Progression

Surviving CA cells leave lymph nodes & enter venous blood & are carried to major organs: bone, liver, lungs, brain Original tumor = primary neoplasm Metastatic site = secondary neoplasm (retains characteristics of primary tumor)

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. So, chemotherapeutic drugs are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction. Why? Doubling time (TD) = time to double total mass of CA cells
GF and TD are very fast until tumor outgrows blood supply, then slows May be influenced by hormones

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; are active continuously & promote unregulated, abnormal & disordered growth. Selected oncogenes have been associated with numerous cancer types
Mutations in p53 gene have been implicated in development of lung, breast, and colon cancer

Mechanism by which a normal cell is transformed into cancer cell by random genetic mutation or mutation induced by exposure to physical (radiation), 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

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

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, or endogenous hormone Progression: process whereby tumor cells get malignant characteristics Metastasis: spread

Mrs. T Has Liver Cancer

Her doctor did an initial molecular diagnosis and put her on targeted therapy; 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 wants to know why the cancer cells stopped responding. Are they not all the same cells?

Cervical Cancer

In Review
Cancer is error in DNA creates abnormal clonal cells which multiply and function inappropriately, leading to:
Unchecked increase in # of cells Ability to invade body structures Ability to metastasize to distant locations Inappropriate cell life span

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, Epstein-Barr virus -> Burkitts lymphoma, human papillomavirus (HPV) skin & cervical CA, Hepatitis B & C liver cancer, HTLV-1 leukemia Oncogenic bacteria--H. Pylori--linked to gastric CA and lymphoma

Chemical carcinogenesis: cause mutations

Polycyclic aromatic hydrocarbons Food and drugs
tobacco smoke CA of head & neck, lungs, pancreas, bladder Plants: aflatoxin (mold) & betel nut liver CA Food preparation: smoked and charbroiled meats Alcohol: carcinogen promotor; 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, cadmium, chromium, nickel, benzene -> Lung & other CAs Nitrogen mustard & mustard gas leukemias & lymphomas

Risk Factors

Industrial Agents

Risk Factors
Immune deficiency
Immune surveillance hypothesis -- 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 cellsNK (natural killer), T & B lymphocytes, macrophages Tumor cells can evade immunosurveillance

Risk Factors
Role is unclear and controversial Excessive hormone use, especially estrogen, 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

Risk Factors
Ionizing radiation (from atomic bomb, diagnostic or work exposure): skin cancer and leukemias, etc. Ultraviolet radiation
Effects are usually additive and usually long delay between time of exposure and time of cancer detection

7 Warning Signs of Cancer

C: Change in bowel / bladder habits A: A sore that doesnt heal U: Unusual bleeding / discharge T: Thickening / lumps in breast, etc. I: Indigestion / difficulty swallowing O: Obvious change in mole or wart N: Nagging cough or hoarseness

Clinical Manifestations
Most body functions affected Initial S&S at primary site, then systemic
S/S due to disrupted tissue integrity: Pain, bleeding, wounds, effusions or edema Cachexia: wt. loss and muscle wasting; weakness, anorexia, & 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, dx, establishing prognosis, monitoring treatment, detecting recurrent disease Eg: PSA prostate cancer screening

Hepatic Adenoma

Breast Cancer

Liver metastases