Neoplasms

• Terminology
• Cancer
– Pathophysiology
– Etiology
– Diagnostics
– Treatment
In order for normal renewal and repair to take place, two
processes must occur:

1. Cell Proliferation – new cells replacing old ones

2. Cell Differentiation – cells acquiring the

characteristics of the tissue that they make up

In neoplasia, one or both of these characteristics is lost

• Neoplasm = new growth = tumor
• Two types of tumors:
1. Benign
• Have lost ability to control proliferation, but
1. growth is usually slow and may come to a stop
2. made of fairly well-differentiated cells and well-organized
stroma (connective tissue framework)
3. do not invade beyond their capsule
4. no metastasis
• Generally named for the tissues from which they arise,
with the suffix “oma”
– e.g., lipoma – benign tumour of fat cells; see Table 8-1
• Can still be a problem if the growth interferes with
function of surrounding tissue
e.g., compression of brain tissue, or inappropriate hormone production
Porth p169
2. Malignant

• More rapid growth rate

• Loss of differentiation (anaplasia) and tissue organization (a spectrum from

low to high grade). Cells are pleomorphic (different sizes and shapes)

• Lack a capsule and invade nearby blood vessels, lymphatics and surrounding
structures

• Most deadly characteristic: the ability to metastasize (spread far beyond the
tissue of origin)

Summary: 4 characteristics = loss of control of growth, anaplasia, can invade

local tissues, can metastasize (See Table 8.2 for comparison to benign)
Malignant tissue is
anaplastic and
pleomorphic
Malignant, cont’d
• Referred to as “cancer”
• Many are named for cell type from which they originate with
suffix “carcinoma” (from epithelial tissue), or “sarcoma” (from
mesenchymal tissue; connective tissue, bone, muscle)
– E.g., adenocarcinomas are from glandular tissue. (Table 8.1)

• Specialized names: “lymphomas” are from lymphatic tissue, and

“leukemias” are cancers of blood-forming cells
• Two categories:
– solid tumours (initially confined to specific tissue/organ)
– hematologic tumours (cells normally found in blood/lymph)

• 90% of adult human cancers are carcinomas from malignant

transformation of epithelial cells
 STOP AND THINK
Which of the following is a benign tumour?

A. Leukemia
B. Glioma
C. Adenocarcinoma
D. Osteosarcoma
E. Squamous cell carcinoma
 Carcinoma In Situ
• Refers to a growth with
malignant characteristics
(increased proliferation rate and
atypical cells) in epithelial tissue
that has not (yet) invaded local
tissue (so technically, not
malignant)
• Difficult to decide how to treat, as it may never spread
(“wait and see” or remove?)
• Can remain stable for a long time, become malignant, or
even regress
• Can occur in breast, cervix, skin, stomach

Porth p171
 Cancer cell characteristics (8)
1. Genetic instability: There is a high frequency of
mutations (deletions/insertions/substitutions of bases,
loss/gain of whole chromosomes) in cancer cells
– normal cells have mechanisms that correct such mutations

2. The cell must become independent of external growth

signals:
– able to make their own
– don’t need any (some breast cancer cells don’t have receptors)
– extremely sensitive to growth factors so will respond to
extremely low levels (e.g., one type of breast cancer has more
receptors on the cell surface, so response to growth factor is
increased)

(Porth Table 8.3)

 3. Loss of contact inhibition:
normal cells usually stop growing
when they come into contact
with each other (E.g. wound Cancer cell

healing) but cancer cells keep

piling up on top of each other

4. Decrease in cell adhesion: normal cells have

membrane structures that allow them to stick
together – cancer cells have less of these and can
then more easily be shed from a tumour,
increasing the possibility of metastasis
5. Loss of anchorage dependence: normal epithelial
cells will die if they are not attached to an
underlying extracellular matrix
• Cancer cells can survive and grow under conditions
that normal cells can’t (may help in metastasis)

6. Production of unusual antigens: cell surface

markers (that are identified as foreign by the immune
system), enzymes, or hormones that are not made by
the tissue of origin
• Cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA)
• ACTH, parathyroid hormone
7. Able to divide without limit
(immortal) – how?
• Telomeres are sections on the end
of each chromosome that get
shorter with each cell division
• When they get short enough, the
cell can’t divide any more
– in the lab, most normal cells can’t divide more
than about 50x

• Cancer cells have a very active enzyme, called

telomerase, that can lengthen telomere. Therefore,
they can divide without limit
8. Altered metabolism; increasing anaerobic
respiration
―Why? They divide rapidly, need a lot of building blocks for
new cell construction, and often live in anoxic environments

―To facilitate this, cancer cells mainly use anaerobic

respiration (glycolysis), even in the presence of oxygen

―This yields much less ATP, but the lactic acid produced can
be used to synthesize other molecules needed for rapid
growth

―This means that they use much more glucose than regular
cells
 Geraldine Grows Adorable Corn And Artichokes In Mud
• This characteristic
can be used as a tool
for detection:

• Use a fluorescent
compound that is
taken up by cells in
the same way as
glucose, but can’t be
metabolized. It
accumulates in cells
that would take up a
lot of glucose (i.e.,
cancer cells).
 STOP AND THINK
TRUE OR FALSE?

Contact inhibition describes the property

in which normal cells need to attach to a
surface to grow.
 Metastasis
• A defining characteristic of cancer

• The spread of cancer cells from the original site to distant

organs and tissues

• Treatment more challenging: cancer that has not

metastasized has a much greater chance of being cured
with surgery, chemotherapy, and/or radiation

Porth p173
 Metastasis, cont’d
• Local spread – helped by enzymes made by the cancer cells that
break down cells and connective tissue of surroundings. Growth is
via “crablike” extensions sent into surrounding tissue (difficult to
remove surgically)
– This is different from benign tissue, which pushes on surrounding connective
tissue that eventually forms a capsule around the growth (easier to remove
surgically)

• Distant spread - cancer cells must be able to invade lymph and

blood vessels (helped by lymphangiogenesis and neoangiogenesis
= growth of lymph and blood vessels into the tumour)

• Carcinomas (epithelial tissue derived) spread through Lymph

• Sarcomas (fibrous tissue derived) spread through Blood

• If the spread is through the lymph, the tumour cells
lodge first in the initial lymph node that drains that
area. This node is known as the “sentinel node”.
Examination of such nodes can show if metastasis has
occurred

• If spread is through the blood, the organ that is next in

the vascular pathway may most likely be affected
(e.g., the liver is a common place for metastasis to be
successful from tumours in the intestines), or it could
be an organ that supplies a similar environment as the
tissue containing the original tumour (e.g., same types
of growth factors)
 Invasion and Metastasis - process
Cancer cells:
1. must evolve characteristics needed to metastasize
(as outlined previously)
2. initially invade the interstitial spaces of local tissue
3. if carried by lymphatic drainage, go to primary or
sentinel lymph node/s
4. enter the venous system as lymph drains into left
and right subclavian veins
5. must evade the innate immune system (e.g. NK
cells, lymphocytes) by mimicking normal cells (e.g.
coating with platelets)
6. secrete proteolytic enzymes in order to penetrate
tissues from blood vessels (and vice versa)
7. once “seeded” release cytokines and growth factors that
control invaded tissue functions:
– to stimulate their growth and proliferation
– if cancer tissue grows more than 1 mm in diameter, it
requires its own blood supply; cancer must develop
ability to perform angiogenesis

****Fewer than 1 in 10,000 cells survives to start a

secondary tumour****
(Study of women with malignant ovarian cancer cells)
Steps in metastasis:
 STOP AND THINK
TRUE OR FALSE?

Benign tumours spread into the lymph

first and malignant tumours spread
directly into blood.
 Local effects of tumours (6)
Local effects of tumour growth often depend on location:
1. Compression: e.g. brain tumor: headaches, nausea, loss of
consciousness, death. Local nerve compression: loss of
function, sensation
2. Obstruction: e.g. blockage to airways or gut
3. Hemorrhage: damage to blood vessels, e.g., intestine, lungs
4. Infarction: growth of mass can obstruct blood vessels,
causing local necrosis of tissues (ulceration and bleeding)
(e.g., blood in stool from colorectal cancer)
5. Rupture or perforation e.g. gut,
ovary
6. Effusions (inappropriate amounts
of fluid) in pleural, pericardial or
peritoneal spaces may occur
– up to 65% of women with ovarian
cancer present with ascites (excess
fluid in the peritoneal cavity)

Effects are usually combined and relate to symptoms:

• e.g. cancer of the lung may present with chest pain, shortness of
breath and cough, wheezing, blood in sputum

Note: All of these can cause pain

 Systemic manifestations of cancer (9)
1. Paraneoplastic syndrome
• Symptoms triggered by substances released by the
cancer cells, but not caused by direct local effects of
the tumour mass.
• E.g., some tumours release hormones that may have
systemic effects
» small cell carcinoma of the lung releases an ACTH-like substance
(usually from adrenal gland), causing Cushing’s syndrome

Porth p185 - 187

2. Pain: Little or none in early stages, can be strong in later
stages. Can result from pressure, stretching, inflammation.
Important to control rapidly and completely
3. Fatigue: Not relieved by sleep or rest. Mechanism not fully
understood. May be due to sleep disturbances, various
biochemical changes, nutritional status, etc
4. Cachexia: Definition: Loss of body mass due to metabolic
disturbances caused by a disease and cannot be reversed
nutritionally; even with adequate caloric intake
Caused by altered metabolism that leads to inefficient use
of energy
Compounded by side-effects of the cancer/treatment:
depression, anorexia, loss of sense of taste, early satiety
5. Anemia, leukocytopenia and thrombocytopenia: caused by
chemotherapy, radiotherapy, malignancy in blood-forming organs
(anemia also caused by chronic bleeding and malnutrition)

6. Infection: most significant cause of complications and death

due to loss of immune cells (as described in 6.).
• increased risk from surgery, poor tissue perfusion, indwelling devices (catheters)

7. GI tract issues: chemotherapy and radiation therapy affects

rapidly multiplying epithelial lining causing: oral ulcers,
malnutrition, nausea and infection

8. Hair and skin issues: alopecia and skin sensitivity/ pain/ burns
due to rapidly growing tissue being affected by therapies
 STOP AND THINK
TRUE OR FALSE?

Cachexia is the wasting seen in cancer

patients solely due to lack of appetite
during chemotherapy.
 Carcinogenesis - what causes a cell
to become cancerous?
A small number of changes in the genetic material of the cell

• These changes allow that cell to divide with less inhibition

– therefore that cell and all of its progeny will divide more
than regular tissue

• The rate of cancer increases dramatically with age, due to

accumulation of small changes in genetic material
(“mutations”) that occur over a lifetime

• When enough mutations occur, cancer may develop

Porth p176-184
 What types of changes in genes
actually occur in cancer?

1. Changes in the actual DNA: two types of genes,

which if they mutate, can lead to cancer:

a. Proto-oncogenes
b. Tumour suppressor genes
a) Proto-oncogenes

• Genes that in their normal non-mutant state code for

proteins that cause the cell to divide
• E.g., a growth factor, growth factor receptor, or a protein
involved in transmitting the signal from a receptor to the nucleus

• If these do mutate and become more active, they are

called oncogenes and cause cell to divide uncontrollably
• E.g., the RAS family of proteins that transmit the growth signal
from the membrane receptor to the nucleus (involved in 30% all
cancers)
 Growth factors –
signal transduction
b) Tumor-suppressor genes
(anti-oncogenes)
• Genes that code for proteins that slow the rate of cell
division or stop it when the cell is damaged
• If one copy of the gene is inactivated, the other copy can still
perform the function
– Remember, we have 2 copies of each gene: (one maternal, one
paternal). Therefore, both copies of the gene must be altered in
order for this to have an effect (“recessive in effect”) on cell growth
• These are usually the type of genes that are involved in
cancer that can be inherited
– Individuals can inherit a defective allele, but have protection of the
other allele. However, if the other allele becomes inactivated, then a
tumor can develop
• E.g, BRCA1 gene in breast cancer, p53 gene (guardian of
genome; inactivated in >50% cancers)
Other cell changes contributing to the
development of cancer:

2. Changes in metabolic pathways inside the cell E.g.,

• loss of DNA repair machinery that could fix an oncogene
• loss of ability to perform apoptosis that would normally
cause a malfunctioning cell to die, etc.

3. Changes in the control mechanisms that govern which

genes are expressed (epigenetics) E.g.,
• you may have normal tumour suppressor genes, but they are
not active
Epigenetics - DNA Sequence remains the same but
genes can be switched on / off

Acetylation of histones Methylation of DNA

• Epigenetics is impacted by lifestyle – stress, diet, exercise

 Carcinogenesis
1. Initiation
• exposure to carcinogenic agent
(single shot or long-term exposure)
• irreversible mutations to genome
• cells in mitosis or meiosis most
susceptible

2. Promotion
• cytokines and growth factors begin
to induce cell proliferation

3. Progression
• tumour cells eventually acquire all
the characteristics needed to invade
and metastasize to other tissues
 STOP AND THINK
Which genetic change (mutation) is most likely to cause
cancer?

A. Decreased activity in proto-oncogene

B. Increased activity in DNA repair gene
C. Decreased activity in tumour suppressor gene
D. Increased activity in apoptosis gene
 Medical conditions:
Uncontrollable factors:
age, spontaneous mutations,
family history (inherited genes)

Risk factors
for cancer

Lifestyle choices: Environmental exposure:

Task: Write 2 examples of causes of cancer development in each blue

box. Discuss in detail how one of the factors can lead to cancer
 Cancer Etiology
• Inflammation
– Chronic inflammation has been recognized for close to 150
years as being an important factor in the development of
cancer.

– Inflammation and cancer both involve

• the migration of neutrophils, lymphocytes and

macrophages and the release of factors that stimulate
the growth of cells and blood vessels.

• Inflammatory cells also release compounds that can

promote mutations (e.g., reactive oxygen species)
• Viral A number of viruses have been associated with cancer,
through virus alteration of the cell DNA, or through inflammation
from the viral disease:
• Up to 80% of liver cancer cases worldwide are associated with chronic
hepatitis (HBV or HCV)
• Virtually all cervical cancer is caused by infection with specific subtypes of
HPV. The viral DNA becomes integrated into the host cell DNA and can
activate proto-oncogenes
• EBV virus (infectious mononucleosis) infects B cells and stimulates their
growth. If the individual is then immunosuppressed (HIV infection or
organ transplant), persistent EBV infection can lead to B cell lymphomas
• Bacterial
• Chronic infection with Helicobacter pylori and inflammation has been
linked to gastric carcinoma, a leading cause of cancer deaths worldwide

• Obviously other factors, in addition to the initial infection, are

required, since not all people with these infections develop the
associated cancer
• e.g., 90% of population can be infected with EBV, yet relatively few
develop EBV-related cancer
 Heredity and Cancer

All Breast Cancer Patients

Inherited factors – e.g. BRCA1 / BRCA2

Other factor(s)

Only 10 - 20% of all cancers linked to heritable factors

 Proportion of women with a TSG
BRCA1 or 2 mutation that develop
breast cancer by a given age

Anglian Breast Cancer Study Group. Br J Cancer. 2000; Easton et al. Am J Hum Genet. 1995; Antoniou et al. Am J Hum
Genet. 2003; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Brose et al. J Natl Cancer Inst. 2002;
Ford et al. Am J Hum Genet. 1998; Schubert et al. Am J Hum Genet. 1997.
45
Heredity Can Affect Many Types of Cancer

Inherited Conditions That Increase Risk for Cancer

• Environmental/lifestyle interactions
– Include: cigarette smoking, excessive alcohol
consumption, poor diet, obesity, lack of exercise,
exposure to UV and ionizing radiation, pesticides and
other chemicals

– May be possible that these are affecting how the

genes are expressed, and not the genes, themselves
(epigenetics)

– Evidence for influence from these sources is strong,

but unclear how these factors affect individual
resistance to cancer-causing agents (carcinogens)
 Population-Based Studies
Regions of Highest Incidence
U.K.:
Lung
cancer

JAPAN:
Stomach
cancer CANADA:
Leukemia

U.S.:
CHINA: Colon
Liver cancer
cancer
BRAZIL:
Cervical
AUSTRALIA: cancer
Skin
cancer
 Heredity? Behaviors? Other Factors?

Colon Cancer Stomach Cancer

(Number of new cases (Number of new cases
per 100,000 people) per 100,000 people)
100 100

70

50

5 7
0 0
Japan Japanese U.S. Japan Japanese U.S.
families families
in U.S. in U.S.

Causation is not always clear cut

 Diet
Correlation Between Meat Consumption and
Colon Cancer Rates in Different Countries

40

30
Number of Cases
(per 100,000
people)
20

10

0 80 100 200 300

Grams (per person per day)
 Chemical
Some Carcinogens in the Workplace
Benzopyrene
Chemical: Alcohol and Tobacco
Combination of Alcohol and Cigarettes
Increases Risk for Cancer of the Esophagus
40x

30x
Risk
Increase
20x

10x

Alcoholic Drinks
Consumed per Day
AND
Packs of Cigarettes
Consumed per Day
 A simplification of the pathways by which alcohol,
as ethanol, might drive carcinogenesis

Rumgay et al., 2021. Alcohol and Cancer: Epidemiology and Biological Mechanisms.
Nutrients. 13(9):3173. doi: 10.3390/nu13093173
 Lag Time
20-Year Lag Time Between
Smoking and Lung Cancer
Cigarette
consumption
(men)
4000
150
Lung
Cigarettes 3000 cancer
Smoked (men) Lung Cancer
per Person 100 Deaths (per
per Year 2000 100,000 people)
50
1000

1900 1920 1940 1960 1980

Year

How does the multi-step process of mutation relate to this?

 Low-Strength Radiation
High

Melbourne

Skin
Cancer
Incidence
Pittsburgh
Ottawa

Low
Least Most
Annual Sunshine
(UV radiation)
 High-Strength Radiation
High

Leukemia
Incidence

Low
Least Most
X-ray Dose
(atomic radiation)
Decreasing cancer risk family history
age

• reduce exposure to harmful chemicals

• vaccinate against certain infections
 Diagnostic Methods
1. Tumour markers
• Substances (hormones, enzymes, antigens, antibodies)
produced by both benign and malignant cells that are either
present in or on tumour cells, or found in blood, spinal fluid, or
urine
– E.g. PSA (prostate specific antigen), secreted by prostate tumours into
blood at high levels
• Can help to identify high risk people, diagnose the tumour and
follow the success of the treatment
• Must be used with caution, however, as can get false positives
and negatives (not the only test used for diagnosis)
• Best use may be to monitor success of therapy

Porth p188-190
2. Cytology/Histology

– The Papanicolaou test (“Pap” test): The secretions surrounding a

tumour can contain cells of the tumour (as these cells are easily
shed). Examination of the secretion can reveal abnormal cells
(cervical, pleural, peritoneal secretions, etc.)

– Biopsy: removal and examination of tissue sample, (through a

needle, an endoscope/laparoscope, or surgically)
 Immunohistochemistry (IHC)
of breast cancer biopsy tissue
- Immunohistochemistry: Use of
antibodies specific for a
particular cell product or
HER2 neg HER2 pos
surface marker to detect the
presence of that product or
marker
For example, breast cancers can now
be sorted into over 4 subclasses
based upon the presence of
estrogen receptor, HER2/Neu (a
gene), and other specific genes
and proteins. Such information is
extremely important in
determining treatment
[Link]
3. Imaging
– endoscopic
– ultrasound
– standard X-rays
– CT (Computerized Tomography):
• Many x-rays taken from different angles, fed through a computer to
produce a 3D image
– MRI (Magnetic Resonance Imaging):
• Uses a magnetic field. Provides more soft tissue detail, but more
expensive and time-consuming
– PET (Positron Emission Tomography):
• Like CT, but uses a biologically active molecule attached to a tracer, to
show metabolically active tissue
Endoscopy - colonoscopy
Staging and Grading

There are two methods for classifying cancers:

1) Grading (according to cellular characteristics)
2) Staging (according to spread)

1) Grading: a portion of the tumour is obtained through a

biopsy. The closer the tumour cells resemble normal
tissue, the lower the grade.

Porth p190
Staging: Includes size and spread of the disease
• One common scheme is the 4-stage system:
– Stage 1: confined to origin
– Stage 2: local invasive

– Stage 3: spread to local lymph nodes

– Stage 4: spread to distant sites (e.g., liver cancer to a lung)

• Another common scheme is the WHO’s TNM system which

describes tumour size, lymph node involvement and extent of
metastasis (Chart 8-2, pg 190)

• The appropriate therapy is then determined. The stage is more

influential in deciding on treatment than the grade
Staging of colon cancer
 Cancer Treatment
Three main treatments:
1. Chemotherapy
– Targets metabolic pathways – hopefully a cancer cell is more
sensitive to a particular chemical.
• E.g., leukemia is very sensitive to folic acid deficiency, unlike non-
malignant cells, so can treat with an antifolate drug

– Usually used in combinations

• to decrease the amount given of any one drug (reducing side effects)
• to increase attack on cancer cells (some cells in a tumour may be
resistant to one drug, but susceptible to another one in the cocktail)

– Chemo given alone = induction

– Chemo given in combination with surgery:
• after surgery =adjuvant - to eliminate small metastasized tumours
• before surgery = neoadjuvant - to minimize removal of normal
tissue
Porth p191-197
2. Radiation therapy

• Targeted cells die through molecular damage (particularly to

the DNA), caused by the ionizing radiation

• Most effective on cells that are rapidly renewing

• Well-suited to localized tissues in areas that are hard to reach

surgically (brain and pelvis)

• Can be through an external beam or by placing small

radioactive capsules in the affected area (brachytherapy) –
e.g., cervical, prostate, head and neck cancers
 3. Surgery
• Often the definitive treatment for localized (accessible)
tumours

• Establish grading and staging of cancer – by obtaining

biopsy tissue / observing local lymph nodes

• May be used prophylactically (women with BRCA1/2

mutations)

• Precautions include:
– Avoiding spread of cancerous cells during operation
 Cancer in children
• Rare, but still the second leading cause of death in children 1-14 yrs of age
• Types of cancer are different to adults (epithelial origin: e.g prostate, breast, lung).
Children develop leukemia, brain, sarcoma (e.g., bone); generally fast-growing
• Childhood cancers usually diagnosed during peak times of physical growth and
maturation (first years of life; puberty/adolescence)
• Causes are largely unknown
– some genetic risk factors/congenital conditions have been implicated (e.g., Down
syndrome is associated with increased susceptibility to acute lymphoblastic leukemia)
– Pre-natal exposure to some drugs or, childhood exposure to ionizing radiation, drugs,
electromagnetic fields or viruses
• More than 70% of children diagnosed with cancer are cured
– but early detection is sometimes difficult, as signs and symptoms are often similar to those of
common childhood diseases
• Chemotherapy is more widely used, as children better tolerate side effects and
the type of tumours respond better to chemotherapy
– Potential benefits of treatment must be balanced against long-term effects, including
physical and mental impairments
• Additionally, there is an increased risk of developing cancer later in life