Download Neoplasia Chap 6

Neoplasia
Pathophysiology of tumors and
cancer
1
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
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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
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.
left ventricular cardiac hypertrophy due
to hypertension.
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Hypertrophy: an increase in cell size.
Increase in skeletal muscle fiber size is a
physiologic response to exercise
Hyperplasia: an increase in the number of
cells. Postpartum breast lobules undergo
hyperplasia for lactation, but endometrial
hyperplasia in a postmenopausal woman is
abnormal.
The endometrium seen in this uterus opened to reveal the
endometrial cavity are a result of hyperplasia.
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.
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.
13
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).
14
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. 16
Malignant – cancer
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.
18
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.
19
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.
20
This is the microscopic appearance of neoplasia, or uncontrolled new growth.
Here, the neoplasm is infiltrating into the underlying cervical stroma.
21
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.
22
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.
23
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.
24
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.
25
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.
26
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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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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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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Angiogenesis
angiogenic factors or vascular
endothelial growth factor (VEGF) possible
source of new therapies
32
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
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
36
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
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Environmental factors
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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
42
Tumor spread
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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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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
1.Size of tumor – T0, T1, T2,T3
2.Degree of local invasion – lymph
node involvement
3.Extent of spread – metastasis
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Patterns of spread:
Metastasis
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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
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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
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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
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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
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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
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Infection
most significant cause of complications
and death
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Cancer Treatment
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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
palliation
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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
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Targeted Therapies
– Drugs that target the processes of cancer
cells specifically
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Thalidomide
– Vaccines
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Side effects of treatment
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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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