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Neoplasia. Pathophysiology of tumors and cancer. The following pictures and descriptions were found at: www-medlib.med.utah.edu/WebPath/NEOHTML. Cells normally differentiate, grow, mature and divide.

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Neoplasia l.jpg

Neoplasia

Pathophysiology of tumors and cancer


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The following pictures and descriptions were found at:

www-medlib.med.utah.edu/WebPath/NEOHTML


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Cells normally differentiate, grow, mature and divide.

These are regulated processes, balanced in a healthy system such that cell birth is nearly equal to cell death


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Regulation of cell division includes:

1. Signaling by biochemicals released from one cell that interact with other cells

growth factors or cytokines

2. Other external factors , such as contact inhibition


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3. Genes and internal factors that promote and regulate cell division

genes and chromosomal factors - telomeres

braking proteins – Rb proteins


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A tumor cell’s growth is autonomous – independent of controls

Neoplasm – a type of tumor – group of neoplasic cells

Study of tumors is oncology from Greek for tumor


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Two major types: Benign and Malignant (table 6.2)

Benign:grow slowly

low mitotic rate

well differentiated

not invasive; well-defined borders

remain localized; do not metastasize


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Any increase in tissue size is not necessarily neoplasia. Here is an example of left ventricular cardiac hypertrophy in which there has been an increase in the size of the myocardial fibers in response to an increased pressure load from hypertension. With hypertrophy, the cells increase in size, but the cells do not increase in number. Except for being larger, the cells are normal in appearance. Alterations in cell growth can be physiologic (normal responses to stimuli) or pathologic. These alterations of cell growth are potentially reversible and include:

Hypertrophy: an increase in cell size. Increase in skeletal muscle fiber size is a physiologic response to exercise, but the cardiac hypertrophy shown above is a pathologic response to abnormally elevated blood pressure.

Hyperplasia: an increase in the number of cells. Postpartum breast lobules undergo hyperplasia for lactation, but endometrial hyperplasia in a postmenopausal woman is abnormal.


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The large fronds of endometrium seen in this uterus opened to reveal the endometrial cavity are a result of hyperplasia. This resulted from increased estrogen. With hyperplasia, there is an increase in cell numbers to produce an increase in tissue size. However, the cells are normal in appearance. Sometimes hyperplasias can be "atypical" and the cells not completely normal. Such conditions can be premalignant.


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The first step toward neoplasia is cellular transformation. Here, there is metaplasia of normal respiratory laryngeal epithelium on the right to squamous epithelium on the left in response to chronic irritation of smoking. The two forms of cellular transformation that are potentially reversible, but may be steps toward a neoplasm, are:

Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away.

Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.


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This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible.


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Of course, neoplasms can be benign as well as malignant, though it is not always easy to tell how a neoplasm will act. Here is a benign lipoma on the serosal surface of the small intestine. It has the characteristics of a benign neoplasm: it is well circumscribed, slow growing, and resembles the tissue of origin (fat).


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At low power magnification, a lipoma of the small intestine is seen to be well demarcated from the mucosa at the lower center-right. This neoplasm is so well-differentiated that, except for its appearance as a localized mass, it is impossible to tell from normal adipose tissue.


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Remember that the most common neoplasm is a benign nevus (pigmented mole) of the skin, and most people have several, as seen here over the skin of the chest. As a general rule, benign neoplasms do not give rise to malignant neoplasms.


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Malignant – cancer – from Latin for crab

autonomy and anaplasia

Grow rapidly ; high mitotic index, poorly differentiated; do not have a capsule; invade surrounding structures; can metastasize from the primary to a secondary site (metastasis).


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Some epithelia are accessible enough, such as the cervix, that cancer screening can be done by sampling some of the cells and sending them to the laboratory. Here is a cervical Pap smear in which dysplastic cells are present that have much larger and darker nuclei than the normal squamous cells with small nuclei and large amounts of cytoplasm.


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When the entire epithelium is dysplastic and no normal epithelial cells are left, then the process is beyond dysplasia and is now neoplasia. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium.


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This is a neoplasm. Neoplasia is uncontrolled new growth. Note the mass of abnormal tissue on the surface of the cervix. The term "tumor" is often used synonymously with neoplasm, but a "tumor" can mean any mass effect, whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a neoplasm has started, it is not reversible.


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This is the microscopic appearance of neoplasia, or uncontrolled new growth. Here, the neoplasm is infiltrating into the underlying cervical stroma.


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This gastric adenocarcinoma is positive for cytokeratin by immunoperoxidase. This is a typical staining reaction for carcinomas and helps to distinguish carcinomas from sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification.


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Here is a small hepatic adenoma, an uncommon benign neoplasm, but one that shows how well-demarcated an benign neoplasm is. It also illustrates how function of the normal tissue is maintained, because the adenoma is making bile pigment, giving it a green color.


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In contrast, this hepatocellular carcinoma is not as well circumscribed (note the infiltration of tumor off to the lower right) nor as uniform in consistency. It is also arising in a cirrhotic (nodular) liver.


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Malignant neoplasms are also characterized by the tendency to invade surrounding tissues. Here, a lung cancer is seen to be spreading along the bronchi into the surrounding lung.


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This is an example of metastases to the liver. Note that the tan-white masses are multiple and irregularly sized. A primary neoplasm is more likely to be a solitary mass. Metastasis is the best indication that a neoplasm is malignant.


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Here are three abnormal mitoses. Mitoses by themselves are not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.


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Nomenclature – In General :

Tissue of origin + “-oma” indicates a benign tumor


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Malignant tumors – use embryonic origin of tissue

Carcinomas come from ectoderm and

Endoderm - epithelial and glandular tissue

Sarcomas arise from mesoderm

connective tissue, muscle, nerve and endothelial tissues


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Genetic Basis of cancer

  • Older theory : Initiation-promotion-progression

  • “Multi-hit” hypothesis

  • Cancer is a disease of aging

  • Clonal proliferation


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Several cellular control pathways must be altered to produce cancer:

Autonomy – proliferate in the absence of external growth signals

autocrine stimulation

increase in growth factor receptors

post-receptor signal cascade inside the cell stuck in the “on” position


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Overcome antigrowth signals:

contact with basement membrane, other cells

inactivation of tumor suppressor genes

or activation of the cyclindependent kinases that drive the cell

Prevention of apoptosis


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Oncogenes

in non-mutant state called

proto-oncogenes

stimulate cell growth and replication

when turned “on” by mutation cause uncontrolled growth


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Tumor suppressor genes

negatively regulate proliferation - antioncogenes

want these to remain intact

takes two “hits” to remove both genes


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Gene silencing

regions of genes normally turned off

can spread without mutation and turn off tumor suppressor genes

drugs that demethylate DNA may turn genes back on


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Loss of caretaker genes

Chromosomal instability


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Angiogenesis

angiogenic factors or vascular endothelial growth factor (VEGF)

possible source of new therapies


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Telomerase

Other factors:

decreased cell-to-cell adhesion

secretions of proteases

ability to grow in new locations


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Genetics and cancer prone families

to be passed down, mutations must occur in germ cells

inherited mutations almost always in tumor suppressor genes (table 9-6)

these individuals are targets for cancer screening


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Viral causes of cancer:

viruses assoc. with about 15 % of cancers world wide – us. Cervix or liver

hepatitis B or C in chronic form

Human papilloma virus

spread through sexual contact

HPV integrates into DNA and usesviral oncogenes


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Epstein-Barr and Kaposi sarcoma

both herpes viruses

Human T cell leukemia-lymphoma virus

blood transfusions, needles, sex and breast feeding

infections may be asymptomatic

may have high incidence, but low #’s of cancer

cofactors increase the risk of cancer


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Bacterial causes of Cancer

Helicobacter pylori infects >1/2 world’s population

assoc. with B cell lymphomas of the stomach

treatment with antibiotics can cause regression of lymphoma

Tumors arise in MALT -MALTomas


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Environmental factors

  • Tobacco use

  • Diet

  • Alcohol use

  • Sexual and reproductive behavior

  • Air pollution

  • Occupation hazards – asbestos

  • UV radiation and other radiation

  • hormones


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Gene-Environment Interactions:

Exposure to environmental agents can cause increased risk of cancer

cancer in lab animals – carcinogens

Comparisons of populations

genetics vs. lifestyle


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“Genetics loads the gun; the environment pulls the trigger.” director of Nat’l Institute of Environmental Health & Safety


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Diagnosis:

screening procedures and blood tests:

Tumor markers

substances on plasma membranes

in blood, spinal fluid or urine

hormones, genes antigens or antibodies


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Markers can be used:

to screen and identify individuals at high risk

to help diagnose the specific type of tumor

to follow the course of the cancer


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Tumor spread

  • Local spread

    • Cellular multiplication

      • Function of generation time

      • Growth if cell reproduction > cell death


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  • Mechanical invasion

  • along path of least resistance

  • compresses blood vessels, leading to tissue death and increased space


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  • Lytic enzymes

  • proteases, collagenases, plasminogen activators, lysosomal enzymes

  • some involved in producing new blood vessels


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  • Decreased cell adhesion

  • loss of anchoring molecules allows cancer to slip between normal cells


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  • Increased motility

  • essential for metastasis

  • intravasation

  • extravasation

  • may secrete autocrine motility factor

  • extend psuedopodia

  • three step hypothesis:

  • attachment to the matrix

  • dissolution of the matrix

  • locomotion through the matrix


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Stages of cancer spread:

Stage 1 – confined to site of origin

Stage 2- cancer is locally invasive

Stage 3 – cancer has spread to regional structures

Stage 4- cancer has spread to distant sites


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TNM system:

tumor spread

node involvement

presence of distant metastasis

Staging may influence choice of treatment


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  • Staging TNM system

  • Size of tumor – T0, T1, T2,T3

  • Degree of local invasion – lymph node involvement

  • Extent of spread – metastasis


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Patterns of spread: Metastasis

  • Direct or continuous extension

  • By lymphatics or blood stream

    • As clumps or as single cells

    • Lymphatics most common


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Patterns of spread: Metastasis

  • Angiogenesis

    • Due to production of angiogenic factors

    • Due to drop in antiangiogenic factors


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A metastasis grows when:

vascular network is developed

host defenses are evaded

a compatible environment is available


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  • Distribution and common sites of distant metastases

  • often occurs in the first capillary bed encountered

  • Others show “organ tropism”

  • Due to:

    • Local growth factors or hormones

    • Preferential adherence to the surface

    • Presence of chemotactic factors


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Clinical manifestations of Cancer

  • Pain

    • Usually not in early stages

    • 60 – 80 % of terminally ill

    • Psychogenic, cultural and physiologic components

    • Due to pressure, obstruction, stretching, tissue damage or inflammation


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Branches of peripheral nerve are invaded by nests of malignant cells. This is often why pain associated with cancers is unrelenting.


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Clinical manifestations of Cancer

Fatigue

sleep disturbances

biochemical changes

loss of muscle function


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Clinical manifestations of Cancer

Cachexia – wasting

anorexia

early satiety

weight loss

anemia

marked weakness

taste alterations

altered metabolism


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Clinical manifestations of Cancer

Anemia

chronic bleeding

malnutrition

medical therapies

malignancy in blood forming organs

Administer erythropoietin


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Clinical manifestations of Cancer

Leukopenia and thrombocytopenia

tumor invasion of bone marrow

chemotherapy or radiation


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Clinical manifestations of Cancer

  • Paraneoplastic Syndromes

    • Release of hormones by cancer cells

    • Hematological complications such as procoagulation factors

    • Causes weakness by attacking neuromuscular junction (similar to myasthenia gravis)


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Clinical manifestations of Cancer

  • Infection

  • most significant cause of complications and death


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Cancer Treatment

  • Chemotherapy

    • Cytotoxic drugs + body defenses

      • Single agent

      • Combination chemotherapy

        • Avoids single agent resistance

        • Can use lower dose

        • Better remission and cure rate


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Cancer Treatment

Radiation

targets DNA

kill tumor without damage to surrounding tissues

tumor must be accessible


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Cancer Treatment

Surgery

method of choice

can remove entire tumor

debulking

adjuvant chemotherapy or radiationpalliation


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Cancer Treatment

Immunotherapy

Nonspecific enhancement of the immune system – interferons or interleukins

protect against recurrence

eliminates cancer cells only

T- cell based or antibody responses

Conjugated antibodies


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Cancer Treatment

  • Targeted Therapies

    • Drugs that target the processes of cancer cells specifically

      • Thalidomide

    • Vaccines


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Side effects of treatment

  • Gastrointestinal tract:

    • Oral ulcers

    • Malabsorption

    • Diarrhea

    • Vomiting – caused by effects on CNS


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Side effects of treatment

Bone marrow:

chemo and radiation suppress bone marrow

decrease in red blood cells, white blood cells and platelets


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Side effects of treatment

Hair and skin:

alopecia

skin breakdown and dryness


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Side effects of treatment

Reproductive tract:

affects gametes

premature menopause

also due to damage of hypothalamus and/or pituitary

sperm or embryo bank


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