PAJ 5101 Clinical Pathophysiology

Abnormal Cell Growth and Differentiation

(act or process of becoming a mature cell)

Lecture prepared and presented by:

Hugh G Rappa, MD
Professor
Academic Director
Associate Dept. Chair

Learning Objectives
At the conclusion of the lecture, in conjunction with
required readings, lecture notes and any
recommended internet web pages, the student
should be able to:
1. Compare and contrast the various etiologies and
risk factors for coronary heart disease
2. Compare and contrast nonneoplastic
abnormalities of cell growth
3. Compare and contrast neoplastic abnormalities
of cell growth
4. Compare and contrast the routes of tumor
spread
5. Compare and contrast the different types of
benign tumors according to origin
6. Compare and contrast the different types of
malignant tumors according to origin
7. Compare and contrast the categories of gene
alterations in carcinogenesis
8. Describe the steps of chemical carcinogenesis2

Learning Objectives
9. Describe microorganisms role in
carcinogenesis
10. Compare and contrast the theories of
heredity and carcinogenesis
11. Define cancer staging
12. Describe the TNM staging system

Nonneoplastic Abnormalities in Cell Growth

Agenesis/aplasia (without creation / growth)
a. Failure of an organ to develop at all

Hypoplasia
a. partial development of an organ
b. results in functional deficiency

Atrophy
a. shrinkage of a tissue or organ that has formed or matured
normally (not loss of cell, cells become smaller)

Hypertrophy (more nourishment)

a. enlargement of a tissue or organ due to enlargement

of individual cells
tissue consists of permanent, non-dividing cells
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Nonneoplastic Abnormalities in Cell Growth

Metaplasia
a. change of 1 cell type to another cell type in response to
a chronically irritating or injurious stimulus; involves change in
differentiation
Dysplasia (cervical dysplasia looking for different cells)
a. disordered growth (difficult) typically occurring in
epithelial cells which results in variation of cellular size and
shape,
b. There is a loss of architectural orientation;
c. cell nuclei may be darker and larger than normal;
d. may progress to cancer: precancerous

Neoplastic Cell Growth and Differentiation

Neoplasm (no insight if benign or malignant)

a. abnormal mass of tissue growing autonomously
thus is self-perpetuating without physiologic
growth stimuli
b. The entire cell population which is proliferating is
derived from 1 cell that underwent genetic
alteration
c. Components of a neoplasm
1. parenchyma: proliferating neoplastic cells
2. stroma: connective tissue and blood vessels
d. Interchangeable with the term tumor
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Neoplastic Cell Growth and Differentiation

Cancer (no contact inhibition, keeps growing

even after it touches surrounding cells)
a. malignant neoplasm (goes into surrounding tissue)
b. features of malignancy ( e.g. invasive growth)
c. derived from Latin term for crab because it adheres to any
tissue that it seizes upon ; it reaches out with claws like
a crab, and invades surrounding tissue

Metastasis
a. portion of a cancer that has migrated from the primary site
to other sites
(EX. Colon cancer liver: from portal system)
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Neoplastic Differentiation
The degree that neoplasm is similar to comparable
normal cells in appearance and function (the more it is
further from the parent cell the more aggressive it is: cancer)

a. Well differentiated (I) - close resemblance (to parent cell)

b.Moderately differentiated (II) - intermediate
resemblance (to parent cell)
c. Poorly differentiated (III) - poor resemblance (to parent
cell)

d. Anaplasia (IV) lack of differentiation. (doesnt

function or look like parent cell)
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Benign vs. Malignant Tumors

Benign Tumors
1. Well circumscribed border
2. Compresses surrounding
tissue
3. Often has a fibrous capsule
4. Usually well differentiated
5. Does not metastasize
(migrate)
6. Slow growing

Malignant tumor
1. Ragged border, not easily
discernable
2. Infiltrates and invades
surrounding tissue
3. Various degrees of
differentiation
4. May metastasize (migrate)
5. Grow rapidly

Routes of Tumor Metastasis

Spread through Blood Vessels (HEMATOgenous spread )
a. spread is typically through VEINS ( especially the portal vein and
inferior vena cava so cancers often spread to liver or lungs respectively)
b. mechanism:
1. tumor cells SEPARATE from each other and
degrade intercellular tissue with enzymes
2. cells invade vessel and multiple tumor fragments travel to other
organs
3. an organ may have multiple metastatic tumor nodules

Spread through Lymphatic System

a. mechanism: cancer spreads into lymphatic vessels located at the tumor
margin and follows the natural route of lymphatic drainage

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Routes of Tumor Metastasis

Seeding Body Cavities and Surfaces
a. Pericardial, pleural, peritoneal cavities: defined by
membrane covering organs in cavity ( heart; lungs;
abdominal organs respectively ) and membrane covering
body cavity wall; joint cavities
b. subarachnoid space
c. mechanism
1. invasion of tumor through organ surface into cavity
2. most commonly occurs in peritoneal cavity

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Classification of Benign Tumors

Mesenchymal tumors
a. tumors derived from supportive tissue
b. e.g.: connective tissue; adipose tissue; cartilage; smooth
and striated muscle; bone

Epithelial tumors:
a. Adenoma- benign epithelial tumor
b. forming a glandular pattern histologically or derived
from a gland
c. sometimes secrete hormone (s) produced by gland of
origin

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Classification of Benign Tumors

papilloma: tumor producing microscopically

or macroscopically visible finger-like or warty
projections from an epithelial surface

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Classification of Malignant Tumors

Mesenchymal origin
a. originate from supportive tissue
b. called sarcomas

epithelial origin: (how they name it)

a. called carcinomas (carcinomata plural?)
1.carcinoma with glandular growth pattern:
adenocarcinoma
2. carcinoma with squamous cell differentiation:
squamous cell carcinoma
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Normal

Tumor

Abnormal regulation of cell growth

Abnormal cell-cell interactions
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Normal
Normal stem cell

Tumor
Cancer stem cell

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Characteristics of Stem

Cells

Unlimited capacity for self-renewal

Cellular immortality
But relatively low rate of proliferation

Capable of differentiation into the mature

cells that constitute organ function
Proliferation can be dramatic once a cell has committed to
differentiation
But differentiated cells have limited life-span
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Normal

Cancer

Stem cell
Compartment
Proliferative
Compartment
Etc.

Maturation
Compartment

Cell loss (apoptosis)

Etc., Etc., Etc.

Maturation
Compartment

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Lessons From Stem Cell Kinetics

Abnormal differentiation of cancer cells results in a
greater percentage of cells in the proliferative pool
(at the expense of the maturation pool)
Tumor (mass) growth exceeds normal growth due to
a higher proliferative fraction and a lower rate of cell
loss (death)

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Benign

Malignant
pleomorphism
abnormal nuclei
mitoses
abnormal differentiation
(far from parent cell)

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Abnormal cell-substratum interaction

(can go through surrounding tissues
In either direction)
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Invasion into adjacent structures

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Penetration of vasculature
Survival in circulation
Survival in a new organ

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metastatic spread is not random but determined by:

-pattern of venous blood flow
-specific receptors on tumor and endothelial cells
-metastatic fitness is genetically determined
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MECHANISMS OF CARCINOGENESIS
1. Multistep process resulting in the formation of cancer
secondary to the damage to multiple normal regulatory
genes

2. damaged genes:
a. may be inherited and/or
b. develop from the effects of
1. chemical carcinogens,
2. ultraviolet and ionizing radiation,
3. microbial organisms ( viruses and a bacterium )

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Categories of Gene Alterations in

Carcinogenesis
1. protooncogenes:
a. promote regulated cell growthb. are growth factors, growth factor receptors, nuclear
regulatory proteins, and proteins involved with signal
transduction
c. mutations convert these genes to oncogenes which
encode
d. oncoproteins: oncoproteins promote continued growth
in an uncontrolled manner

2. tumor suppressor genes:

a. inhibit cell growth
b. important examples: NF-1; NF-2; RB; APC2.

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Categories of Gene Alterations in

Carcinogenesis
3. genes promoting repair of damaged DNA
a. important examples: BRCA-1 and BRCA-2
4. genes promoting self destruction of cells with
damaged DNA ( apoptosis ):
a. necessary to prevent damage from becoming
continued in dividing cells and permanent

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Chemical Carcinogenesis
Initiation (caused by initiators):
a. chemicals cause permanent damage to DNA
b. Examples:
1. polycyclic aromatic hydrocarbons ( produced by
combustion of tobacco ) bladder and lung
cancer (some of most powerful carcinogens
known )

Promotion (caused by promoters):

a. cause sustained or enhanced proliferation of cells
damaged by initiating agents resulting in increased risk of
successive mutations leading to cancer
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Microbes and Cancer

VIRUSES

1. human papilloma virus ( HPV): cervical cancer

a. many genetic subtypes; types 16 and 18 most
commonly cause cervical cancer
b. HPV incorporates its viral DNA into the host
cell genome in a location resulting in
excessive production of the viral proteins,
E6 and E7:
c. E6 blocks p53 ( is needed to promote self
destruction of mutated cells ) and
d. E7 blocks RB ( is needed to inhibit cell growth
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,
tumor suppressor gene)

Microbes and Cancer

Epstein Barr virus: (family of Herpes)
a. certain B cell lymphomas and nasopharyngeal
carcinoma
b. infects B lymphocytes and immortalizes them
c. also infects epithelial cells of oropharynx
d. patients with normal immune function do not
have immortalization of their B lymphocytes
resulting in cancer, but are instead
asymptomatic, or have self limited infectious
mononucleosis
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Microbes and Cancer

Hepatitis B virus (HBV):

a. hepatocellular carcinoma
b. by infecting the liver chronically and
causing chronic liver cell injury, it stimulates
continuous regenerative attempts and
proliferation of liver cells; these cells are at
RISK for genetic mutations

c. encodes a protein which binds to p53

and interferes with its function
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Radiation and Cancer

Ultraviolet radiation
a. UVB
Ionizing radiation
Can cause abnormal DNA
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Heredity and Cancer

1. alterations of tumor suppressor proteins
a. normally suppress cell growth
b. Rb protein: associated with development of
retinoblastoma ( a rare childhood tumor of eye) as well as
osteosarcoma ( bone cancer)
c. NF 1 and 2: neurofibromatosis which is associated with
a variety of tumors of both central and peripheral nervous
system ( NF-1 = neurofibromatosis type 1;
NF-2 = neurofibromatosis type 2 )
d. p16 ( INK4a ): malignant melanoma
e. APC: familial adenomatosis polyposis syndrome:
patients develop 500- 2500 premalignant colon tumors
(adenomatous polyps ) in their teens and twenties; they
develop colon cancer by age 50
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Heredity and Cancer

2. Inherited alterations of genes that allow repair of damaged
DNA
a. a minority of breast cancer patients have an inherited mutation of
the DNA repair genes BRCA- 1 and BRCA- 2

b. xeroderma pigmentosum: patients inherit defective

DNA repair genes and cannot repair mutations caused by
UVB radiation increased risk of developing skin cancer in
sun exposed skin areas
3. Inherited alterations of genes necessary for preventing
propagation of DNA mutations by causing mutated cells to
self destruct ( undergo apoptosis )

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Cancer Staging
1. Purposes

of cancer staging:

a. indicates extent of spread of a cancer within the

patient
b. determines prognosis
c.guides management

2.Staging is based on:

a. size of primary lesion
b. extent of spread to regional lymph nodes
c. presence or absence of blood-borne
metastases

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TMN Cancer Staging

T = Primary Lesion
a. Tis: lesion has not invaded through tissue basement membrane
( is refers to in situ )
b.

T1- T3 ( or higher ): increasing size of primary lesion; increasing

depth of invasion (through substratum)

N = Regional Lymph Nodes

a. Nx: regional lymph nodes cannot be assessed
b. N0: no regional lymph node metastasis
c. N1 N2 ( or higher ): involvement of increasing # and range of
lymph nodes

M = Metastasis
a. Mx: distant metastasis cannot be assessed
b. M0: (NO) distant metastasis
c. M1: (YES) distant metastasis

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