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Neoplasia
Pathophysiology of tumors and
cancer
1
The following pictures and descriptions
were found at:
wwwmedlib.med.utah.edu/WebPath/NEOHTML
2
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
3
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
4
3. Genes and internal factors that
promote and regulate cell division
genes and chromosomal factors telomeres
braking proteins – Rb proteins
5
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
6
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
7
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.
8
9
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.
10
11
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.
12
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.
15
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 – 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).
17
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.
27
Nomenclature – In General :
Tissue of origin + “-oma” indicates a
benign tumor
28
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
29
Genetic Basis of cancer
• Older theory : Initiation-promotionprogression
• “Multi-hit” hypothesis
• Cancer is a disease of aging
• Clonal proliferation
30
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
31
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
32
Oncogenes
in non-mutant state called
proto-oncogenes
stimulate cell growth and replication
when turned “on” by mutation cause
uncontrolled growth
33
Tumor suppressor genes
negatively regulate proliferation antioncogenes
want these to remain intact
takes two “hits” to remove both genes
34
35
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
36
Loss of caretaker genes
Chromosomal instability
37
Angiogenesis
angiogenic factors or vascular endothelial
growth factor (VEGF)
possible source of new therapies
38
Telomerase
Other factors:
decreased cell-to-cell adhesion
secretions of proteases
ability to grow in new locations
39
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
40
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
41
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
42
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
43
Environmental factors
•
•
•
•
•
•
•
•
Tobacco use
Diet
Alcohol use
Sexual and reproductive behavior
Air pollution
Occupation hazards – asbestos
UV radiation and other radiation
hormones
44
Gene-Environment Interactions:
Exposure to environmental agents can
cause increased risk of cancer
cancer in lab animals – carcinogens
Comparisons of populations
genetics vs. lifestyle
45
“Genetics loads the gun; the
environment pulls the trigger.” director of
Nat’l Institute of Environmental Health &
Safety
46
Diagnosis:
screening procedures and blood tests:
Tumor markers
substances on plasma membranes
in blood, spinal fluid or urine
hormones, genes antigens or
antibodies
47
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
48
Tumor spread
• Local spread
– Cellular multiplication
• Function of generation time
• Growth if cell reproduction > cell death
49
Mechanical invasion
along path of least resistance
compresses blood vessels, leading to
tissue death and increased space
50
Lytic enzymes
proteases, collagenases, plasminogen
activators, lysosomal enzymes
some involved in producing new blood
vessels
51
Decreased cell adhesion
loss of anchoring molecules allows
cancer to slip between normal cells
52
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
53
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
54
TNM system:
tumor spread
node involvement
presence of distant metastasis
Staging may influence choice of treatment
55
Staging TNM system
1.Size of tumor – T0, T1, T2,T3
2.Degree of local invasion – lymph
node involvement
3.Extent of spread – metastasis
56
Patterns of spread: Metastasis
• Direct or continuous extension
• By lymphatics or blood stream
– As clumps or as single cells
– Lymphatics most common
57
Patterns of spread: Metastasis
• Angiogenesis
– Due to production of angiogenic factors
– Due to drop in antiangiogenic factors
58
A metastasis grows when:
vascular network is developed
host defenses are evaded
a compatible environment is available
59
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
60
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
61
Branches of peripheral nerve are invaded by nests of malignant cells. This is
often why pain associated with cancers is unrelenting.
62
Clinical manifestations of Cancer
Fatigue
sleep disturbances
biochemical changes
loss of muscle function
63
Clinical manifestations of Cancer
Cachexia – wasting
anorexia
early satiety
weight loss
anemia
marked weakness
taste alterations
altered metabolism
64
Clinical manifestations of Cancer
Anemia
chronic bleeding
malnutrition
medical therapies
malignancy in blood forming organs
Administer erythropoietin
65
Clinical manifestations of Cancer
Leukopenia and thrombocytopenia
tumor invasion of bone marrow
chemotherapy or radiation
66
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)
67
Clinical manifestations of Cancer
• Infection
•
most significant cause of complications
and death
68
Cancer Treatment
• Chemotherapy
– Cytotoxic drugs + body defenses
• Single agent
• Combination chemotherapy
–Avoids single agent resistance
–Can use lower dose
–Better remission and cure rate
69
Cancer Treatment
Radiation
targets DNA
kill tumor without damage to
surrounding tissues
tumor must be accessible
70
Cancer Treatment
Surgery
method of choice
can remove entire tumor
debulking
adjuvant chemotherapy or
radiation
palliation
71
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
72
Cancer Treatment
• Targeted Therapies
– Drugs that target the processes of cancer
cells specifically
• Thalidomide
– Vaccines
73
Side effects of treatment
• Gastrointestinal tract:
– Oral ulcers
– Malabsorption
– Diarrhea
– Vomiting – caused by effects on CNS
74
Side effects of treatment
Bone marrow:
chemo and radiation suppress bone
marrow
decrease in red blood cells, white blood
cells and platelets
75
Side effects of treatment
Hair and skin:
alopecia
skin breakdown and dryness
76
Side effects of treatment
Reproductive tract:
affects gametes
premature menopause
also due to damage of hypothalamus
and/or pituitary
sperm or embryo bank
77