Neoplasia

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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 cells 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 Hypertroph
y 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
uses viral 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 gt1/2 worlds 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 Natl 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 gt 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 erythropoeitin
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Clinical manifestations of Cancer
Leukopenia and thrombocytopenia tumor invasion
of bone marrow chemotherapy or
radiation 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
radiation
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Cancer Treatment

• Immunotherapy
• eliminates cancer cells only
• provides protection against recurrence
• T- cell based or antibody responses
• Conjugated antibodies
• Nonspecific enhancement of the immune system

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Side effects of treatment

• Gastrointestinal tract
• Oral ulcers
• Malabsorption
• Diarhhea
• 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