General Pathology (autoimmune & immunodeficiency diseases / neoplasia) Flashcards
1
Q
autoimmune diseases
A
break down of tolerance of AG on own cells (SELF-AG)
2
Q
diagnosis of autoimmune disease
A
auto-Antibodies
immune mechanisms cause pathological lesions
can be difficult to find evidence of immune nature of disorder
“pathogenicity difficult to prove”
3
Q
AI disease genetic factor
A
increased frequency via Family history
genetic component
4
Q
more common in
A
women
E.g.
SLE
RA
5
Q
systemic vs localized
A
can be systemic or local
how localized?
6
Q
E.g. of systemic (multi-organ) AI disease
A
systemic lupus erythematosus
rheumatic fever
rheumatoid arthritis
systemic sclerosis
polyarteritis nodosa
7
Q
E.g. of AI diseases limited to single organ (more localized)
A
multiple sclerosis (CNS)
Hashimoto’s thyroiditis (thyroid)
Grave’s disease (thyroid)
Autoimmune hemolytic anemia (blood)
Pemphigus vulgaris (skin)
Myasthenia Gravis (muscle)
8
Q
Systemic Lupus Erythematosus
A
“prototype of AI disease”
multisystemic
1/2500 people
10x more common in women
genetic component (family history?)
more common in young adults
but can happen any age
9
Q
signs symptoms
A
CNS symptoms
pattern baldness
butterfly rash
Endocarditis, Pericarditis
Pleuritis, Pneumonitis
lupus nephritis
raynaud’s phenomenon
myositis, arthritis
osteoporosis
splenomegaly
lymphadenopathy (lymph nodes, aka lymph glands)
anemia, neutropenia, thrombocytopenia
10
Q
pathogenesis SLE
A
poorly understood
Malfunction of T suppressor cells which allows polyclonal activation of B cells
“Plasma cells derived from uncontrolled B cell clones secrete antibodies against autoantigens and foreign antigens”
“Many antibodies to DNA, RNA and nuclear proteins = called antinuclear antibodies (ANA)”
11
Q
antinuclear antibodies (ANA)
A
“The antinuclear antibody (ANA) is a defining feature of autoimmune connective tissue disease. ANAs are a class of antibodies that bind to cellular components in the nucleus, including proteins, DNA, RNA, and nucleic acid-protein complexes.”
12
Q
Agab complexes during SLE
A
Antigens that reach circulation form complexes with antibodies in the serum
“Circulating Ab-Ag complexes deposited in membranes e.g. synovial membrane, serous membranes, endocardium, choroid plexus, ant. eye chamber”
E.g.
synovial membrane (joints)
serous membranes (heart, lungs, abdomen)
endocardium
choroid plexus (brain)
anterior eye chamber (eyes)
13
Q
atnerior eye chamber sle
A
“Anterior uveitis in patients with SLE is usually mild and rarely leads to a deterioration in visual acuity, and also may present as synechiae or a fibrinous inflammatory exudate in the anterior chamber of the eye.”
14
Q
complement system activation vs immune complexes
A
“Immune complexes are large and retained and activate complement, which elicits an inflammatory reaction resulting in many organ-specific inflammatory diseases”
e.g.
glomerulnonephritis,
arthritis,
etc
15
Q
clinical features sle
A
variable
Inflammation of joints (arthritis) – most common; redness, swelling, pain
Kidney involvement (75%)
Cutaneous lesions (butterfly rash) (30-60%)
Damage to RBCs causing anemia
Enlargement of lymph nodes and spleen
16
Q
treatment sle
A
Corticosteroids
cyclophosphamide (immunosuppressive)
17
Q
cyclophosphamide
A
“a synthetic cytotoxic drug used in treating leukemia and lymphoma and as an immunosuppressive agent.”
18
Q
sle and kidneys
A
kidney transplant as treatment if kidneys severely affected
19
Q
immunodeficiency
A
Primary (congenital) or
secondary (due to infections, metabolic diseases, cancer, or treatment/chemotherapy, etc.)
20
Q
which type of immunodeficiency more common
A
secondary
cancer, infection, chemotherapy, metabolic disease
21
Q
E.g. of secondary immunodeficiency
A
AIDS
acquired immunodeficiency syndrome
22
Q
involvement of B/T cells vs entire immune system
A
Primary or secondary may involve just B cells or T cells
or may be generalized and involve the whole immune system
23
Q
how are ID diseases characterized
A
All ID diseases are characterized by lymphopenia – low lymphocyte count in peripheral blood
24
Q
lymphopenia
A
low lymphocyte count in peripheral blood
25
B cell deficiency
associated with low levels of serum antibodies
(low plasma, low AB production)
26
reduced resistance to infection
All ID disorders cause reduced resistance to infections
27
primary ID diseases
genetic disorders affecting differentiation and maturation of T cells and B cells
28
when occur?
Can occur at any step along the developmental sequence that leads from stem cells to fully differentiated cells
29
leads to
Leads to heterogenous group of disorders with mild or severe symptoms
30
e.g. primary ID disease
DiGeorge’s syndrome
T-cell deficiency related to aplasia of thymus, associated with aplasia of parathyroid glands
31
aplasia
the failure of an organ or tissue to develop or to function normally.
32
AIDS
Acquired immune deficiency syndrome
Set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV)
33
what does AIDS do
Progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumours
34
HIV transmitted how
transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV
Transmission can involve sex, blood transfusion, contaminated needles, exchange between mother and baby during pregnancy, childbirth, breastfeeding, or other exposure to bodily fluids
35
HIV how?
sex
blood transfusion
contaminated needles
between mother/baby during pregnancy
during childbirth
breastfeeding (virus in breastmilk)
exposure to bodily fluids (semen, pre-ejaculate, etc.)
36
direct contact?
direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV
certain bodily fluids
37
epidemiology
..
38
etiology HIV
RNA retrovirus
38
retrovrius define
RNA viruses that have an enzyme (reverse transcriptase) capable of making a complementary DNA copy of the viral RNA, which then is integrated into a host cell’s DNA. The family includes a number of significant pathogens, typically causing tumors or affecting the function of the immune system, e.g. HIV.
39
why called retrovirus?
While transcription was classically thought to occur only from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the usual direction of transcription.
40
where highest prevalence?
Africa
41
how many worldwide
35 million
42
how many new cases per year
100,000 in US
43
percentage of college students
1% (18-25)
An estimated 3% to 6% of U.S. college students are HIV positive (different source)
44
HIV pathogenesis
Transmitted through the transfer of body fluids
Virus can’t survive outside host cell
HIV has affinity for T helper cells and monocytes (macrophage outside BV)
...
Macrophages can also become infected ...
45
other cells infected
Fixed tissue phagocytic cells can also become infected (e.g. microglia)
46
what do infected cells do
Infected cells can serve as reservoir for virus
47
what happens to infected cells often/eventually
HIV virus is cytotoxic thus infected cells often die
48
hiv initial infection
Initial infection stimulates B cells to produce antibodies within weeks
49
hiv latent phase
The second stage of HIV infection is chronic HIV infection (also called asymptomatic HIV infection or clinical latency). During this stage, HIV continues to multiply in the body but at very low levels. People with chronic HIV infection may not have any HIV-related symptoms
50
hiv latency vs AIDS onset
Latent infection can persist for years
As virus replicates and destroys more helper T cells, symptoms of AIDS begin to appear
51
immunity during AIDS
Cell mediated immunity becomes depressed and humans cannot defend against infections (opportunistic infections)
Death generally occurs due to infection but can also occur due to tumours
52
phases of hiv
acute (inital infection)
chronic (latent)
crisis (AIDS)
53
acute
primary infection
sharp increase in presence of HIV virus in blood
sudden decrease in presence of CD4+ helper T cells in blood
acute stage lasts a few weeks
54
chronic/latent stage -- and crisis stage
after immune system responds with antibodies to HIV
there is huge dip in presence of virus in blood
there is an increase in CD4+ helper cells (not to original amount, but close)
during actual clinical latency there is a relatively small presence of HIV virus in blood
presence of CD4+ helper cells very gradually declines throughout many many years
at the end of clinical latency, the amount of CD4+ helper cells decline to an extent that they can no longer contribute to defending against HIV virus (antibody production)
at this stage, virus overtakes immune system, and AIDS symptoms appear (crisis stage)
virus level increases and CD4+ level continues to decrease, until opportunistic infections/diseases lead to death
55
how long can latent stage be
chronic/latent stage = many many years
56
how long crisis stage
also can be few years
57
viremia
the presence of viruses in the blood.
"uncontrolled virus proliferation leads to chronic viremia"
58
4 phases of illness (hiv/aids)
..
59
Phase of acute illness (Group I)
Usually 3-6 wks after exposure
Symptoms typically non-specific, include fever, night sweats, nausea, myalgia, headache, sore throat, skin rash, lymph node enlargement
Symptoms last 2-3wks, then disappear
Pt. develop antibodies to HIV
60
Phase of asymptomatic infection (Group II)
Variable duration, months to years
theoretically can last a long time, and allow patient to live a relatively full life with currently available medicine/treatment
Asymptomatic patient carries virus and is infectious
Approx. 50% of HIV+ patients develop AIDS within 10 years of initial diagnosis if untreated
61
Phase of generalized lymphadenopathy (III)
Persistent lymphadenopathy develops in asymptomatic pts or early in disease
May persist for months or years
62
AIDS (Group IV)
Pt shows signs of AIDS which reflect opportunistic disorders including GI disorders, CNS involvement, neoplasia
Clinically, ratio of CD4+ /CD8+ cells decr.
In the last stages, almost no CD4+ cells present
-->
opportunistic diseases and death
63
AIDS define
AIDS is defined as HIV infection that leads to any of the disorders in clinical category B or C of HIV infection or a CD4+ T lymphocyte count of < 200/μL.
(less than 200 per cubic mm -- aka microlitre)
The normal CD4 count range is between 500 and 1400 cells/microliters., taking into consideration laboratory variations.
64
disorders in clinical category B or C of HIV infection
Serious opportunistic infections
Certain cancers,
such as Kaposi's sarcoma and
non-Hodgkin lymphoma,
to which defective cell-mediated immunity predisposes
Neurologic dysfunction
65
pathology..
Non-specific; vary with time, extent of viremia and degree of immunosuppression
66
@ lymph nodes
Initially lymph nodes enlarge and show hyperplasia
After time, lymph nodes become depleted of lymphocytes and eventually become infected
After time, lymph nodes become depleted of lymphocytes and eventually become infected (decreased CD4+)
67
@ brain
Microglia in the brain and multinucleated giant cells form nodules
Opportunistic infection leads to meningitis or encephalitis (CMV, herpes, fungi, protozoa)
May destroy part of the brain directly or through infarct
68
@ respiratory tract
Initially localized to URT but often progresses to LRT (pneumonia or TB)
--> Pneumocystis jiroveci/carinii (named after individuals)
69
cyst vs abscess
"While a cyst is a sac enclosed by distinct abnormal cells, an abscess is a pus-filled infection in your body caused by, for example, bacteria or fungi. The main difference in symptoms is: a cyst grows slowly and isn't usually painful, unless it becomes enlarged."
70
pneumocystis pneumonia define
fungal infection in one or both lungs. It is common in people who have a weak immune system, such as people who have AIDS.
71
@ GI tract
Infections are similar to respiratory tract and can also include parasites
Diarrhea and malabsorption of nutrients can also be present
72
@ skin
Can include dermatitis or infections (fungi, herpes, bacteria)
73
tumours
Often lead to mortality
Increased incidence of tumours esp. lymphomas (lymph nodes, spleen, liver, brain, etc.) and Kaposi’s sarcoma
74
pathologic findings in AIDS
meningitis
encephalitis
AIDS dementia
herpes labialis (more frequent/severe outbreaks)
thrush
pneumonia
malabsorption
colitis
proctitis (anus, rectum)
dermatitis
folliculitis
impetigo
Kaposi's sarcoma
AIDS nephropathy
lymphomas
lymphadenopathy
75
Kaposi's sarcoma
Malignant disease of endothelial cells
Caused by herpesvirus
Often occurs in skin and internal organs
Nodules composed of anastamosing vascular spaces filled with blood
Can cause bleeding or compress vital organs
76
diagnosis
Presence of HIV antibodies in blood (HIV+)
T cell count – decreased ratio of CD4+ /CD8+ (less than 200 per nanolitre of CD4+)
AIDS diagnosed by presence of opportunistic infection and tumours
77
treatment
Medications - replication inhibition (of virus)
Expensive & not readily available worldwide
Vaccines unsuccessful
78
Amyloidosis (disease)
Caused by deposition of a fibrillar substance called amyloid
Multi-factorial disease
Often related to abnormalities of the immune system or an abnormal response to chronic infection
Amyloid: any fibrillar protein that forms a beta-pleated sheet
79
where amyloid deposited
Amyloid is deposited in the extra-cellular spaces
Changes the function of tissues and cells
Deposits in blood vessels changes their permeability
Leads to proteinuria in kidney
Vessels in liver and adrenal glands becomes solid
80
amyloidosis -- what happens
Atrophy and loss of cell function
Amyloid in heart causes weakened contractions
Amyloid in brain causes dementia
Clinical presentation is variable and depends on the organ system involved
No effective treatment
(treat symptoms as they appear)
81
Clinical Presentation of Amyloid Deposition
Systemic amyloidosis: usually caused by deposition of AA or AL amyloid in various organs (e.g., liver, kidneys, adrenals, spleen, heart)
Localized organ: specific amyloid deposits (e.g., Alzheimer’s disease)
82
LECTURE 6
..
83
neoplasm
new growth
"Uncontrolled cell growth whose proliferation cannot be adequately controlled by normal regulatory mechanisms"
84
neoplasm define
"An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Neoplasms may be benign (not cancer) or malignant (cancer)."
"Benign neoplasms may grow large but do not spread into, or invade, nearby tissues or other parts of the body."
85
normal cell gorwth requires
genetic material, aka DNA and RNA
signals from one cell to another
growth inhibiting or growth promoting substances
1) genetic material
2) signaling
3) growth inhibiting/promoting substance
86
differentiating
Once a cell stops growing it needs to differentiate - to become specialized -
by activating some genes, and suppressing other genes
87
tumour cells vs differentiation
Tumour cells do not achieve the same level of differentiation as normal cells
88
neoplastic cell growth
Autonomous - independent of normal growth factors and inhibitors
Excessive - doesn’t respond to normal regulators
Disorganized – compared to the formation of normal tissues
1) independent
2) excessive
3) disorganized
89
benign/malignant neoplasm (tumour)
enign – limited growth potential and good outcome
Malignant – grow uncontrollably with poor outcome
90
histological classifcaiton of benign vs malignant based on
based on how cells look under the microscope
91
benign tumours, macroscopic features
Sharply demarcated
Often encapsulated (by CT tissue)
Can have expansive growth which compresses adjacent tissue leading to atrophy and fibrosis
Can be easily removed by surgery
No hemorrhage or necrosis
92
benign tumours microscopic features
Resemble the original tissue from which they have arisen
Show high levels of differentiation
93
benign tumours -- cellular features
Uniform cell populations (homogenous)
Regularly shaped/same sized nuclei
Well developed cytoplasm
Nucleus occupies a small portion of the cell
Nucleus has even distribution of chromatin
Nucleoli are not overprominent
94
benign tumours -- chromosomal & biological features
Has normal number of chromosomes
Retain normal complex functions
95
Malignant tumours, macroscopic features
No clear margins from normal tissue
No encapsulation (CT)
Can have invasive growth
Cannot be removed easily by surgery
Hemorrhage and necrosis present
96
malignant tumours microscopic features
Differ considerably from original tissues
Show anaplasia (cells take on new characteristics)
Undifferentiated
97
anaplasia
the loss of the mature or specialized features of a cell or tissue, as in malignant tumors.
losing degree of differentiation (?)
98
anaplasia..
"Anaplasia is a qualitative alteration of differentiation. Anaplastic cells are typically poorly differentiated or undifferentiated and exhibit advanced cellular pleomorphism."
"In fact, anaplasia and pleomorphism are sometimes used incorrectly as synonyms. Pleomorphism refers to variation in the size and shape of cells."
99
anaplasia etymology
Ancient Greek: ἀνά ana, "backward" + πλάσις plasis, "formation"
100
malignant tumours -- cellular features
Don’t have uniform cell populations (heterogenous)
Cells vary in size and shape
Nuclei vary in shape and size
Variable amounts of cytoplasm
Nucleus is larger
Hyperchromatic (more chromatin, unevenly distributed, nucleoli prominent, multiple)
101
hyperchromatic
Hyperchromatic (more chromatin, unevenly distributed, nucleoli prominent, multiple)
102
hyperchromatic..
"the development of excess chromatin or of excessive nuclear staining especially as a part of a pathological process."
103
malignant tumours chromosome features
Aneuploid (abnormal number of chromosomes)
104
aneuploid etymology
Greek
an- "not, without" (see an- (1))
+
euploid,
from Greek
eu "well, good" (see eu-)
+
-ploid, from -ploos "fold" (from PIE root *pel- (2) "to fold")
105
aneuploid
having an abnormal number of chromosomes in a haploid set.
106
malignant tumours biological features
No specialization or differentiation
Metabolism is geared toward supporting growth and replication (metastasis?)
107
beniign vs malginatn expansion rate
benign slow expansion (& limited)
malignant fast expansion (& more uncontrolled)
108
metastases?
no benign
yes malignant
109
metastasis
the development of secondary malignant growths at a distance from a primary site of cancer.
2) a metastatic growth.
110
b vs m -- external surface texture
benign smooth
malignant irregular
111
encaspulated?
b YES
m NO
112
Necrosis?
b NO
m YES
113
hemorrhage
b NO
m YES
114
"architecture"
benign = Resembles normal tissue of origin
malignant = does not
115
cells?
b DIFFERENTIATED
m NOT
116
nuclei?
uniform (size/shape)
vs
Pleomorphic
117
"mitoses"
few
vs
many; irregular
118
metastasis
A process by which cells move from one site to another in the body.
Only malignant tumours metastasize.
Benign tumours never metastasize.
Involves a spread of tumour cells from a primary location to another site in the body.
Spread can occur through 3 main pathways:
119
how metastases SPREAD? (3 ways)
1) via lymphatics
2) via blood (hematogenous spread)
3) via body cavities
120
hematogenous
"originating in or carried by the blood."
121
metastatic cascade
Not all malignant cells are capable of metastasis.
Cells must acquire the capacity to metastasize.
Cells then expand clonally.
Clone expands, cells reach lymphatics or blood vessels or body cavity.
122
can all malignant cells metastasize?
no
must acquire the capacity to metastasize.
123
how carried?
Fluid carries the cells from the primary site to distant locations where cells attach and begin forming a new tumour mass.
Metastatic cells must escape immune cells including macrophages, T cells, NK cells.
Malignant tumour must form new blood vessels (angiogenesis).
124
what cells target metastatic cells?
immune cells, specific and non-specific (natural)
macrophages, T cells, NK cells
125
angiogenesis and malignant tumours
Malignant tumour must form new blood vessels (angiogenesis).
126
note tumour-induced angiogenesis
chemotactic factors
enzymes
tumour angiogenic factors (E.g. FGF -- fibroblast growth factor ??)
127
E.g. metastasis
tumour starts @ respiratory epithelial cells
grows into CT below
continues growing into smooth muscle further below
reaches deeper BV / lymph vessel structures
cells from tumour break off into LV & BV
E.g. = carcinoma of lung
128
histological classification (how tumours named?)
Tumours are named for the cell type that they resemble the most.
129
end in "-oma"
Benign tumours of mesenchymal cells (i.e. cells of CT, bone and muscle)
130
e.g. benign tumours
Fibroma - from fibroblasts
Chondroma - from cartilage
Lipoma - from adipose
Leiomyoma - from smooth muscle cells
Osteoma – from bone
Rhabdomyoma - from striated muscle cells
131
adenoma
from epithelial cells; composed of glands or ducts
132
E.g. Adenoma
..
133
1) Tubular or villous adenomas
from epithelial cells in the GI tract; aka polyps
134
polyp
a small growth, usually benign and with a stalk, protruding from a mucous membrane.
135
2) Papillomas (adenoma)
protuberant tumours of the skin, urinary bladder, mouth, larynx
136
papilloma
"a benign tumor (as a wart or condyloma) resulting from an overgrowth of epithelial tissue on papillae of vascularized connective tissue (as of the skin) see papillomavirus"
"a small wartlike growth on the skin or on a mucous membrane, derived from the epidermis and usually benign."
137
3) Cystadenomas
cystic tumours composed of hollow spaces lined by neoplastic epithelium
138
cystadenoma
Cystadenomas are rare cystic tumors of epithelial origin that arise in the liver, the majority in the right lobe, or less commonly in the extrahepatic biliary system. There are two histological variants, a mucinous type and a serous type.
139
malignant tumours
Malignant tumours of mesenchymal cells are named for the root of the cell type plus the suffix “sarcoma”
140
E.g.
Fibrosarcoma - from fibroblasts
Chondrosarcoma - from cartilage
Liposarcoma – from fat
141
carcinomas vs sarcomas
Malignant tumours of epithelial cells are called carcinomas
E.g.
squamous cell carcinoma
142
Adenocarcinomas (vs adenoma)
malignant tumours from glands and ducts
143
note, some malignant tumours end in "-oma"
Lymphoma - malignant tumours of lymphoid cells
Glioma - malignant tumours of glial cells
Seminomas - malignant tumours of testicles
144
why?
could just be for linguistic/phonetic reasons (?)
"seminsarcoma" / "glisarcoma" / "lymphsarcoma" does not sound as natural (?)
145
nomenclature
Some tumours of the same name can be benign or malignant in which case we must designate “malignant”:
E.g.
Malignant islet cell tumour
146
blastoma
malignant tumors composed of embryonic cells originating from embryonic primordia
147
E.g. blastoma
Retinoblastoma: eye
Neuroblastoma: adrenal medulla or immature neural cells
Hepatoblastoma: liver
Nephroblastoma: kidney
148
embryonic primordia
"Primordia are those primitive embryonic structures from which. various structures of the body develop. ▶ They are primarily derivatives of the Trilaminar Embryonic Germ. Disc layers i.e. Ectoderm, Mesoderm and Endoderm; which are one. of the outcomes of Gastrulation."
149
gastrulation define
Gastrulation is an early developmental process in which an embryo transforms from a one-dimensional layer of epithelial cells, a blastula, and reorganizes into a multilayered and multidimensional structure called the gastrula.
150
teratomas
Benign tumours derived from germ cells (egg and sperm) are called teratomas.
151
teratoma
teratogen
teratoma
“monstrous” and “tumor”
152
teratoma..
Derived from germ cells; contain tissues formed from all three germ layers:
Ectoderm
Mesoderm
Endoderm
153
Eponymous tumours – named after somebody
Hodgkin’s lymphoma
Ewing’s sarcoma
Kaposi’s sarcoma
154
tumour staging
based on clinical assessment during gross examination, surgery, x-ray/imaging examinations, etc
155
tumour grading
based on histologic examination
156
tumour staging done to
to clinically assess the extent of tumour spread
Based on clinical exam, x-ray, biopsy, surgery
157
TNM system of staging
TNM system of staging takes into account:
1) size of Tumor (T),
2) presence of lymph NODE metastases (N),
3) distant Metastases (M)
158
staging 1-4 (or A-D)
TNM system of staging assigns a number to: tumour size, lymph node involvement and distant metastasis
E.g. T1, N1, M1
159
grading based on histological examination (differentiation)
Grade I – well differentiated
Grade II – moderately well differentiated
Grade III – undifferentiated
160
which used for prognosis?
Staging and grading used for prognosis.
161
which better predictive value?
Staging has more predictive value.
162
biochemistry of cancer cells
Metabolism of cancer cells is simpler
Require less oxygen
Better adapted for survival
Fewer mitochondria
Fewer enzymes
RER is simpler and less abundant
Simplified metabolism leads to loss of functional capacity
(loss of parenchyma?)
163
anaplasia and (malignant) tumour cells
E.g. acquire fetal characteristics
Produce proteins such as alpha-fetoprotein (AFP)
164
alpha-fetoprotein test (AFP test)
"An alpha-fetoprotein (AFP) test can be used to help diagnose and manage liver or germ cell tumours."
"High levels of AFP may be a sign of cancer of the liver, ovaries, or testicles. But having a high AFP level doesn't mean you have cancer "
165
growth properties
Lack contact inhibition – tend to pile up forming aggregates and nodules
Do not require firm support for growth
Autonomous – do not depend on growth stimuli
Excessive and unregulated – do not respond to normal inhibitory influences
(disorganized)
166
contact inhibition (lacking @ malignant tumours)
"CONTACT INHIBITION is cessation of cellular movement, growth, and division upon contact with other cells"
"Contact inhibition is the term used to describe the abrupt arrest of the cell cycle that occurs in cultures of rapidly proliferating epithelial cells"
167
causes of cancer / risk factors
..
168
carcinogen
Carcinogen – cancer causing agent
169
exogenous carcinogen
Chemicals, physical agents, viruses
170
engogenous carcinogen
Genetic
Oncogene – human cancer gene; can be identical to exogenous viral gene
171
human carcinogens
uv rays = skin cancer
radiation = thyroid/skin
viruses --> lymphoma
metabolic carcinogen --> intestinal
contact caricinogen --> skin
metabolic liver/excretory carcinogens --> liver/bladder
172
ID of carcinogens (3 elements)
1) Clinical studies -- gathering data by practicing physicians observing cancer patients (case studies)
2) Epidemiologic studies – involve studying populations and families
3) Experimental studies – performed on animals and in labs (in vitro)
173
epidemiology
the branch of medicine which deals with the incidence, distribution, and possible control of diseases and other factors relating to health.
174
how do carcinogens act
Locally at the site of contact (e.g. skin and lungs)
At the site of digestion
At the site of metabolic activation in the liver
At the site of excretion in the urine
175
carcinogenesis
1) Ingestion of the potentially harmful substance (procarcinogen) - activated metabolically in the liver
2) Starts initiation - induction of genetic changes in the exposed cells
3) Promotion - initiated cells are stimulated to proliferate
4) Conversion - convert to new cell (tissue?) type
5) Progression - acquisition of new genetic features
6) Clonal expansion - expansion of cell clones
Some will be dormant in new location, some will metastasize
Selection – the most adaptable and vital clones will survive
176
carcinogenesis steps
1) ingestion
2) initiation
3) promotion
4) conversion
5) progression
6) clonal expansion
177
physical carcinogen
UV light
X-rays
Radioactive isotopes
Atomic bombs
178
biological carcinogens
Aflatoxin (fungi) on peanuts causes liver cancer especially in Africa and Asia
Parasites in Egypt cause bladder cancer
179
aflatoxin
Aflatoxins are a family of toxins produced by certain fungi that are found on agricultural crops such as maize (corn), peanuts, cottonseed, and tree nuts.
180
viral carcinogens
Classified as DNA or RNA viruses
RNA can be further classified:
a) acute-transforming or slow-transforming
b) Retrovirus
...
181
retrovirus
"A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell"
"While transcription was classically thought to occur only from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the usual direction of transcription."
182
Human DNA viruses
HPV
EBV
HBV
183
Human RNA virus
HTLV-1
184
HPV
human papillomavirus (HPV)
70 subtypes linked to human lesions such as warts
Can cause benign or malignant tumours
Some strains of HPV cause genital warts which is linked to invasive cervical carcinoma
185
EBV
Epstein-Barr Virus
(note also INFECTIOUS MONONUCLEOSIS)
Human herpesvirus with a predilection for B cells
Extremely prevalent (90%)
Can be asymptomatic or can produce infectious mononucleosis (IM)
Related to Burkitt’s lymphoma and nasopharyngeal carcinoma
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ebv -- B cells
EBV is transmitted from the carrier through the saliva and enters the host via the oropharynx region.
B cells are the principal targets of EBV infection, primarily due to their expression of CD21, the major receptor for the virus.
"Epstein-Barr virus (EBV) infection is known to convert resting B lymphocytes into immortal cells that continuously multiply, leading to posttransplant lymphoproliferative disorder (PTLD)."
"After Epstein-Barr virus (EBV) infection in vivo, B-cells with latent virus infection persist indefinitely through life. These cells grow in vitro on explanation and can be established as immortal B-cell lines."
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EBV -- Burkitt’s lymphoma
"Epstein-Barr virus (EBV) causes Burkitt's lymphoma (BL), which is endemic in Africa, and, as we demonstrate, promotes survival of the tumor cells even long after their explantation."
"Epstein–Barr Virus (EBV) can transform B cells and contributes to the development of Burkitt lymphoma and other cancers."
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EBV -- nasopharyngeal carcinoma
Nasopharyngeal carcinoma (NPC) and gastric carcinoma accounted for 82% of EBV-attributed malignancies and 89% of deaths attributed to EBV-associated neoplasms. EBV is known to cause lifelong persistent infection asymptomatically in over 90% of the global population.
"Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection in regions in which it is endemic"
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HBV
hepatitis B virus
Transmitted by blood
Associated with liver cancer
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HBV associated with
liver cancer
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HTLV-1 (RNA virus)
HUMAN T-CELL LYMPHOMA/ LEUKEMIA VIRUS 1
RNA retrovirus
Causes a rare form of adult T cell leukemia
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oncogenes, proto-oncogenes
Normal cellular genes, called proto-oncogenes, encode for proteins important for basic cell functions
Proto-oncogenes are transformed into oncogenes (mutated normal cellular genes) by four mechanisms:
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proto-oncogene
"Proto-oncogenes are normal genes which affect normal cell growth and proliferation, but which have the potential to contribute to cancer development if their expression is altered."
"A variety of events may activate proto-oncogenes and convert them from benign genes to cancer genes."
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4 mechanisms that can convert proto-oncogene to oncogene
1) point mutation
(change structure)
2) gene amplification
(change quanitity)
3) chromosomal rearrangement
(change location)
4) Insertion of viral genome
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1) Point mutation
single base substitution in the DNA chain
196
2) Gene amplification
increased number of copies of the proto-oncogene
197
3) Chromosomal rearrangement
translocations of one chromosomal fragment onto another or deletion of a fragment or insertion of a fragment
198
4) Insertion of viral genome
..
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second contributing factor (if proto-oncogene becomes oncogene)
TUMOUR SUPRESSOR GENES
200
Tumour suppressor gene
Cells regulatory genetic mechanisms to protect against activated or newly acquired oncogenes
"If a tumour cell is fused with a normal cell, the hybrid cell will be benign because the tTUMOUR SUPPRESSOR GENES of the normal cell will suppress the oncogenes of the malignant cell"
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what happens if Tumour suppressor genes don't function
1st mutation = proto-oncogene --> oncogene
(I.e.
SUSCEPTIBLE CARRIER)
2nd mutation = defective Tumour Suppressor Genes
--> leads to cancer
Note cancer can also occur with Tumour Suppressor Genes
--> (more active oncogenes?)
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hereditary cancer
Certain cancers occurs more often in families.
family history, genetic component
"linked to an absence of a specific tumour suppressor gene."
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hereditary cancer vs tumour supressor genes
linked to an absence of a specific tumour suppressor gene.
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Hereditary cancer -- E.g.
Neurofibromatosis type I
Familial adenomatous polyposis coli
Wilms’ tumor
Skin tumors in xeroderma pigmentosum
Chromosomal fragility syndromes (Bloom’s syndrome, Fanconi’s syndrome)
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Wilm's tumour
rare kidney cancer
mainly affects children
AKA nephroblastoma
the most common cancer of the kidneys in children
affects children ages 3 to 4
less common after age 5
can affect older children and even adults
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Familial adenomatous polyposis coli
Familial adenomatous polyposis (FAP) is an inherited disorder characterized by cancer of the large intestine (colon ) and rectum. People with the classic type of familial adenomatous polyposis may begin to develop multiple noncancerous (benign) growths (polyps ) in the colon as early as their teenage years.
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***Neurofibromatosis Type I***
common autosomal dominant disease in humans
numerous subcutaneous neural sheath tumours
also with pigmented lesions of the skin (café au lait spots)
E.g. “The Elephant Man”
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autosomal dominant
Autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child.
One copy of a mutated (changed) gene from one parent can cause the genetic condition.
A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.
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neurofibromatosus type 1 -- clinical features
lisch nodules (nodular aggregate of dendritic melanocytes affecting the iris)
Neurofibromas (lumps on/under skin)
skin fold freckling
cafe au lait spots (pigmented lesions)
210
immune response to tumours
Malignancy may alter tumour cells so much that they become “foreign” to the body’s immune system
211
how does immune system respond to tumour cell antigens?
Tumour antigens will induce antibody production and cell-mediated immune response (T suppressor/cytotoxic cells)
-->
(ACQUIRED IMMUNITY)
Innate immunity – NK kills, macrophages
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what can immune response do to tumour
Ultimately, immune response can limit growth of tumour
Many small tumours are perhaps eliminated by immune system
Immunotherapy treatment can be successful in eliminating tumours
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immunotherapy
the prevention or treatment of disease with substances that stimulate the immune response.
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HIV/AIDS & cancer risk
People with HIV often have weakened immune systems, which means they will have a greater chance of getting cancer.
215
CLINICAL MANIFESTATION OF NEOPLASIA
variable
signs include:
Change in bowel/bladder habits
A sore that won’t heal
Unusual bleeding or discharge
Thickening or lump in breast or elsewhere
Indigestion or difficulty in swallowing
Obvious change in wart or mole
Nagging cough or hoarseness
216
clinical features of tumour depend on:
1) Type of tumour
2) Location of tumour
3) Histological grade of tumour
4) Clinical stage of tumour
5) Immune status of person
6) Sensitivity of tumour to therapy
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local symptoms
tumour growth compressing adjacent structures
Compression of brain causes epileptic seizures
Compression of lung causes coughing
Can cause atrophy
Can cause hemorrhage
Can cause obstruction
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systemic conditions
Cachexia - wasting
Anorexia – loss of appetite
Weight loss
Thrombosis
Paraneoplastic syndromes
219
Paraneoplastic
Paraneoplastic comes from the Greek words for alongside (para), new (neo) and formation (plasis)
220
Paraneoplastic syndromes
a consequence of the presence of cancer in the body,
NOT due to the local presence of cancer cells;
can be caused by substances secreted by cancer cells
221
Paraneoplastic Syndromes, E.g.
Cushing’s syndrome: small-cell carcinoma of the lung
Hypercalcemia: squamous cell carcinoma of the lung
Polycythemia (erythrocytosis): renal cell carcinoma
Venous thrombosis: pancreatic carcinoma
Myasthenia gravis: thymoma
222
Cushing's syndrome risk factors
Risk factors for Cushing's syndrome are adrenal or pituitary tumors, long-term therapy with corticosteroids, and being female.
223
epidemiology (?)
Incidence – the number of new cases in a specific time period in a given population
Prevalence – the number of all cases within a given population at a given time
Mortality – the number of deaths attributed to a specific population during a specific period
224
most common cancer with highest mortality rate
Lung cancer ("lung and bronchus")
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