Ch05.pdf

CHAPTER

Alterations in Cell Growth

and Replication: Neoplasia

Concepts of Cell Growth

The Cell Cycle

Cell Proliferation

Cell Differentiation

Characteristics of Benign and Malignant Neoplasms

Terminology

Benign Neoplasms

Malignant Neoplasms

Cancer Cell Characteristics

Invasion and Metastasis

Tumor Growth

Carcinogenesis and Causes of Cancer

Oncogenesis: The Molecular Basis of Cancer

Tumor Cell Transformation

Heredity

Carcinogenic Agents

Chemical Carcinogens

Radiation Carcinogenesis

Oncogenic Viruses

Immunologic Defects

Clinical Features

Diagnosis and Staging

The Pap Smear

Biopsy

Tumor Markers

Staging and Grading of Tumors

Cancer Treatment

Surgery

Radiation Therapy

Systemic Cancer Therapy

Childhood Cancers

Diagnosis and Treatment

Adult Survivors of Childhood Cancer

States after cardiovascular disease. The disease affects all

age groups, causing more death in children 3 to 15 years

of age than any other disease. The American Cancer Society es-

timates that 1.3 million Americans will develop cancer in 2003,

and that one in two males and one in three females will have

cancer during their lifetime. It also is estimated that approxi-

mately 556,500 Americans will die in the year from neoplastic

diseases. 1 As age-adjusted cancer mortality rates increase and

heart disease mortality decreases, it is predicted that cancer will

become the leading cause of death in a few decades. 2 Trends in

cancer survival demonstrate that relative 5-year survival rates

have improved since the early 1960s. It is estimated that ap-

proximately 59% of people who develop cancer each year will

be alive 5 years later.

CONCEPTS OF CELL GROWTH

Cancers result from a process of altered cell differentiation and

growth. The resulting tissue is called neoplasia. The term neo-

plasm comes from a Greek word meaning new formation. Unlike

the tissue growth that occurs with hypertrophy and hyperpla-

sia, the growth of a neoplasm is uncoordinated and relatively

autonomous in that it lacks normal regulatory controls over

cell growth and division. Neoplasms tend to increase in size

and continue to grow after the stimulus has ceased or the needs

of the organism have been met.

Cancer is not a single disease. The term describes almost all

forms of malignant neoplasia. Cancer can originate in almost

any organ, with the prostate being the most common site in

men and the breast in women. The ability of cancer to be cured

varies considerably and depends on the type of cancer and

the extent of the disease at diagnosis. Cancers such as acute

lymphocytic leukemia, Hodgkin’s disease, testicular cancer,

and osteosarcoma, which only a few decades ago had poor

prognoses, are today cured in many cases. However, lung

cancer, which is the leading cause of death in men and women

in the United States, is resistant to therapy, and although some

progress has been made in its treatment, mortality rates remain

high.

Tissue renewal and repair involves cell proliferation and dif-

ferentiation. Proliferation, or the process of cell division, is an

C ancer is the second leading cause of death in the United

Chapter 5: Alterations in Cell Growth and Replication: Neoplasia

inherent adaptive mechanism for replacing body cells when

old cells die or additional cells are needed. Differentiation is the

process of specialization whereby new cells acquire the struc-

ture and function of the cells they replace. In adult tissues, the

size of a population of cells is determined by the rates of cell

proliferation, differentiation, and death by apoptosis. 3 Apop-

tosis, which is discussed in Chapter 2, is a form of programmed

cell death designed to eliminate senescent cells or unwanted

cells. A balance of cellular signals that regulate cell prolifera-

tion, differentiation, and apoptosis regulates the size of cell

populations.

tinually dividing cells, such as the crypt cells in the intestinal

mucosa, pass through restriction point (R) in G 1 that commits

them to progression to the synthesis (S) phase and a new round

of cell division. During the S phase, DNA synthesis occurs, giv-

ing rise to two separate sets of chromosomes, one for each

daughter cell. G 2 ( gap 2 ) is the premitotic gap and is similar to

G 1 in that DNA synthesis ceases while RNA and protein syn-

thesis continues. The M phase is the phase of cellular division

or mitosis. Stable cells, such as hepatocytes, enter a quiescent

period in the cell cycle, the G 0 gap. These quiescent cells re-

enter the cell cycle in response to extracellular nutrients, growth

factors, hormones, and other signals, such as blood loss or

tissue injury, that signal for cell renewal. 4,5

The duration of the phases of the cell cycle vary depending

on the cell type, the frequency with which the cells divide,

and host characteristics, such as the presence of appropriate

growth factors. Very rapidly dividing cells can complete the

cell cycle in less than 8 hours, whereas others can take longer

than 1 year. Most of this variability occurs in the G 0 and G 1

phases. The duration of the S phase (10 to 20 hours), the

G 2 phase (2 to 10 hours), and the M phase (0.5 to 1 hour)

appears to be relatively constant. 5

The Cell Cycle

The cell cycle is the interval between each cell division. It regu-

lates the duplication of genetic information and appropriately

aligns the duplicated chromosomes to be received by the

daughter cells. In addition, pauses or checkpoints in the cell

cycle determine the accuracy with which deoxyribonucleic acid

(DNA) is duplicated. These checkpoints allow for any defects

to be edited and repaired, thereby assuring that the daughter

cells receive the full complement of genetic information, iden-

tical to that of the parent cell. 3

The cell cycle is divided into four distinct phases referred to

as G 1 , S, G 2 , and M (Fig. 5-1). G 1 ( gap 1 ), is the postmitotic

phase during which DNA synthesis ceases while ribonucleic

acid (RNA) and protein synthesis and cell growth take place.

This is the phase during which cells pursue their own special-

ized type of function. Some cells such as neurons become ter-

minally differentiated after mitosis and remain in G 1 . Con-

Cell Proliferation

Cell proliferation is the process by which cells divide and re-

produce. Cell division provides the body with the means for

replacing cells that have a limited life span such as skin and

blood cells, increasing tissue mass during periods of growth,

and providing for tissue repair and wound healing. In normal

Labile cell

■ FIGURE 5-1 ■ The cell cycle. ( A ) Labile

cells ( e.g., intestinal crypt cells) undergo con-

tinuous replication and the interval between

two consecutive mitoses is designated the

cell cycle. After division, the cells enter a gap

(G 1 ) during which DNA synthesis ceases and

RNA and protein synthesis takes place as

the cell develops its own specialized type of

function. Cells that continue in the cell cycle

pass the restriction point (R), which commits

them to a new round of cell division and con-

tinuation to the synthesis (S) phase during

which all the chromosomes are replicated.

The S phase is followed by the short gap (G 2 )

during which DNA synthesis ceases and pro-

tein synthesis continues. The M phase is

the period of mitosis. After each cycle, one

daughter cell will become committed to dif-

ferentiation and the other will continue

cycling. ( B ) Some cell types, such as hepato-

cytes, are stable. After cell mitosis, the cells

take up their specialized functions (G 0 ) and

not reenter the cell cycle unless stimulated by

the loss of other cells. ( C ) Permanent cells

(neurons) become terminally differentiated

after mitosis and cannot reenter the cell

cycle. (Rubin E., Farber J.L. [1999]. Pathology

[3rd ed., p. 85]. Philadelphia: Lippincott

Williams & Wilkins)

G 2

Permanent cell

(e.g., neuron)

Mitosis

CELL CYCLE

G 1

G 0

Interphase

Stable cell

(e.g., hepatocyte)

G 1 -Diploid labile cells

(e.g., stem cells of intestinal crypts)

Unit One: Mechanisms of Disease

tissue, cell proliferation is regulated so that the number of

cells actively dividing is equivalent to the number dying or

being shed.

In terms of cell proliferation, the 200 or more cell types

of the body can be divided into 3 large groups: the well-

differentiated neurons and cells of skeletal and cardiac muscle

that are unable to divide and reproduce; the parent, or progen-

itor cells, that continue to divide and reproduce, such as blood

cells, skin cells, and liver cells; and the undifferentiated stem

cells that can be triggered to enter the cell cycle and produce

large numbers of progenitor cells when the need arises. The

rates of reproduction of these cells vary greatly. White blood

cells and cells that line the gastrointestinal tract live several days

and must be replaced constantly. In most tissues, the rate of cell

reproduction is greatly increased when tissue is injured or lost.

For example, bleeding stimulates the rapid reproduction of the

blood-forming cells of the bone marrow. In some types of tis-

sue, the genetic program for cell replication normally is re-

pressed but can be resumed under certain conditions. For ex-

ample, the liver has extensive regenerative capabilities under

certain conditions.

volves the expression of specific genes and external stimuli

provided by neighboring cells, exposure to substances in the

maternal circulation, and a variety of growth factors, nutrients,

oxygen, and ions. 6 What makes the cells of one organ different

from those of another organ is the type of gene that is ex-

pressed. Although all cells have the same complement of genes,

only a small number of these genes are expressed in postnatal

life. When cells, such as those of the developing embryo, dif-

ferentiate and give rise to committed cells of a particular tissue

type, the appropriate genes are maintained in an active state

while the remainder are inactive. Normally, the rate of cell re-

production and the process of cell differentiation are precisely

controlled in prenatal and postnatal life so that both of these

mechanisms cease once the appropriate numbers and types of

cells are formed.

The process of differentiation occurs in orderly steps; with

each progressive step, increased specialization is exchanged for

a loss of ability to develop different cell characteristics and dif-

ferent cell lines. The more highly specialized a cell becomes, the

more likely it is to lose its ability to undergo mitosis. Neurons,

which are the most highly specialized cells in the body, lose

their ability to divide and reproduce once development of

the nervous system is complete. More important, there are no

reserve or parent cells to direct their replacement. However, ap-

propriate numbers of these cell types are generated in the em-

bryo such that loss of a certain percentage of cells does not

affect the total cell population. Although these cells never

divide and are not replaced if lost, they exist in sufﬁcient num-

bers to carry out their speciﬁc functions. In other, less special-

ized tissues, such as the skin and mucosal lining, cell renewal

continues throughout life.

Even in the continuously renewing cell populations, highly

specialized cells are similarly unable to divide. An alternative

mechanism provides for their replacement. There are progeni-

tor cells of the same lineage that have not yet differentiated to

the extent that they have lost their ability to divide. These cells

are sufﬁciently differentiated that their daughter cells are lim-

ited to the same cell line, but they are insufﬁciently differenti-

ated to preclude the potential for active proliferation. As a

result, these parent or progenitor cells are able to provide large

numbers of replacement cells. However, the progenitor cells

have limited capacity for self-renewal and they become re-

stricted to producing a single type of cell.

Another type of cell, called a stem cell, remains incompletely

differentiated throughout life. Stem cells are reserve cells that

remain quiescent until there is a need for cell replenishment,

in which case they divide, thereby producing other stem cells

and cells that can carry out the functions of the differentiated

cell (Fig. 5-2). There are several types of stem cells, some of

which include the muscle satellite cell, the epidermal stem cell,

the spermatogonium, and the basal cell of the olfactory ep-

ithelium. These stem cells are unipotent in that they give rise

to only one type of differentiated cell. Oligopotent stem cells

can produce a small number of cells, and pluripotent stem

cells, such as those involved in hematopoiesis, give rise to nu-

merous cell types. 4 Stem cells are the primary cellular compo-

nent of bone marrow transplantation, in which the stem

cells in the transplanted marrow re-establish the recipient’s

blood production and immune system. Peripheral blood stem

cell transplantation is a transplantation procedure that by-

Cell Differentiation

Cell differentiation is the process whereby proliferating cells

are transformed into different and more specialized cell types.

This process leads to a fully differentiated, adult cell that has

achieved its specific set of structural, functional, and life

expectancy characteristics. For example, a red blood cell is

programmed to develop into a concave disk that functions

as a vehicle for oxygen transport and lives approximately

120 days.

All of the different cell types of the body originate from a

single cell—the fertilized ovum. As the embryonic cells in-

crease in number, they engage in an orderly process of differ-

entiation that is necessary for the development of all the

various organs of the body. The process of differentiation is

regulated by a combination of internal programming that in-

KEY CONCEPTS

CELL PROLIFERATION AND GROWTH

■

Tissue growth and repair involve cell proliferation

and differentiation.

■

Cell proliferation is the process whereby tissues ac-

quire new or replacement cells through cell division.

■

Cell differentiation is the orderly process in which

proliferating cells are transformed into different and

more specialized types. It determines the micro-

scopic characteristics of the cell, how the cell

functions, and how long it will live.

■

Cells that are fully differentiated are no longer capa-

ble of cell division.

Chapter 5: Alterations in Cell Growth and Replication: Neoplasia

Stem cell

CHARACTERISTICS OF BENIGN

AND MALIGNANT NEOPLASMS

Stem cell

Progenitor cell

Neoplasms are composed of two types of tissue: parenchymal

tissue and the stroma or supporting tissue. The parenchymal

cells represent the functional components of an organ. The sup-

porting tissue consists of the connective tissue, blood vessels,

and lymph structure. The parenchymal cells of a tumor deter-

mine its behavior and are the component for which a tumor is

named. The supporting tissue carries the blood vessels and

provides support for tumor survival and growth.

Daughter cells

Differentiated cells

■ FIGURE 5-2 ■ Mechanism of stem cell–mediated cell replace-

ment. Division of a stem cell with an unlimited potential for prolif-

eration results in one daughter cell, which retains the characteris-

tics of a stem cell, and a second daughter cell, which differentiates

into a progenitor or parent cell, with a limited potential for differ-

entiation and proliferation. As the daughter cells of the progeni-

tor cell proliferate, they become more differentiated, until reach-

ing the stage where they are fully differentiated and no longer able

to divide.

Terminology

By deﬁnition, a tumor is a swelling that can be caused by a num-

ber of conditions, including inflammation and trauma.

Although they are not synonymous, the terms tumor and neo-

plasm often are used interchangeably. Neoplasms usually are

classiﬁed as benign or malignant. Neoplasms that contain well-

differentiated cells that are clustered together in a single mass

are considered to be benign. These tumors usually do not cause

death unless their location or size interferes with vital func-

tions. In contrast, malignant neoplasms are less well differen-

tiated and have the ability to break loose, enter the circulatory

or lymphatic systems, and form secondary malignant tumors

at other sites. Malignant neoplasms usually cause suffering and

death if untreated or uncontrolled.

Tumors usually are named by adding the sufﬁx -oma to the

parenchymal tissue type from which the growth originated.

Thus, a benign tumor of glandular epithelial tissue is called an

adenoma, and a benign tumor of bone tissue is called an

osteoma. The term carcinoma is used to designate a malignant

tumor of epithelial tissue origin. In the case of a malignant

adenoma, the term adenocarcinoma is used. Malignant tumors

of mesenchymal origin are called sarcomas ( e.g., osteosarcoma).

Papillomas are benign microscopic or macroscopic ﬁngerlike

projections that grow on any surface. A polyp is a growth that

projects from a mucosal surface, such as the intestine. Although

the term usually implies a benign neoplasm, some malignant

tumors also appear as polyps. 3 Oncology is the study of tumors

and their treatment. Table 5-1 lists the names of selected

benign and malignant tumors according to tissue types.

Benign and malignant neoplasms usually are differentiated

by their (1) cell characteristics, (2) manner of growth, (3) rate

of growth, (4) potential for metastasizing or spreading to other

parts of the body, (5) ability to produce generalized effects,

(6) tendency to cause tissue destruction, and (7) capacity

to cause death. The characteristics of benign and malignant

neoplasms are summarized in Table 5-2.

passes the need for bone marrow infusion by infusing stem

cells that have been separated and removed from the donor

blood.

In summary, the term neoplasm refers to an abnormal

mass of tissue in which the growth exceeds and is uncoordi-

nated with that of the normal tissues. Unlike normal cellular

adaptive processes such as hypertrophy and hyperplasia,

neoplasms do not obey the laws of normal cell growth. They

serve no useful purpose, they do not occur in response to an

appropriate stimulus, and they continue to grow at the

expense of the host.

Cell proliferation is the process whereby cells divide and

bear offspring; it normally is regulated so that the number of

cells that are actively dividing is equal to the number dying or

being shed. The process of cell growth and division is called

the cell cycle. It is divided into four phases: G 1 , the postmitotic

phase, during which DNA synthesis ceases while RNA and

protein synthesis and cell growth take place; S, the phase dur-

ing which DNA synthesis occurs, giving rise to two separate

sets of chromosomes; G 2 , the premitotic phase, during which

RNA and protein synthesis continues; and M, the phase of cell

mitosis or cell division. The G 0 phase is a resting or quiescent

phase in which nondividing cells reside.

Cell differentiation is the process whereby cells are trans-

formed into different and more specialized cell types as they

proliferate. It determines the structure, function, and life span

of a cell. There are three types of cells: well-differentiated cells

that are no longer able to divide, progenitor or parent cells

that continue to divide and bear offspring, and undifferenti-

ated stem cells that can be recruited to become progenitor

cells when the need arises. As a cell line becomes more differ-

entiated, it becomes more highly specialized in its function

and less able to divide.

Benign Neoplasms

Benign tumors are characterized by a slow, progressive rate of

growth that may come to a standstill or regress, an expansive

manner of growth, the presence of a well-deﬁned ﬁbrous cap-

sule, and failure to metastasize to distant sites. Benign tumors

are composed of well-differentiated cells that resemble the cells

of the tissue of origin. For example, the cells of a uterine

Unit One: Mechanisms of Disease

Names of Selected Benign and Malignant Tumors

According to Tissue Types

Tissue Type

Benign Tumors

Malignant Tumors

Epithelial

Surface

Glandular

Connective

Fibrous

Adipose

Cartilage

Bone

Blood vessels

Lymph vessels

Lymph tissue

Muscle

Smooth

Striated

Neural Tissue

Nerve cell

Glial tissue

Nerve sheaths

Meninges

Hematologic

Granulocytic

Erythrocytic

Plasma cells

Lymphocytic

Monocytic

Endothelial Tissue

Blood vessels

Lymph vessels

Papilloma

Adenoma

Squamous cell carcinoma

Adenocarcinoma

Fibroma

Lipoma

Chondroma

Osteoma

Hemangioma

Lymphangioma

Fibrosarcoma

Liposarcoma

Chondrosarcoma

Osteosarcoma

Hemangiosarcoma

Lymphangiosarcoma

Lymphosarcoma

Leiomyoma

Rhabdomyoma

Leiomyosarcoma

Rhabdomyosarcoma

Neuroma

Glioma (benign)

Neurilemmoma

Meningioma

Neuroblastoma

Glioblastoma, astrocytoma, medulloblastoma, oligodendroglioma

Neurilemmal sarcoma

Meningeal sarcoma

Myelocytic leukemia

Erythrocytic leukemia

Multiple myeloma

Lymphocytic leukemia or lymphoma

Monocytic leukemia

Hemangioma

Lymphangioma

Hemangiosarcoma

Lymphangiosarcoma

TABLE 5-2

Characteristics of Benign and Malignant Neoplasms

Characteristics

Benign

Malignant

Cell characteristics

Well-differentiated cells that resemble normal cells

of the tissue from which the tumor originated

Tumor grows by expansion and does not inﬁltrate

the surrounding tissues; usually encapsulated

Rate of growth usually is slow

Cells are undifferentiated and often bear little resemblance

to the normal cells of the tissue from which they arose

Grows at the periphery and sends out processes that inﬁl-

trate and destroy the surrounding tissues

Rate of growth is variable and depends on level of differ-

entiation; the more anaplastic the tumor, the more

rapid the rate of growth

Gains access to the blood and lymph channels and metas-

tasizes to other areas of the body

Often causes generalized effects such as anemia, weak-

ness, and weight loss

Mode of growth

Rate of growth

Metastasis

Does not spread by metastasis

General effects

Usually is a localized phenomenon that does not

cause generalized effects unless its location

interferes with vital functions

Usually does not cause tissue damage unless its

location interferes with blood ﬂow

Tissue destruction

Often causes extensive tissue damage as the tumor out-

grows its blood supply or encroaches on blood ﬂow to

the area; also may produce substances that cause cell

damage

Usually causes death unless growth can be controlled

Ability to cause death

Usually does not cause death unless its location

interferes with vital functions

TABLE 5-1

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