Neoplasia
Cancer
Neoplasia
A Disorder of Altered
Cell Differentiation
and Growth
Cancer
• The second leading cause of death in the
United States
– Estimated 1.45 million diagnosed
– 559,650 die each year
• Prostate is the most common cancer for
men
• Breast is the most common cancer for
women
– Excluding skin cancer
• Lung cancer is the leading cause of death in
both men and women
Definitions
• Benign – not capable of metastasizing and
usually not capable of causing death
• Malignant – capable of metastasizing and
capable of causing death
• Neoplasm – an uncontrolled growth of new
cells, benign or malignant
• Tumor – literally, a mass; however, in everyday
language, a neoplasm
• Cancer – any kind of malignant neoplasm
• Carcinoma – a malignant neoplasm of
epithelial cells
• Sarcoma – a malignant neoplasm of
mesenchymal cells
Growth Layers
More Definitions
• -oma is used for benign tumors
– There is a matching malignant variety
for every benign variety
– For example, adenoma – aden =
gland and oma = swelling
• A benign tumor of fibrous tissue is a
fibroma
Even More Definitions
• Malignant tumors are named by adding
carcinoma if the tumor is of epithelial origin
– Breast duct epithelium, prostate
epithelium, bronchial epithelium and so
on
• Sarcoma if the tumor is from mesenchymal
tissue
– Bone, cartilage, fat, muscle or fibrous
tissue
• Adenocarcinoma if the tumor is of glandular
epithelial cells
• Fibrosarcoma if the tumor
Mutations
• The root cause of all cancer is damaged
(mutant) DNA
• This causes the normal cycle of cellular
reproduction to go awry
Cell Cycle
•
Cell proliferation
–
–
Process of cell division
Inherent adaptive mechanism for replacing body cells
• Sequence of events that occurs
as a cell duplicates
– Genetic information is also
duplicated
–
• Duplicated chromosomes are
appropriately aligned for
distribution between two
genetically identical daughter cells
Process of specialization
http://highered.mcgrawhill.com/sites/9834092339/student_view0/cha
pter10/control_of_the_cell_cycle.html
Interphase
• G1 (gap 1)
– From the end of the M phase until the
beginning of DNA synthesis
– Growth Phase
– The cell determines its readiness to
commit to DNA synthesis
• S (DNA Synthesis)
– DNA replication
• G2 (gap 2)
– DNA replication is assessed and errors are
corrected
– the gap between DNA synthesis and
mitosis, the cell will continue to grow.
Cell Cycle
• M-Phase (Mitotic Phase)
– The replicated chromosomes are separated and
packaged into two new nuclei by mitosis
– The cytoplasm is divided between the two
daughter cells by cytokinesis
– Prophase
– Metaphase
– Anaphase
– Telophase
• http://highered.mcgrawhill.com/sites/9834092339/student_view0/ch
apter10/stimulation_of_cell_replication.html
Cyclins and CDK’s
• Two key classes of regulatory proteins,
Cyclins and Cylin-Dependent Kinases (CDKs),
determine a cell’s progress through the cell’s
cycle
Cell Cycle
• Cyclins are proteins that control the entry and
progression of cells through the cell cycle
• Cyclins bind to cyclin-dependent kinases
(CDK), which are enzymes that
phosphorylate proteins
• Cyclin-dependent kinase inhibitorsregulates cell cycle checkpoints to prevent
DNA replication mistakes.
Cyclins and CDK’s
• Progression from one phase of the cell
cycle to the next is controlled by the
orderly activation of cyclin dependent
kinases
• Cyclin proteins bind to CDK’s to cause
phosphorylation and activation
• http://highered.mcgrawhill.com/sites/9834092339/student_view0/chapter1
0/how_tumor_suppressor_genes_block_cell_divisio
n.html
Cell Growth Control Genes
• All cells contain genes that function as
“go” or “stop” switches (restrains cell
growth)
• The “go” genes are proto-oncogenes
• Proto-oncogenes produce growthpromoting proteins that stimulate
normal cell division
• Oncogenes (cancer genes) come from
mutations of proto-oncogenes
– Their function is to stimulate
uncontrolled cellular division
Tumor Suppressor Genes
• “stop” genes are the opposite of protooncogenes
– Called Tumor suppressor genes
• Produce proteins that inhibit cell
division
– Mutation of tumor suppressor genes
leaves cell growth uninhibited
http://highered.mcgrawhill.com/sites/9834092339/student_view
0/chapter9/cell_proliferation_signaling_p
athway.html
Tumor Suppressor Genes
• Retinoblastoma is a rare childhood
cancer due to the inactivation of a
specific tumor suppressor gene
• Retinoblastoma (pRB) gene
• Prevents cell division
– Retinoblastoma tumor suppressor protein
(pRB)
• Phosphorylation of pRB causes progression
of the cell into the S-phase
– A point mutation renders the pRB pathway
non-functional
• Thought to occur in almost all human cancers
Tumor Suppressor Genes
• p53 gene
• Found on the small arm of chromosome
17
• Its protein product is in virtually all
normal tissues
• Controls p53 protein levels
• p53 proteins increase with damage to
DNA
• Initiates apoptosis of DNAdamaged cells
p53 Gene
• “Guardian of the genome”
– Restricts uncontrolled cellular
proliferation under circumstances in
which cells with abnormal DNA might
propagate
• Deleted or mutated in 70% to 80% of
cases of colorectal cancer, breast
cancer, small cell carcinoma of the lung,
hepatocellular carcinoma, astrocytoma
and numerous other tumors
Epigenetics
• Involves changes of gene expression
without a change in the DNA
– “silence” genes such as tumor
suppressor genes
– Methylation of the promoter region
• Prevents transcription to cause gene
inactivity
• Can be inherited
Genetic and Molecular Basis of Cancer
• Epigenetic factors
• http://youtu.be/Xjq5eEslJhw
• http://youtu.be/wFsxVkuChdU
The Spread of Neoplasms
• Direct invasion and extension
• Seeding of cancer cells in body
cavities
• Metastases
Premalignant States and Conditions
• Neoplasms evolve over time from normal
tissue
• Dysplasia
– A pre-malignant state of tissue that is atypical and
clearly abnormal but not yet malignant
– Dysplasia does NOT always progress to malignancy
• Carcinoma in situ
– Cancer that never metastasizes
Invasion
• Cancer is latin for crablike
– Cancer grows by sending crablike
projections into the surrounding
tissues
• Cancers secrete enzymes to break down
proteins to increase invasion and
penetration of surrounding tissues
– Prevents sharp demarcation for
surgical removal
Seeding
• A tumor erodes and shed cells into body
cavities
– Peritoneal, pleural, pericardial cavity
and joint spaces
• Floating in body space from one surface
to another
• These cancers grow in masses and
secrete fluids
– Ascites, pleural effusion
Metastasis
• The ability to skip from one place to
another
– Via lymphatics or the bloodstream
• Breast via lymphatics to lymph nodes
• Via blood to bone
– Metastases may occur by seeding
Metastasis
Nourishment of Tumors
• Angiogenesis
– Neoplasms develop their own blood
supply
Liver Metastasis
Human Papilloma Virus
• Infection in the cervix
– Causes dysplasia, carcinoma in situ and invasive
carcinoma
– Takes many years and repeated infections to
produce dysplasia or malignancy
Grading and Staging of
Malignancies
• Cancer Grading
– Microscopic assessment of the
degree of differentiation, atypia and
other features of malignancy
• Cancer Staging
– Evaluation of behavior by assessing
size of the primary tumor and its
spread
• Assessed by physical exam, history and
pathologic and diagnostic imaging
Grade
• I
• II
• III
• IV
Definition
Well differentiated
Moderately differentiate
Poorly differentiated
Nearly anaplastic (cells that
have become less differentiated)
Staging
• TNM classification.
– A "T" score is based upon the size
and/or extent of invasion.
– The "N" score indicates the extent of
lymph node involvement.
– The "M" score indicates whether
distant metastases are present.
Stage Definition
Tis
T1
T2
In situ, non-invasive (confined to epithelium)
Small, minimally invasive within primary organ site
Larger, more invasive within the primary organ
site
T3
Larger and/or invasive beyond margins of
primary organ site
T4
Very large and/or very invasive, spread to
adjacent organs
N0
No lymph node involvement
N1
Nearby lymph node involvement
N2
Regional lymph node involvement
N3
More distant lymph node involvement
M0
No distant metastases
M1
Distant metastases present
Benign v Malignant Tumors
BENIGN VERSUS MALIGNANT
TUMORS
Benign Tumors
Do not penetrate (invade) adjacent tissue
Do no spread (metastasize) to different
sites.
Malignant Tumors
Invades contiguous tissues
Metastasizes to distant sites
Takes up residence, grows and
invades again
BENIGN VERSUS MALIGNANT
TUMORS
• BENIGN
– Malignant tumors kill
– Benign tumors don’t kill (mostly)
• Benign intracranial tumor in the
meninges (meningioma) can kill by
exerting pressure on the brain
• Benign mesenchymal tumor of the left
atrium (myxoma) can kill by blocking the
orifice of the mitral valve
Benign Tumors
• The primary descriptor of any tumor, benign
or malignant is its cell or tissue of origin.
• Benign tumors are identified by the suffix
“oma” which is preceded by reference to
the cell or tissue of origin
– Chondroma, resembles chondrocytes
– Epithelioma, tumor of squamous cells
– Adenoma, arising from glandular
epithelium such as in the colon or
endocrine glands
Types of Tumors
• Adenoma: benign tumor of glandular epithelial
tissue
• Adenocarcinoma: malignant tumor of glandular
epithelial tissue
• Carcinoma: malignant tumor of epithelial tissue
• Osteoma: benign tumor of bone tissue
• Sarcoma: malignant tumors of mesenchymal origin
• Papilloma: benign microscopic or macroscopic
fingerlike projection growing on a surface
Histologic Diagnosis of Benign Tumors
• Benign tumors in general resemble their
parent tissues both histologically and
cytologically
• The lining epithelium may resemble that of
the normal tissue
– May be surrounded by a connective tissue capsule
(or not)
Normal Cartilage
Benign Chondroma
Normal Thyroid Tissue
Benign Thyroid Adenoma
Lung Hemartoma
Malignant Tumors
• Malignant tumors usually carry the same name,
except the suffix “carcinoma” is applied to
epithelial cancers and “sarcoma” to mesenchymal
cancers
• Gastric adenocarcinoma
– Malignant tumor of the stomach
• Squamous cell carcinoma
– An invasive tumor of the skin
• Transitional cell carcinoma
– Malignant neoplasm of the bladder
Characteristics of Malignant
Neoplasms
• Tend to grow rapidly
• Invades and infiltrates nearby tissue
• Spreads widely
• Lack of defined capsule
• Margins are not clearly separated
from normal surrounding tissue
• Have the potential to kill regardless of
their original location
Characteristics of Malignant
Neoplasm
• Tends to compress blood vessels and
outgrow their blood supply, causing
ischemia and tissue necrosis
• Robs normal tissues of essential
nutrients
• Secretes hormones and/or cytokines,
liberates enzymes and toxins that
destroy tumor tissue and normal tissue
Historically Important
•
•
•
•
Hepatoma of the liver
Melanoma of the skin
Seminoma of the tesis
Lymphoma or lymphoproliferation tumor are
all highly malignant
• “emia” – relationship with the blood
– Leukemia
Histologic Diagnosis of Malignant
Tumors
• In Malignant tumors cells have a different
structure than the parent tissue and they take
on a different function
– Anaplasia
• Loss of differentiation of cells and of their orientation to one
another
– Lack of differentiated features in a cancer cell
– The degree of anaplasia correlates with the aggressiveness of the
tumor
– Mitotic Activity
– Invasion
– Metastases
Anaplasia
1. Variation in the size and shape of cells and cell
nuclei (pleomorphism)
2. Enlarged and hyperchromatic nuclei with
coarsely clumped chromatin and prominent
nucleoli
3. Atypical mitoses
4. Bizarre cells
Mitotic Activity
• Abundant mitoses are characteristic of
many malignant tumors but are not a
necessary criterion
Invasion
• Invasion, particularly of blood vessels
and lymphatics
Squamous Cell Carcinoma of the Skin
Malignant v Benign
Characteristics
Benign
Malignant
Tissue differentiation
Well differentiated,
structure fairly close to
tissue of origin
Poorly differentiated; little
structure resemblance to
tissue of origin
Nuclear atypia
Minimal atypia; nuclei
small and uniform
Substantial atypia; nuclei
large, dark, irregular
(hyperchromatism)
Local Growth
Slow growth; cut surface
uniform; regular expansion
compresses surrounding
tissue into fibrous capsule
Rapid growth; cut surface
variegated; irregular
growth at margins;
infiltration of adjacent
tissue
Metastasis
None
Frequent
Cancer Treatment Modalities
• Radiation
• Can be used as a
primary method of
therapy or as an
adjuvant treatment
with surgery and/or
chemotherapy
• Uses high-energy
particles or waves to
destroy or damage
cancer cells
• Absorption of energy
from radiation in tissue
leads to the ionization of
molecules or creation of
free radicals
• Can kill cells, halt cell
proliferation or cause
damage to cell’s DNA
resulting in cellular
death
• Can be injurious to
other cells
Administration of Radiation
• 3 Ways
– External beam or teletherapy
• Beams generated at a distance and aimed at the tumor
– Brachytherapy
• Sealed radioactive source is placed close to or directly
in the tumor site
– Systemic therapy
• Radioisotopes with a short half-life are given by mouth
or injected into the tumor site
Chemotherapy
• Systemic treatment that enables drugs to reach the
site of the tumor as well as other distant sites
– Direct DNA-interacting
– Damages DNA or block cellular division
–
Hair loss or alopecia
– Indirect DNA-interacting
– Interrupts biochemical pathways relating to
nucleotide and nucleic acid synthesis = No DNA
– Toxic to all cells =Handler beware
Cancer Treatment Modalities
• Hormonal therapy
• Drugs designed to disrupt the hormonal environment of cancer
cells
• Used for Cancers that are responsive to hormones for growth
• Biotherapy
– Immunotherapy
– Monoclonal Antibodies
– Biologic response
– Interferons
–
Stimulate NK cells and T-lymphocytes
– Targeted Therapy
– Small molecules that block specific enzymes and
growth factors
Types of Surgery for Cancer
• Cryosurgery: instilling liquid nitrogen into the
tumor through a probe
• Chemosurgery: using corrosive paste with
multiple frozen sections to ensure complete
removal of tumor
• Laser surgery: using a laser beam to resect
tumor
• Laparoscopic surgery: performing surgery
through two small incisions
Stem Cell Transplantation
Bone marrow transplantation (BMT)
Peripheral blood stem cell
transplantation (PBSCT)
Two treatment approaches for
individuals with leukemias, certain
solid tumors, and other cancers
previously thought to be incurable
Clinical Manifestations of Cancer
• Tissue integrity
– Compressed and eroded blood vessels,
ulceration and necrosis, frank bleeding, and
hemorrhage
• Cancer cachexia
– Weight loss and wasting of body fat and
muscle tissue; profound weakness,
anorexia, and anemia
Clinical Manifestations of
Cancer
• Paraneoplastic syndromes
– Inappropriate hormone release,
circulating hematopoietic,
neurologic, and dermatologic
factors
– Not directly at the site of the cancer
• Cancer may cause Cushing syndrome
due to ectopic ACTH production and
hypercalcemia
• Lambert-Eaton myasthenic syndrome
Host and Environmental Factors Leading to
Cancer
• Stem cells
•Heredity
•Hormones
• Angiogenesis
•Carcinogens
– Angiogenic factor
Chemical
production or loss of
angiogenic inhibitors
Radiation
•Oncogenic viruses
• Microenvironmental effects
•Immunologic mechanisms
– Multiple cell types,
cytokines, and growth
factors
Heredity
• BRCA1 and BRCA2
– Tumor Suppressor genes
– Mutation to become Oncogene
– Implicated in the risk of breast, ovarian,
pancreatic, colon and other cancers
Immune System
• Immune Surveillance Hypothesis
– Cancers may be associated with the decline of
surveillance ability
– Tumor Antigens on cancer cells stimulate the
immune response
• Immunosuppression may lead to cancer
Chemical Carcinogens
• Sir Percivall Pott, 1775
– First to relate the high incidence of scrotal cancer
in chimney sweeps
– Ruled that chimney sweeps must bathe daily
• Many chemicals can cause cellular mutations
– Carcinogenic Chemicals
– Food Fried in Fat that is Re-Used
– Smoked or BBQ meats
– Dose dependent
Radiation
• Ionizing radiation
– Depends on the dose of radiation
– Hiroshima and Nagasaki
• Ultraviolet radiation
– Skin cancer
Oncogenic Viruses
• Epstein-Barr virus
– Herpes virus
– Burkitt lymphoma (B-cell lymphoma)
• Hepatitis B virus
– Hepatocellular carcinoma (liver cancer)
• Human Herpes virus 8
– Kaposi Sarcoma in AIDS
• Human Papilloma Virus (60 types)
– Squamous Cell Carcinoma of the Cervix
Diagnostic Measures for Cancer
Detection
• Lab tests
– Pap smear
– Biopsy
– Immunohistochemistry
and tissue biopsy
– Microarray Technology
– Endoscopic examinations
– Ultrasound
– X-ray studies, MRI
– CT and PET
• Staging and grading of
tumors
• Grades I, II, III, and IV
• Level of
differentiation
• Screening for early
detection
– Observation
– Palpation
– Laboratory tests
Diagnostic Measures for Cancer
Detection
• Tumor markers
– Antigens expressed on the surface of tumor cells
– Substances released from normal cells in
response to the presence of a tumor
– Used for screening for cancer
•
•
•
•
hCG
PSA
α-Fetoprotein (AFP)
May express fetal antigens normally present only in
embryonic development
Question
Which of the following does not apply to benign tumor
cells?
A. A slow, progressive rate of growth that may come to a
standstill or regress
B. An expansive manner of growth
C. Liberation of enzymes and toxins that destroy tumor
tissue and normal tissue
D. Composed of well-differentiated cells that resemble
the cells of the tissue of origin
Answer
Which of the following does not apply to benign tumor
cells?
A. A slow, progressive rate of growth that may come to a
standstill or regress
B. An expansive manner of growth
C. Liberation of enzymes and toxins that destroy tumor
tissue and normal tissue
D. Composed of well-differentiated cells that resemble
the cells of the tissue of origin
Goals of Cancer Treatment
• Curative
• Control
• Palliative
• Palliative care is the active total care of the
one's body, mind and spirit, and also involves
giving support to the family
• http://cancerhelp.cancerresearchuk.org/abou
t-cancer/what-is-cancer/
Common Solid Tumors of Childhood
• Brain and nervous system tumors
• Neuroblastoma
• Wilms tumor
• Rhabdomyosarcoma and embryonal
sarcoma
• Retinoblastoma
• Osteosarcoma
• Ewing sarcoma
Characteristics of Childhood Cancers
• Most involve the hematopoietic system, nervous
system, or connective tissue
• Heritable forms of cancer tend to have
– An earlier age of onset
– A higher frequency of multifocal lesions in a
single organ
– Bilateral involvement of paired organs or
multiple primary tumors
Question
Is the following statement true or false?
Radiation is a common treatment for childhood
cancers.
A. True
B. False
Question
Is the following statement true or false?
Radiation is a common treatment for childhood
cancers.
A. True
B. False: Radiation will have long-lasting
effects, whereas other methods of
treatment are not as damaging.
p53
• Acquired mutation in p53 is the most
common genetic alteration found in
human cancer
– One p53 allele may be deleted while
the other is mutated
• Therapies are directed at re-establishing
the p53 genes to cause massive
apoptosis of cancer cells
Telomeres
• http://www.youtube.com/watch?v=qQCecSuP
a1w&feature=related
Telomerase
• DNA polymerase can’t replicate the
ends of chromosomes
– Ends of chromosomes called
telomeres
• Telomeres
– 15 to 20 kilobase pairs long
– Cut off with each cell division
• If pRB and p53 are nonfunctional, cells
bypass non-growth function to become
cancerous
• Cancer cells can reactivate Telomerase
Oncogene
• A gene that has the potential to cause
cancer
• Activated oncogenes can cause cells
that ought to die to survive and
proliferate instead
Proto-oncogenes
• A normal gene that can become an
oncogene due to mutations or increased
expression
• Proto-oncogenes code for proteins
that help to regulate cell growth and
differentiation.
• Proto-oncogenes are often involved
in signal transduction
Types of Proto-Oncogenes
• Examples of proto-oncogenes
– RAS and MYC
http://www.youtube.com/watch
v=0nA2xhNiAow&feature=related
RAS ONCOGENE
• Ras uses a bound guanine nucleotide to toggle
between its “on” and “off” states.
• Normally, Ras binds GDP in its neutral state.
• A message is passed from the receptor to Ras
by guanine nucleotide exchange factors
(GEFs) that expel this GDP, allowing GTP,
which is more plentiful in the cytoplasm, to
bind in its place.
Genetic Events Leading to Oncogene
Formation
• Ras proto-oncogene family
– Signal relaying proteins that transmit
growth signals to the nucleus
• Mutations in ras genes can permanently activate
it and cause inappropriate transmission inside
the cell, even in the absence of extracellular
signals
– These signals result in cell growth and division,
dysregulated ras signaling can ultimately lead to
oncogenesis and cancer
Genetic Events Leading to Oncogene
Formation
• Myc proto-oncogene
• Encodes for growth signal proteins
• Myc (c-Myc) codes for a transcription factor
that is located on chromosome 8 in humans
is believed to regulate expression of 15% of
all genes
– A mutated version of Myc is found in many
cancers
– Myc is persistently expressed. This leads to
the unregulated expression of many genes
some of which are involved in cell
proliferation and results in the formation of
cancer
Tissue evidence of
carcinogenic factors at work
• 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.
Definitions
• Tumor or "mass lesion”
– a "growth" or "enlargement" which may not be
neoplastic (such as a granuloma).
• Cancer
– implies malignancy
– neoplasms can be subclassified as either benign or
malignant.
Characteristics of Malignant
Neoplasms
• Two categories
– Solid tumors
– Hematologic cancers
Solid Tumor
• Cells detach from the original tumor
mass
– Invade surrounding tissue
– Enter blood and lymph system
• Metastasize
Hematologic Cancers
• Cells normally found within the blood
and lymph
– Automatically metastasizes
• Benign characteristics include:
– Slow growth
– Resemblance to tissue of origin (well
differentiated)
– Lack of invasion
– Absence of metastases
– Benign neoplasms usually arise in a solitary
manner (e.g., lipoma of colon, meningioma
of brain), but may be multiple (e.g.,
leiomyomata of uterus).
– Though benign, they may cause problems
through mass effect, particularly in tight
quarters (pituitary adenoma in the sella
turcica).
Differentiation of Tumor Cells
• The degree of differentiation of a
neoplasm = the degree to which it
resemble normal tissue
– 100% differentiated tissue is normal or
not neoplastic
• Neoplasms are called well differentiated
– Having some microscopic appearance
of normal
• Poorly differentiated
– Little appearance or function of
normal cells