Answer one of the discussion questions from the attached document. You can use the provided document to answer the questions  and other sources.

PORTH’s Essentials of Pathophysiology, 4th ed., Tommie L. Norris

ISBN 13: 978-1-975107-19-2

General Anatomy & Physiology Textbook

Choose 1 of the following Discussion Topics and provide your answers using appropriate medical terminology. Please reference the scoring rubric to assure full credit. 

1. As a health care professional, you have been asked to speak about the potential use of stem cells in research and the treatment of disease.

• How would you describe stem cells to lay persons?
• What would you say to those who think that stem cells have no rightful place in health care research or practice?

2. You are a scientist working for a pharmaceutical company that has charged you with developing a new cancer drug that leads to a major drop in cancer mortality.

• Based on your understanding of the pathophysiology of carcinogenesis and tumor growth, where would you target your “miracle drug”?
• What would be the most likely drawbacks or undesired effects of your “miracle drug”?

Unit 7 neoplasia

Cancer is a major health problem in the United States

and many other parts of the world. It is estimated

that 1.66 million Americans were newly diagnosed with

cancer in 2013 and 580,350 died of the disease.1

Cancer

affects all age groups, and is the second leading cause

of death among children ages 1 to 14 years.1

As age-

adjusted cancer mortality rates increase and heart dis-

ease mortality decreases, it is predicted that cancer will

soon become the leading cause of death. The good news,

however, is that the survival rates have improved to the

extent that almost 64% of people who develop cancer

each year will be alive 5 years later.

Cancer is not a single disease. It can originate in

almost any organ, with skin cancers being the most com-

mon site in persons in the United States. Excluding skin

cancers, the prostate is the most common site in men and

the breast is the most common site in women (Fig. 7-1).

The ability of cancer to be cured varies considerably and

depends on the type of cancer and the extent of the disease

at the time of diagnosis. Cancers such as acute lympho-

blastic leukemia, Hodgkin disease, testicular cancer, and

osteosarcoma, which only a few decades ago had poor

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

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

women in the United States,1

remains resistant to therapy.

This chapter is divided into five sections: characteris-

tics of benign and malignant neoplasms, etiology of can-

cer, clinical manifestations, diagnosis and treatment, and

childhood cancers and late effects on cancer survivors.

Hematologic malignancies (lymphomas and leukemias)

are presented in Chapter 11.

Characteristics of Benign

and Malignant Neoplasms

Cancer is a disorder of altered cell differentiation and

growth. The resulting process is called neoplasia, and

the new growth is called a neoplasm. Unlike the pro-

cesses of hypertrophy and hyperplasia that are discussed

in Chapter 2, the cell changes that occur with neoplasia

tend to be relatively uncoordinated and autonomous,

lacking normal regulatory controls over cell growth and

division.

Normal renewal and repair involves two components:

cell proliferation and differentiation (see Chapter 4).

Proliferation, or the process of cell division, is an inherent

adaptive mechanism for cell replacement when old cells

die or additional cells are needed. Fundamental to the

origin of all neoplasms are the genetic changes that allow

excessive and uncontrolled proliferation that is unregu-

lated by normal growth-regulating stimuli to occur.

Differentiation is the process of specialization whereby

new cells acquire the structural, microscopic, and func-

tional characteristics of the cells they replace. Neoplasms

are commonly classified as benign or malignant. Benign

neoplasms are composed of well-differentiated cells that

resemble the normal counterpart both in terms of struc-

ture and function but have lost the ability to control cell

proliferation. Malignant neoplasms are less differentiated

and have lost the ability to control both cell differentia-

tion and proliferation. In general, the better the differen-

tiation of a neoplasm, the slower its rate of growth and

the more completely it retains the functional capabilities

found in its normal counterparts. For example, benign

neoplasms and even well-differentiated cancers of endo-

crine glands frequently elaborate the hormones charac-

teristic of their origin.

Apoptosis, which is discussed in Chapter 2, is a form

of programmed cell death that eliminates senescent

cells, deoxyribonucleic acid (DNA), and damaged or

unwanted cells. In adult tissues, the size of a population

of cells is determined by the rates of cell proliferation and

death by apoptosis. In malignant neoplasms, the accu-

mulation of neoplastic cells may result not only from

excessive and uncontrolled proliferation, but also from

evasion of apoptosis.

All tumors—benign and malignant—are composed

of two types of tissue: (1) parenchymal or specific func-

tional cells of an organ or tissue, and (2) connective

tissue that forms the supporting tissue framework or

stroma.2.3 The parenchymal tissue, which is made up of

the transformed or neoplastic cells of a tumor, deter-

mines its behavior and is the component for which the

tumor is named. The supporting nonneoplastic stromal

tissue component is made up of connective tissue, extra-

cellular matrix, and blood vessels. It is essential to the

growth of the tumor since it carries the blood supply

and provides support for the parenchymal tumor cells.

Terminology

Cancers are commonly referred to as tumors or neo-

plasms. Although defined in the medical literature as

a swelling that can be caused by a number of condi-

tions, including inflammation and trauma, the term

tumor is increasingly being used to describe a neoplasm.

Oncology, from the Greek term onkos, for a “swelling,”

refers to the study or science of neoplasms. Clinical

oncology deals with neoplastic disorders in the clinical

setting, primarily in terms of diagnosis and treatment.

Benign tumors usually are named by adding the suf-

fix -oma to the parenchymal tissue type from which the

growth originated.2

Thus, a benign epithelial neoplasm of

glandular tissue is called an adenoma, and a benign tumor

arising in fibrous tissue is called a fibroma. The term car-

cinoma is used to designate a malignant tumor of epithe-

lial tissue origin. In the case of malignancies that originate

from glandlike structures, the term adenocarcinoma is

used, and for those that originate from squamous cells,

the term squamous cell carcinoma is used. Malignant

tumors of mesenchymal origin are called sarcomas. A

cancer of fibrous tissue is a fibrosarcoma and a malignant

tumor composed of chondrocytes is a chondrosarcoma.

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 pol-

yps. Adenomatous polyps are considered precursors to

adenocarcinomas of the colon. Table 7-1 lists the names

and tissue types of selected benign and malignant tumors.

Biology of Benign and

Malignant Tumors

The differences between benign and malignant tumors

are determined by (1) the characteristics of the tumor

cells, (2) the rate of growth, (3) local invasion, and (4)

the ability to metastasize. The characteristics of benign

and malignant neoplasms are summarized in Table 7-2.

Estimated New Cases

Estimated Deaths

Prostate (28%)

Lung and bronchus (14%)

Colon and rectum (9%)

Urinary bladder (6%)

Melanoma of the skin (5%)

Kidney and renal pelvis (5%)

Non-Hodgkin lymphoma (4%)

Leukemia (3%)

Oral cavity and pharynx (3%)

Pancreas (3%)

Breast (29%)

Lung and bronchus (14%)

Colon and rectum (9%)

Uterine corpus (6%)

Thyroid (6%)

Non-Hodgkin lymphoma (4%)

Melanoma of the skin (4%)

Ovary (3%)

Kidney and renal pelvis (3%)

Pancreas (3%)

Lung and bronchus (28%)

Prostate (10%)

Colon and rectum (9%)

Pancreas (6%)

Liver and

intrahepatic bile duct (5%)

Leukemia (4%)

Esophagus (4%)

Urinary bladder (4%)

Non-Hodgkin lymphoma (3%)

Kidney and renal pelvis (3%)

Lung and bronchus (26%)

Breast (14%)

Colon and rectum (9%)

Pancreas (7%)

Ovary (5%)

Leukemia (4%)

Non-Hodgkin lymphoma (3%)

Uterine corpus (3%)

Brain and other

nervous system (2%)

Liver and intrahepatic

bile duct (2%)

*Excludes basal and squamous cell skin cancers and in situ

carcinomas except urinary bladder.

Note: Estimates are rounded to the nearest 10.

FIGURE 7-1. Ten leading cancer types for the estimated new

cancer cases and deaths in the United States by sex and site,

2013. (Adapted from Siegel R, Naishadham D, Jemel A. Cancer

statistics, 2013. CA Cancer J Clin. 2013;63[1]:11–30.)

0002114681.INDD 130 7/7/2014 9:54:07 AM

Benign Neoplasms

Benign tumors are composed of well-differentiated cells

that resemble the cells of the tissues of origin and are

generally characterized by a slow, progressive rate of

growth that may come to a standstill or regress.2,3 For

unknown reasons, benign tumors have lost the ability to

suppress the genetic program for cell proliferation but

have retained the program for normal cell differentiation.

They grow by expansion and remain localized to their

site of origin and do not have the capacity to infiltrate,

invade, or metastasize to distant sites. Because they

expand slowly, they develop a surrounding rim of com-

pressed connective tissue called a fibrous capsule.

3

The

capsule is responsible for a sharp line of demarcation

between the benign tumor and the adjacent tissues, a

factor that facilitates surgical removal.

TABLE 7-2 Characteristics of Benign and Malignant Neoplasms

Characteristics Benign Malignant

Cell characteristics Well-differentiated cells that resemble cells

in the tissue of origin

Cells are undifferentiated, with anaplasia

and atypical structure that often bears little

resemblance to cells in the tissue of origin

Rate of growth Usually progressive and slow; may come

to a standstill or regress

Variable and depends on level of differentiation;

the more undifferentiated the cells, the more

rapid the rate of growth

Mode of growth Grows by expansion without invading the

surrounding tissues; usually encapsulated

Grows by invasion, sending out processes that

infiltrate the surrounding tissues

Metastasis Does not spread by metastasis Gains access to blood and lymph channels to

metastasize to other areas of the body

TABLE 7-1 Names of Selected Benign and Malignant Tumors

According to Tissue Types

Tissue Type Benign Tumors Malignant Tumors

Epithelial

Surface Papilloma Squamous cell carcinoma

Glandular Adenoma Adenocarcinoma

Connective

Fibrous Fibroma Fibrosarcoma

Adipose Lipoma Liposarcoma

Cartilage Chondroma Chondrosarcoma

Bone Osteoma Osteosarcoma

Blood vessels Hemangioma Hemangiosarcoma

Lymph vessels Lymphangioma Lymphangiosarcoma

Lymph tissue Lymphosarcoma

Muscle

Smooth Leiomyoma Leiomyosarcoma

Striated Rhabdomyoma Rhabdomyosarcoma

Neural Tissue

Nerve cell Neuroma Neuroblastoma

Glial tissue Glioma Glioblastoma, astrocytoma, medulloblastoma,

oligodendroglioma

Nerve sheaths Neurilemmoma Neurilemmal sarcoma

Meninges Meningioma Meningeal sarcoma

Hematologic

Granulocytic Myelocytic leukemia

Erythrocytic Erythrocytic leukemia

Plasma cells Multiple myeloma

Lymphocytic Lymphocytic leukemia or lymphoma

Monocytic Monocytic leukemia

Endothelial Tissue

Blood vessels Hemangioma Hemangiosarcoma

Lymph vessels Lymphangioma Lymphangiosarcoma

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132 UNIT 1 Cell and Tissue Function

Malignant Neoplasms

In contrast to benign tumors, malignant neoplasms tend

to grow rapidly, invade and infiltrate nearby tissue, and

spread to other parts of the body. They lack a well-defined

capsule and their margins are not clearly separated from

the normal surrounding tissue.2,3

Because of their rapid

rate of growth, malignant tumors may compress blood

vessels and outgrow their blood supply, causing ischemia

and tissue injury. Some malignancies secrete hormones

and/or cytokines, liberate enzymes and toxins, and/or

induce an inflammatory response that injures normal tis-

sue as well as the tumor itself.

There are two categories of malignant neoplasms—

solid tumors and hematologic cancers. Solid tumors

initially are confined to a specific tissue or organ. As

the growth of the primary solid tumor progresses, cells

detach from the original tumor mass, invade the sur-

rounding tissue, and enter the blood and lymph system

to spread to distant sites, a process termed metasta-

sis. Hematologic cancers involve cells normally found

within the blood and lymph, thereby making them dis-

seminated diseases from the beginning.

Cancer in situ is a localized preinvasive lesion. For

example, in ductal carcinoma in situ of the breast, the

malignant cells have not crossed the basement mem-

brane. Depending on its location, an in situ lesion usu-

ally can be removed surgically or treated so that the

chances of recurrence are small. For example, cancer in

situ of the cervix is essentially 100% curable.

Tumor Cell Characteristics

Whether a tumor is benign or malignant is determined by

an examination of its cells. Typically, such an examination

includes macroscopic (naked eye) inspection to determine

the presence or absence of a tumor capsule and inva-

sion of the surrounding tissue, supplemented by micro-

scopic examination of histologic sections of the tumor.

Additional information may be obtained from electron

microscopy, immunochemistry techniques, chromosomal

studies, and DNA analysis. The growth and behavior of

tumor cells may be studied using culture techniques.

Differentiation and Anaplasia. Differentiation refers

to the extent to which the parenchymal (specific organ

versus supportive tissue) cells of a tumor resemble their

normal forbearers morphologically and functionally.2,3

Malignant neoplasms that are composed of poorly dif-

ferentiated or undifferentiated cells are described as

being anaplastic, anaplasia literally means to “form

backward” to an earlier dedifferentiated state. On histo-

logic examination, benign tumors are composed of cells

that resemble the tissue from which they have arisen.

By contrast, the cells of malignant tumors are character-

ized by wide changes of parenchymal cell differentiation

from well differentiated to completely undifferentiated.

Undifferentiated cancer cells are marked by a number

of morphologic changes. Both the cells and nuclei dis-

play variations in size and shape, a condition referred to

as pleomorphism.

2,3 Their nuclei are variable in size and

bizarre in shape, their chromatin is coarse and clumped,

and their nucleoli are often considerably larger than

normal (Fig. 7-2A). Characteristically, the nuclei con-

tain an abundance of DNA and are extremely dark

staining. The cells of undifferentiated tumors usually

display a large number of mitoses, reflecting a higher

rate of proliferation. They also display atypical, bizarre

mitotic figures, sometimes producing tripolar, tetrapo-

lar, or multipolar spindles (Fig. 7-2B). Highly anaplas-

tic cancer cells, whatever their tissue of origin, begin to

resemble undifferentiated or embryonic cells more than

they do their tissue of origin.

Some cancers display only slight anaplasia and others

marked anaplasia. The cytologic/histologic grading of

tumors is based on the degree of differentiation and the

number of proliferating cells. The closer the tumor cells

resemble comparable normal tissue cells, both morpho-

logically (structurally) and functionally, the lower the grade. Accordingly, on a scale ranging from grade I to IV,

grade I neoplasms are well differentiated and grade IV

are poorly differentiated and display marked anaplasia.2

Genetic Instability and Chromosomal Abnormalities.

Most cancer cells exhibit a characteristic called genetic

instability that is often considered to be a hallmark of

cancer.3,4

The concept came about after the realization

that uncorrected mutations in normal cells are rare

due to many cellular mechanisms to prevent them. To

account for the high frequency of mutations in cancer

cells, it is thought that cancer cells have a genotype

that is highly divergent from the genotype of normally

transformed cells. Characteristics of genetic instability

are alterations in growth regulatory genes and genes

involved in cell cycle progression and arrest.

Genomic instability most commonly results in gross

chromosomal abnormalities. Benign tumors usually have

a normal number of chromosomes. By contrast, malig-

nant cells often display a feature called aneuploid, in

which they have an abnormal number of chromosomes.2–4

The chromosomes may be structurally abnormal due to

insertions, deletions, amplifications, or translocations

of parts of their arms (see Chapter 6). They may also

display microsatellite instability, which involves short

repetitive sequences of DNA, and point mutations.

Growth Properties. The characteristics of altered prolif-

eration and differentiation are associated with a number

of growth and behavioral changes that distinguish cancer

cells from their normal counterparts. These include growth

factor independence, lack of cell density–dependent

inhibition, impaired cohesiveness and adhesion, loss of

anchorage dependence, faulty cell-to-cell communication,

and an indefinite cell life span or immortality.

Cell growth in test tubes or culture dishes is referred

to as in vitro cell culture because the first containers used

for these cultures were made of glass (vitrium, mean-

ing “glass” in Latin). It is assumed that the in vivo (in

the body) growth of tumor cells mimics that of in vitro

studies. Most normal cells require a complex growth

medium and survive for only a limited time in vitro. In

the case of cancer cells, the addition of serum, which is

rich in growth factors, is unnecessary for the cancers to

proliferate. Some cancer cells produce their own growth

factors and secrete them into the culture medium, while

others have abnormal receptors or signaling proteins

that may inappropriately activate growth-signaling

pathways within the cells. Breast cancer cells that do not

express estrogen receptors are an example. These cancer

cells grow even in the absence of estrogen, which is the

normal growth stimulus for breast duct epithelial cells.

Normal cells that are grown in culture tend to dis-

play a feature called cell density–dependent inhibition, in

which they stop dividing after the cell population reaches

a particular density.5

This is sometimes referred to as con-

tact inhibition since cells often stop growing when they

come into contact with each other. In wound healing, for

example, contact inhibition causes fibrous tissue growth

to cease at the point where the edges of a wound come

together. Malignant cells show no such contact inhibition

and grow rampantly without regard for adjacent tissue.

There is also a reduced tendency of cancer cells to stick

together (i.e., loss of cohesiveness and adhesiveness)

owing, in part, to a loss of cell surface adhesion molecules.

This permits shedding of the tumor’s surface cells; these

cells appear in the surrounding body fluids or secretions

and often can be detected using cytologic examination.

Cancer cells also display a feature called anchorage

independence.

5,6

Studies in culture show that normal cells,

with the exception of hematopoietic cells, will not grow

and proliferate unless they are attached to a solid sur-

face such as the extracellular matrix. For some cell types,

including epithelial tissue cells, even survival depends

on such attachments. If normal epithelial cells become

detached, they often undergo a type of apoptosis known

as anoikis due to not having a “home.” In contrast to nor-

mal cells, cancer cells often survive in microenvironments

different from those of the normal cells. They frequently

remain viable and multiply without normal attachments

to other cells and the extracellular matrix. Another charac-

teristic of cancer cells is faulty cell-to-cell communication,

a feature that may contribute to the growth and survival

of cancer cells. Impaired cell-to-cell communication may

interfere with formation of intercellular connections and

responsiveness to membrane-derived signals. For exam-

ple, changes in gap junction proteins, which enable cyto-

plasmic continuity and communication between cells,

have been described in some types of cancer.7

Cancer cells also differ from normal cells by being

immortal; that is, they have an unlimited life span. If nor-

mal noncancerous cells are harvested from the body and

grown under culture conditions, most cells divide a lim-

ited number of times, usually about 50 population dou-

blings, then achieve senescence and fail to divide further.

In contrast, cancer cells may divide an infinite number

of times, and hence achieve immortality. Telomeres are

short, repetitive nucleotide sequences at the outermost

extremities of chromosome arms (see Chapter 2). Most

cancer cells maintain high levels of telomerase, an enzyme

that prevents telomere shortening, which keeps telomeres

from aging and attaining a critically short length that is

associated with cellular replicative senescence.

Functional Features. Because of their lack of differen-

tiation, cancer cells tend to function on a more primitive

level than normal cells, retaining only those functions

that are essential for their survival and proliferation.

They may also acquire some new features and become

quite different from normal cells. For example, many

transformed cancer cells revert to earlier stages of gene

expression and produce antigens that are immunologi-

cally distinct from the antigens that are expressed by cells

of the well-differentiated tissue from which the cancer

originated. Some cancers may elaborate fetal antigens

that are not produced by comparable cells in the adult.

Tumor antigens may be clinically useful as markers to

indicate the presence, recurrence, or progressive growth

of a cancer. Response to treatment can also be evaluated

based on an increase or decrease in tumor antigens.

Cancers may also engage in the abnormal production

of substances that affect body function. For example,

0002114681.INDD 133 7/7/2014 9:54:33 AM

134 UNIT 1 Cell and Tissue Function

cancer cells may produce procoagulant materials that

affect the clotting mechanisms, or tumors of nonendo-

crine origin may assume the ability to engage in hor-

mone synthesis. These conditions are often referred to

as paraneoplastic syndromes (to be discussed).

Tumor Growth

The rate of growth in normal and cancerous tissue

depends on three factors: (1) the number of cells that are

actively dividing or moving through the cell cycle, (2) the

duration of the cell cycle, and (3) the number of cells that

are being lost relative to the number of new cells being pro-

duced. One of the reasons cancerous tumors often seem to

grow so rapidly relates to the size of the cell pool that is

actively engaged in cycling. It has been shown that the cell

cycle time of cancerous tissue cells is not necessarily shorter

than that of normal cells. Rather, cancer cells do not die

on schedule and growth factors prevent cells from exiting

the cell cycle and entering the G0 or noncycling phase (see

Chapter 4, Understanding the Cell Cycle). Thus, a greater

percentage of cancer cells are actively engaged in cycling as

compared to cells in normal tissue.

The ratio of dividing cells to resting cells in a tissue

mass is called the growth fraction. The doubling time

is the length of time it takes for the total mass of cells

in a tumor to double. As the growth fraction increases,

the doubling time decreases. When normal tissues reach

their adult size, an equilibrium between cell birth and

cell death is reached. Cancer cells, however, continue to

divide until limitations in blood supply and nutrients

inhibit their growth. When this occurs, the doubling

time for cancer cells decreases. If tumor growth is plot-

ted against time on a semilogarithmic scale, the initial

growth rate is exponential and then tends to decrease

or flatten out over time. This characterization of tumor

growth is called the Gompertzian model.

5

By conventional radiographic methods, a tumor usu-

ally is undetectable until it has doubled 30 times and

contains more than 1 billion (109

) cells. At this point,

it is approximately 1 cm in size (Fig. 7-3). Methods

to identify tumors at smaller sizes are under investiga-

tion; in some cases the application of ultrasound and

magnetic resonance imaging (MRI) enable detection

of tumors less than 1 cm. After 35 doublings, the mass

contains more than 1 trillion (1012) cells, which is a suf-

ficient number to kill the host.

Invasion

The word cancer is derived from the Latin word mean-

ing crablike because cancers grow and spread by sending

crablike projections into the surrounding tissues. Unlike

benign tumors, which grow by expansion and usually

are surrounded by a capsule, cancer spreads by direct

invasion into surrounding tissues, seeding of cancer cells

in body cavities, and metastatic spread.

Most cancers synthesize and secrete enzymes that

break down proteins and contribute to the infiltration,

invasion, and penetration of the surrounding tissues.

The lack of a sharp line of demarcation separating

them from the surrounding tissue makes the complete

surgical removal of malignant tumors more difficult

than removal of benign tumors. Often it is necessary

for the surgeon to excise portions of seemingly normal

tissue bordering the tumor for the pathologist to estab-

lish that cancer-free margins are present around the

excised tumor and to ensure that the remaining tissue

is cancer free.

 The seeding of cancer cells into body cavities occurs

when a tumor erodes and sheds cells into these spaces.2,3

Most often, the peritoneal cavity is involved, but other

spaces such as the pleural cavity, pericardial cavity, and

joint spaces may be involved. Seeding into the perito-

neal cavity is particularly common with ovarian can-

cers. Similar to tissue culture, tumors in these sites grow

in masses and often produce fluid (e.g., ascites, pleural

effusion).2

The seeding of cancers is often a concern dur-

ing the surgical removal of cancers, where it is possible

to inadvertently introduce free cancer cells into a body

cavity such as the peritoneal cavity.8

Metastatic Spread

The term metastasis is used to describe the development

of a secondary tumor in a location distant from the pri-

mary tumor.2,3

Metastatic tumors frequently retain many

of the microscopic characteristics of the primary tumor

from which they were derived. Because of this, it usually

is possible to determine the site of the primary tumor

from the cellular characteristics of the metastatic tumor.

Some tumors tend to metastasize early in their devel-

opmental course, while others do not metastasize until

later. Occasionally, a metastatic tumor will be found far

advanced before the primary tumor becomes clinically

detectable.

Malignant tumors disseminate by one of two path-

ways: lymph channels (lymphatic spread) or blood ves-

sels (hematogenous spread).2

Lymphatic spread is more

typical of carcinomas, whereas hematogenous spread is

favored by sarcomas.

Lymphatic Spread. In many types of cancer, the first

evidence of disseminated disease is the presence of

tumor cells in the lymph nodes that drain the tumor

area.9

When metastasis occurs by way of the lymphatic

channels, the tumor cells lodge first in the initial lymph

node that receives drainage from the tumor site. Once

in this lymph node, the cells may die because of the lack

of a proper environment, remain dormant for unknown

reasons, or grow into a discernible mass (Fig. 7-4). If

they survive and grow, the cancer cells may spread from

more distant lymph nodes to the thoracic duct, and then

gain access to the blood vasculature. Furthermore, can-

cer cells may gain access to the blood vasculature from

the initial node and more distant lymph nodes by way

of tumor-associated blood vessels that may infiltrate the

tumor mass.

The term sentinel node is used to describe the ini-

tial lymph node to which the primary tumor drains.10

Because the initial metastasis in breast cancer is almost

always lymphatic, lymphatic spread and, therefore,

extent of disease may be determined through lymphatic

mapping and sentinel lymph node biopsy. This is done

by injecting a radioactive tracer and blue dye into the

tumor to determine the first lymph node in the route

of lymph drainage from the cancer. Once the sentinel

lymph node is identified, it is examined to determine

the presence or absence of cancer cells. The procedure

is also used to map the spread of melanoma and other

cancers that have their initial metastatic spread through

the lymphatic system.

Hematogenous Spread. With hematogenous spread,

cancer cells commonly invade capillaries and venules,

whereas thicker-walled arterioles and arteries are rela-

tively resistant. With venous invasion, blood-borne neo-

plastic cells follow the venous flow draining the site of

the neoplasm, often stopping in the first capillary bed

they encounter. Since venous blood from the gastroin-

testinal tract, pancreas, and spleen is routed through the

portal vein to the liver, and all vena caval blood flows

to the lungs, the liver and lungs are the most frequent

metastatic sites for hematogenous spread.2,3

Although the site of hematologic spread usually is

related to vascular drainage of the primary tumor, some

tumors metastasize to distant and unrelated sites. For

example, prostatic cancer preferably spreads to bone,

bronchogenic cancer to the adrenals and brain, and neu-

roblastomas to the liver and bones. The selective nature

of hematologic spread indicates that metastasis is a finely

orchestrated and multistep process, in which only a

small, select clone of cancer cells has the right combina-

tion of gene products to perform all of the steps needed

for establishment of a secondary tumor (Fig. 7-5). To

metastasize, a cancer cell must be able to break loose

from the primary tumor, invade the surrounding extra-

cellular matrix, gain access to a blood vessel, survive

its passage in the bloodstream, emerge from the blood-

stream at a favorable location, invade the surrounding

tissue, and begin to grow and establish a blood supply.

Considerable evidence suggests that cancer cells

capable of metastasis secrete enzymes that break down

the surrounding extracellular matrix, allowing them to

FIGURE 7-4. Metastatic carcinoma in periaortic lymph nodes.

Aorta has been opened and nodes bisected. (From Strayer

DS, Rubin E. Neoplasia. In: Rubin R, Strayer DS, eds. Rubin’s

Pathology: Clinicopathologic Foundations of Medicine. 6th ed.

Philadelphia, PA: Wolters Kluwer Health | Lippincott Williams &

Wilkins; 2012:167.)

0002114681.INDD 135 7/7/2014 9:54:35 AM

136 UNIT 1 Cell and Tissue Function

move through the degraded matrix and gain access to

a blood vessel. Once in the circulation, the tumor cells

are vulnerable to destruction by host immune cells.

Some tumor cells gain protection from the antitumor

host cells by aggregating and adhering to circulating

blood components, particularly platelets, to form tumor

emboli. Exit of the tumor cells from the circulation

involves adhesion to the vascular endothelium followed

by movement through the capillary wall into the site of

secondary tumor formation by mechanisms similar to

those involved in invasion.

Once in the distant site, the process of metastatic

tumor development depends on the establishment of

blood vessels and specific growth factors that promote

proliferation of the tumor cells. Tumor cells as well as

other cells in the microenvironment secrete factors that

enable the development of new blood vessels within

the tumor, a process termed angiogenesis (to be dis-

cussed).11–13 The presence of stimulatory or inhibitory

growth factors correlates with the site-specific pattern

of metastasis. For example, a potent growth-stimulating

factor has been isolated from lung tissue, and stromal

cells in bone have been shown to produce a factor that

stimulates growth of prostatic cancer cells.

Recent evidence indicates that chemoattractant cyto-

kines called chemokines that regulate the trafficking of

leukocytes (white blood cells) and other cell types under

a variety of inflammatory and noninflammatory con-

ditions may play a critical role in cancer invasion and

metastasis.14,15 Tumor cells have been shown to express

functional chemokine receptors, which can sustain cancer

cell proliferation, angiogenesis, and survival and promote

organ-specific localization of metastasis. Insights into the

presence and role of chemokines in cancer spread and

metastasis provide directions for development of future

diagnostic and treatment methods. The implications

include methods to diminish metastasis by blocking the

action of selected chemokines and/or their receptors.

Primary tumor

Platelets

Metastatic tumor

Metastatic subclone

Intravasation

Interaction with

lymphocytes

Tumor cell

embolus

Extravasation

Angiogenesis

FIGURE 7-5. The pathogenesis of metastasis. (Adapted

from Kumar V, Abbas AK, Fausto N, eds. Robbins and Cotran

Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Elsevier

Saunders; 2005:311.)

SUMMARY CONCEPTS

■ The term neoplasm refers to an abnormal mass

of tissue in which the uncontrolled proliferation

of cells exceeds and is uncoordinated with that

of the normal tissues. Differentiation refers to the

extent to which neoplastic cells resemble their

normal counterparts.

■ Neoplasms are commonly classified as being

either benign or malignant. Benign neoplasms

are well-differentiated tumors that resemble

their tissues of origin, but have lost the ability to

control cell proliferation. They grow by expansion,

are enclosed in a fibrous capsule, and do not

cause death unless their location is such that

it interrupts vital body functions. Malignant

neoplasms are less–well-differentiated tumors

that have lost the ability to control both cell

proliferation and differentiation. They grow in a

disorganized and uncontrolled manner, invade

surrounding tissues, have cells that break loose

and travel to distant sites to form metastases, and

inevitably cause suffering and death unless their

growth can be controlled through treatment.

■ Anaplasia is the loss of cell differentiation in

cancerous tissue. Undifferentiated cancer cells

are marked by a number of morphologic changes,

referred to as pleomorphism. The characteristics

of altered proliferation and differentiation are

associated with a number of other changes

including genetic instability, growth factor

independence, loss of cell density–dependent

inhibition, loss of cohesiveness, and anchorage

dependence, faulty cell-to-cell communication,

an indefinite cell life span (immortality), and

expression of fetal antigens not produced by

their normal adult counterparts, and abnormal

production of hormones and substances that

affect body function.

■ The rate of growth of cancerous tissue depends

on the ratio of dividing to resting cells (growth

fraction) and the time it takes for the total mass

of cells in the tumor to double (doubling time). A

tumor is usually undetectable until it has doubled

30 times and contains more than a billion cells.

0002114681.INDD 136 7/7/2014 9:54:48 AM

Chap ter 7 Neoplasia 137

Etiology of Cancer

The cause or causes of cancer can be viewed from two

perspectives: (1) the genetic and molecular mechanisms

that characterize the transformation of normal cells into

cancer cells and (2) the external and more contextual

factors such as age, heredity, and environmental agents

that contribute to its development and progression.

Together, both mechanisms contribute to a multidimen-

sional web of causation by which cancers develop and

progress over time.

Genetic and Molecular Basis

of Cancer

The pathogenesis of most cancers is thought to originate

from genetic damage or mutation with resultant changes

that transform a normally functioning cell into a cancer

cell. Epigenetic factors that involve silencing of a gene or

genes may also be involved. In recent years, the role of

cancer stem cells in the pathogenesis of cancer has been

identified. Finally, the cellular microenvironment that

involves the extracellular matrix and a complex milieu

of cytokines, growth factors, and other cell types is also

recognized as an important contributor to cancer devel-

opment and its growth and progression.

Cancer-Associated Genes

Most cancer-associated genes can be classified into two

broad categories based on whether gene overactiv-

ity or underactivity increases the risk for cancer. The

category associated with gene overactivity involves

proto-oncogenes, which are normal genes that become

cancer-causing genes if mutated.2,3

Proto-oncogenes

encode for normal cell proteins such as growth fac-

tors, growth factor receptors, transcription factors

that promote cell growth, cell cycle proteins (cyclins or

cyclin-dependent proteins), and inhibitors of apoptosis.

The category of cancer-associated underactivity genes

includes the tumor-suppressor genes, which, by being

less active, create an environment in which cancer is

promoted.

Genetic Events Leading to Oncogene Formation or

Activation. There are a number of genetic events that

can cause or activate oncogenes.16 A common event is

a point mutation in which there is a single nucleotide

base change due to an insertion, deletion, or substitu-

tion. An example of an oncogene caused by point muta-

tions is the ras oncogene, which has been found in many

cancers.2

Members of the ras proto-oncogene family are

important signal-relaying proteins that transmit growth

signals to the cell nucleus. Hence, activation of the ras

oncogene can increase cell proliferation.

Chromosomal translocations have traditionally been

associated with cancers such as Burkitt lymphoma and

chronic myeloid leukemia. In Burkitt lymphoma the

c-myc gene, which encodes a growth signal protein,

is translocated from its normal position on chromo-

some 8 to chromosome 14, placing it at the site of an

immunoglobulin gene.2

The outcome of the transloca-

tion in chronic myeloid leukemia is the appearance of

the so-called Philadelphia chromosome involving chro-

mosomes 9 and 22 and the formation of an abnormal

fusion protein that promotes cell proliferation3

(see

Chapter 11, Fig. 11-6). Recent advances in biotechnol-

ogy and genomics are enabling the identification and

increased understanding of how gene translocations,

even within the same chromosome, contribute to the

development of cancer.

Another genetic event that is common in cancer is

gene amplification. Multiple copies of certain genes

may cause overexpression with higher than normal

levels of proteins that increase cell proliferation. For

example, the human epidermal growth factor receptor-2

(HER-2/neu) gene is amplified in up to 30% of breast

cancers and indicates a tumor that is aggressive with

a poor prognosis.17 One of the agents used in treat-

ment of HER-2/neu overexpressing breast cancers is

trastuzumab (Herceptin), a monoclonal antibody that

selectively binds to HER-2, thereby inhibiting the prolif-

eration of tumor cells that overexpress HER-2.

Genetic Events Leading to Loss of Tumor-Suppressor

Gene Function. Normal cells have regulatory genetic

mechanisms that protect them against activated or

newly acquired oncogenes. These genes are called tumor-

suppressor genes. When this type of gene is inactivated,

a genetic signal that normally inhibits cell proliferation is

removed, thereby causing unregulated growth to begin.2,3

Mutations in tumor-suppressor genes are generally reces-

sive, in that cells tend to behave normally until there is

homologous deletion, inactivation, or silencing of both

the maternal and paternal genes.

Two of the best-known tumor-suppressor genes are

the p53 and retinoblastoma (RB) genes. The p53 gene,

named after the molecular weight of the protein it encodes,

is the most common target for genetic alteration in

■ The spread of cancer occurs through three

pathways: direct invasion and extension, seeding

of cancer cells in body cavities, and metastatic

spread through lymphatic or vascular pathways.

Only a proportionately small clone of cancer cells

is capable of metastasis. To metastasize, a cancer

cell must be able to break loose from the primary

tumor, invade the surrounding extracellular

matrix, gain access to a blood vessel, survive its

passage in the bloodstream, emerge from the

bloodstream at a favorable location, and invade

the surrounding tissue. Once in the distant

tissue site, the metastatic process depends on

the establishment of blood vessels and specific

growth factors that promote proliferation of the

tumor cells.

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138 UNIT 1 Cell and Tissue Function

human cancers. Mutations in the p53 gene can occur in

virtually every type of cancer including lung, breast, and

colon cancer—the three leading causes of cancer death.2

Sometimes called the “guardian of the genome,” the p53

gene acts as a molecular police officer that prevents the

propagation of genetically damaged cells.2

Located on

the short arm of chromosome 17, the p53 gene normally

senses DNA damage and assists in DNA repair by caus-

ing arrest of the cell cycle in G1 and inducing DNA repair

or initiating apoptosis in a cell that cannot be repaired.2,3

With homologous loss of p53 gene activity, DNA dam-

age goes unrepaired and mutations occur in dividing

cells leading to malignant transformations. The p53

gene also appears to initiate apoptosis in radiation- and

chemotherapy-damaged tumor cells. Thus, tumors that

retain normal p53 function are more likely to respond to

such therapy than tumors that carry a defective p53 gene.2

The RB gene was isolated in studies involving a

malignant tumor of the eye known as retinoblastoma.

The tumor occurs in a hereditary and sporadic form and

becomes evident in early life. Approximately 60% of

cases are sporadic, and the remaining 40% are heredi-

tary, inherited as an autosomal dominant trait.2

Known

as the “two hit” hypothesis of carcinogenesis, both nor-

mal alleles of the RB gene must be inactivated for the

development of retinoblastoma (Fig. 7-6).2,3

In heredi-

tary cases, one genetic change (“first hit”) is inherited

from an affected parent and is therefore present in all

somatic cells of the body, whereas the second mutation

(“second hit”) occurs in one of the retinal cells (which

already carries the first mutation). In sporadic (nonin-

herited) cases, both mutations (“hits”) occur within a

single somatic cell, whose progeny then form the cancer.

The RB gene represents a model for other genes that

act similarly. In persons carrying an inherited mutation,

such as a mutated RB allele, all somatic cells are per-

fectly normal, except for the risk of developing cancer.

That person is said to be heterozygous or carrying one

mutated gene at the gene locus. Cancer develops when

a person becomes homozygous with two defective genes

for the mutant allele, a condition referred to as loss

of heterozygosity.2

For example, loss of heterozygos-

ity is known to occur in hereditary cancers, in which a

mutated gene is inherited from a parent and other con-

ditions (e.g., radiation exposure) are present that cause

mutation of the companion gene, making an individual

more susceptible to cancer.

Epigenetic Mechanisms

In addition to mechanisms that involve DNA and chro-

mosomal structural changes, there are molecular and

cellular mechanisms termed “epigenetic” mechanisms

that involve changes in the patterns of gene expression

without a change in the DNA.18 Epigenetic mechanisms

may “silence” genes, such as tumor-suppressor genes,

so that even if the gene is present, it is not expressed

and a cancer-suppressing protein is not made. One such

mechanism of epigenetic silencing is by methylation of

the promoter region of the gene, a change that prevents

transcription and causes gene inactivity. Genes silenced

by hypermethylation can be inherited, and epigenetic

silencing of genes can be considered a “first hit” in the

“two hit” hypothesis described earlier.19

MicroRNAs (miRNA) are small, noncoding, single-

stranded ribonucleic acids (RNAs), about 22 nucleotides

in length, which function at the post-transcriptional level

as negative regulators of gene expression.2,3,20 miRNAs

pair with messenger RNA (mRNA) containing a nucle-

otide sequence that complements the sequence of the

microRNA, and through the action of the RNA-induced

silencing, mediate post-transcriptional gene silencing.

miRNAs have been shown to undergo changes in expres-

sion in cancer cells, and frequent amplifications and dele-

tions of miRNA loci have been identified in a number

of human cancers, including those of the lung, breast,

colon, pancreas, and hematopoietic systems.3

They can

participate in neoplastic transformation by increasing the

expression of oncogenes or reducing the expression of

tumor suppressor genes. For example, down-regulation

or deletion of certain miRNAs in some leukemias and

lymphomas results in increased expression of BCL2, an

Mutant

Rb gene

Mutation

Normal

Rb gene

A

Offspring

Retinoblastoma

Retinoblastoma

Offspring

B

First

mutation

Second

mutation

FIGURE 7-6. Pathogenesis of retinoblastoma. Two mutations

of the mutant retinoblastoma (Rb) gene lead to development of

neoplastic proliferation of retinal cells. (A) In the familial form

all offspring become carriers of the mutant Rb gene. A second

mutation affects the other Rb gene locus after birth. (B) In the

sporadic form, both mutations occur after birth.

0002114681.INDD 138 7/7/2014 9:54:50 AM

Chap ter 7 Neoplasia 139

anti-apoptotic protein that protects tumor cells from

apoptosis.

Molecular and Cellular Pathways

Numerous molecular and cellular mechanisms with a

myriad of associated pathways and genes are known or

suspected to facilitate the development of cancer. These

mechanisms include defects in DNA repair mechanisms,

disorders in growth factor signaling pathways, evasion

of apoptosis, development of sustained angiogenesis,

and evasion of metastasis.

Mechanisms and genes that regulate repair of dam-

aged DNA have been implicated in the process of

oncogenesis (Fig. 7-7). The DNA repair genes affect

cell proliferation and survival indirectly through their

ability to repair nonlethal damage in other genes

including proto-oncogenes, tumor-suppressor genes,

and the genes that control apoptosis.2.3 These genes

have been implicated as the principal targets of genetic

damage occurring during the development of a can-

cer cell. Such genetic damage may be caused by the

action of chemicals, radiation, or viruses, or it may

be inherited in the germ line. Significantly, it appears

that the acquisition of a single-gene mutation is not

sufficient to transform normal cells into cancer cells.

Instead, cancerous transformation appears to require

the activation of many independently mutated genes.

A relatively common pathway by which cancer cells

gain autonomous growth is by mutations in genes

that control signaling pathways between growth fac-

tor receptors on the cell membrane and their targets in

the cell nucleus.2

Under normal conditions, cell prolif-

eration involves the binding of a growth factor to its

receptor on the cell membrane, activation of the growth

factor receptor on the inner surface of the cell mem-

brane, transfer of the signal across the cytosol to the

nucleus via signal-transducing proteins that function as

second messengers, induction and activation of regula-

tory factors that initiate DNA transcription, and entry

of the cell into the cell cycle (Fig. 7-8). Many of the pro-

teins involved in the signaling pathways that control the

action of growth factors in cancer cells exert their effects

through enzymes called kinases that phosphorylate pro-

teins. In some types of cancer such as chronic myeloid

leukemia, mutation in a proto-oncogene controlling

tyrosine kinase activity occurs, causing unregulated cell

growth and proliferation.

Carcinogenic

agent

• Activation of growth-promoting oncogenes

• Inactivation of tumor-suppressor genes

• Alterations in genes that control apoptosis

Unregulated cell

differentiation and growth

DNA repair

(DNA repair genes)

Failure of DNA

repair

Normal

cell

Malignant

neoplasm

DNA damage

FIGURE 7-7. Flow chart depicting the stages in the

development of a malignant neoplasm resulting from exposure

to an oncogenic agent that produces DNA damage. When DNA

repair genes are present (red arrow), the DNA is repaired and

gene mutation does not occur.

P

P

P

P

P

Outer cell

membrane

Inner cell

membrane

P

MAP kinase

Active

Activation

Inactive

MAP kinase

Nucleus

Signal-

tranducing

proteins

Activation of

transcriptase

Growth factor

Growth factor receptor

FIGURE 7-8. Pathway for genes regulating cell growth

and replication. Stimulation of a normal cell by a growth

factor results in activation of the growth factor receptor and

signaling proteins that transmit the growth-promoting signal

to the nucleus, where it modulates gene transcription and

progression through the cell cycle. Many of these signaling

proteins exert their effects through enzymes called kinases that

phosphorylate (P) proteins. MAP, mitogen-activating protein.

The accumulation of cancer cells may result not only

from the activation of growth-promoting oncogenes or

inactivation of tumor-suppressor genes, but also from

genes that regulate cell death through apoptosis or pro-

grammed cell death.2,3,21,22 Faulty apoptotic mechanisms

have an important role in cancer. The failure of can-

cer cells to undergo apoptosis in a normal manner may

be due to a number of problems. There may be altered

cell survival signaling, down-regulation of death recep-

tors, stabilization of the mitochondria, or inactivation

of proapoptotic proteins. Alterations in apoptotic and

antiapoptotic pathways have been found in many can-

cers. One example is the high levels of the antiapoptotic

protein BCL2 that occur secondary to a chromosomal

translocation in certain B-cell lymphomas. The mito-

chondrial membrane is a key regulator of the balance

between cell death and survival. Proteins in the BCL2

family reside in the inner mitochondrial membrane and

are either proapoptotic or antiapoptotic. Since apoptosis

is considered a normal cellular response to DNA dam-

age, loss of normal apoptotic pathways may contribute

to cancer by enabling DNA-damaged cells to survive.

Even with all the genetic abnormalities described ear-

lier, tumors cannot enlarge unless angiogenesis occurs

and supplies them with the blood vessels necessary for

survival. Angiogenesis is required not only for continued

tumor growth, but also for metastasis.2,3,23 The molecu-

lar basis for the angiogenic switch is unknown, but it

appears to involve increased production of angiogenic

factors or loss of angiogenic inhibitors. These factors

may be produced directly by the tumor cells themselves

or by inflammatory cells (e.g., macrophages) or other

stromal cells associated with the tumors. In normal cells,

the p53 gene can stimulate expression of antiangiogenic

molecules and repress expression of proangiogenic

molecules, such as vascular endothelial growth factor

(VEGF).2

Thus, loss of p53 activity in cancer cells both

promotes angiogenesis and removes an antiangiogenic

switch. Because of the crucial role of angiogenic factors

in tumor growth, much interest is focused on the devel-

opment of antiangiogenesis therapy.

Finally, multiple genes and molecular and cellular

pathways are known to be involved in tumor invasion

and metastasis. Evidence suggests that genetic pro-

grams that are normally operative in stem cells dur-

ing embryonic development may become operative in

cancer stem cells, enabling them to detach, cross tis-

sue boundaries, escape death by anoikis or apoptosis,

and colonize new tissues.24 The MET proto-oncogene,

which is expressed in both stem and cancer cells, is a

key regulator of invasive growth. Recent findings sug-

gest that adverse conditions such as tissue hypoxia,

which are commonly present in cancerous tumors,

trigger this invasive behavior by activating the MET

tyrosine kinase receptor.

Tumor Cell Transformation

The process by which carcinogenic agents cause nor-

mal cells to become cancer cells is hypothesized to be

a multistep mechanism that can be divided into three

stages: initiation, promotion, and progression (Fig. 7-9).

Initiation involves the exposure of cells to doses of a

carcinogenic agent that induce malignant transforma-

tion.2

The carcinogenic agents can be chemical, physical,

or biologic, and they produce irreversible changes in the

genome of a previously normal cell. Because the effects

of initiating agents are irreversible, multiple divided

doses may achieve the same effects as single exposures

of the same comparable dose or small amounts of highly

carcinogenic substances. The cells most susceptible to

mutagenic alterations in the genome are those that are

actively synthesizing DNA.

Promotion involves the induction of unregulated

accelerated growth in already initiated cells by various

chemicals and growth factors.2

Promotion is reversible

if the promoter substance is removed. Cells that have

been irreversibly initiated may be promoted even after

long latency periods. The latency period varies with the

type of agent, the dosage, and the characteristics of the

target cells. Many chemical carcinogens are called com-

plete carcinogens because they can initiate and promote

neoplastic transformation.

Progression is the process whereby tumor cells acquire

malignant phenotypic changes. These changes may

promote the cell’s ability to proliferate autonomously,

invade, or metastasize. They may also destabilize its

karyotype.

Normal cell Normal cell line

DNA damage

and cell mutation

Mutated cell

Progression

Promotion

Initiation Carcinogenic agent

(chemicals,

radiation, viruses)

Activation of

oncogenes by

promoter agent

Malignant tumor

FIGURE 7-9. The processes of initiation, promotion, and

progression in the clonal evolution of malignant tumors.

Initiation involves the exposure of cells to appropriate doses

of a carcinogenic agent; promotion, the unregulated and

accelerated growth of the mutated cells; and progression, the

acquisition of malignant characteristics by the tumor cells.

0002114681.INDD 140 7/7/2014 9:54:53 AM

Chap ter 7 Neoplasia 141

Host and Environmental Factors

Because cancer is not a single disease, it is reasonable to

assume that it does not have a single cause. More likely,

cancers develop because of interactions among host and

environmental factors. Among the host factors that have

been linked to cancer are heredity, hormonal factors,

obesity, and immunologic mechanisms. Environmental

factors include chemical carcinogens, radiation, and

microorganisms.

Heredity

The genetic predisposition for development of cancer

has been documented for a number of cancerous and

precancerous lesions that follow mendelian inheritance

patterns. Two tumor suppressor genes, called BRCA1

(breast carcinoma 1) and BRCA2 (breast carcinoma 2),

have been implicated in a genetic susceptibility to breast

cancer.2,3

These genes have also been associated with an

increased risk of ovarian, prostate, pancreatic, colon,

and other cancers.

Several cancers exhibit an autosomal dominant

inheritance pattern that greatly increases the risk of

developing a tumor. The inherited mutation is usually

a point mutation occurring in a single allele of a tumor-

suppressor gene. Persons who inherit the mutant gene are

born with one normal and one mutant copy of the gene.

In order for cancer to develop, the normal allele must

be inactivated, usually through a somatic mutation. As

previously discussed, retinoblastoma is an example of a

cancer that follows an autosomal dominant inheritance

pattern. Approximately 40% of retinoblastomas are

inherited, and carriers of the mutant RB suppressor gene

have a 10,000-fold increased risk of developing retino-

blastoma, usually with bilateral involvement.2

Familial

adenomatous polyposis of the colon also follows an

autosomal dominant inheritance pattern. In people who

inherit this gene, hundreds of adenomatous polyps may

develop, some of which inevitably become malignant.

Hormones

Hormones have received considerable research atten-

tion with respect to cancer of the breast, ovary, and

endometrium in women and of the prostate and testis

in men. Although the link between hormones and the

development of cancer is unclear, it has been suggested

that it may reside with the ability of hormones to drive

the cell division of a malignant phenotype.2

Because of

the evidence that endogenous hormones affect the risk

of these cancers, concern exists regarding the effects on

cancer risk if the same or closely related hormones are

administered for therapeutic purposes.

Obesity

There has been recent interest in obesity as a risk factor

for certain types of cancer, including breast, endome-

trial, and prostate cancer.25 The process relating obesity

to cancer development is multifactorial and involves a

network of metabolic and immunologic mechanisms.

Obesity has been associated with insulin resistance

and increased production of pancreatic insulin, both of

which can have a carcinogenic effect. Insulin enhances

insulin-like growth factor-1 (IGF-1) synthesis and its

bioavailability. Both insulin and IGF-1 are anabolic

molecules that can promote tumor development by

stimulating cell proliferation and inhibiting apoptosis.

Obesity has also been associated with increased levels

of sex hormones (androgens and estrogens), which act

to stimulate cell proliferation, inhibit apoptosis, and

therefore increase the chance of malignant cell transfor-

mation, particularly of endometrial and breast tissue,

and possibly of other organs (e.g., prostate and colon

cancer). And lastly, obesity has been related to a condi-

tion of chronic inflammation characterized by abnormal

production of inflammatory cytokines that can contrib-

ute to the development of malignancies.

Immunologic Mechanisms

There is substantial evidence for the participation of

the immune system in resistance against the progression

and spread of cancer.2,3,26 The central concept, known

as the immune surveillance hypothesis, which was first

proposed by Paul Ehrlich in 1909, postulates that the

immune system plays a central role in protection against

the development of tumors.27 In addition to cancer–host

interactions as a mechanism of cancer development,

immunologic mechanisms provide a means for the detec-

tion, classification, and prognostic evaluation of cancers

and a potential method of treatment. Immunotherapy

(discussed later in this chapter) is a cancer treatment

modality designed to heighten the patient’s general

immune responses so as to increase tumor destruction.

The immune surveillance hypothesis suggests that

the development of cancer might be associated with

impairment or decline in the surveillance capacity of the

immune system. For example, increases in cancer inci-

dence have been observed in people with immunodefi-

ciency diseases and in those with organ transplants who

are receiving immunosuppressant drugs. The incidence

of cancer also is increased in the elderly, in whom there

is a known decrease in immune activity. The association

of Kaposi sarcoma with acquired immunodeficiency

syndrome (AIDS) further emphasizes the role of the

immune system in preventing malignant cell prolifera-

tion (discussed in Chapter 16).

It has been shown that most tumor cells have molec-

ular configurations that can be specifically recognized

by immune cells or antibodies. These configurations are

therefore called tumor antigens. Some tumor antigens are

found only on tumor cells, whereas others are found on

both tumor cells and normal cells; however, quantitative

and qualitative differences in the tumor antigens permit the

immune system to distinguish tumor from normal cells.2

Virtually all of the components of the immune system

have the potential for eradicating cancer cells, including

T and B lymphocytes, natural killer (NK) cells, and mac-

rophages (see Chapter 15). The T-cell response, which

is responsible for direct killing of tumor cells and for

activation of other components of the immune system, is

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142 UNIT 1 Cell and Tissue Function

one of the most important host responses for controlling

the growth of tumor cells. The finding of tumor-reactive

antibodies in the serum of people with cancer supports

the role of the B lymphocyte as a member of the immune

surveillance team. Antibodies cause destruction of can-

cer cells through complement-mediated mechanisms

or through antibody-dependent cellular cytotoxicity,

in which the antibody binds the cancer cell to another

effector cell, such as the NK cell, that does the actual

killing of the cancer cell. NK cells do not require antigen

recognition and can lyse a wide variety of target cells.

Chemical Carcinogens

A carcinogen is an agent capable of causing cancer. The

role of environmental agents in causation of cancer was

first noted in 1775 by Sir Percivall Pott, a English physi-

cian who related the high incidence of scrotal cancer in

chimneysweeps to their exposure to coal soot.2,3

Coal

tar has since been found to contain potent polycyclic

aromatic hydrocarbons. Since then, many chemicals

have been suspected of being carcinogens. Some have

been found to cause cancers in animals, and others are

known to cause cancers in humans (Chart 7-1).

Chemical carcinogens can be divided into two

groups: (1) direct-reacting agents, which do not require

activation in the body to become carcinogenic, and

(2) indirect-reacting agents, called procarcinogens or

initiators, which become active only after metabolic

conversion.2,3

Direct- and indirect-acting initiators form

highly reactive species (such as free radicals) that bind

with residues on DNA, RNA, or cellular proteins. They

then prompt cell mutation or disrupt protein synthesis

in a way that alters cell replication and interferes with

cell regulatory controls. The carcinogenicity of some

chemicals is augmented by agents called promoters that,

by themselves, have little or no cancer-causing ability. It

is believed that promoters, in the presence of these car-

cinogens, exert their effect by altering gene expression,

increasing DNA synthesis, enhancing gene amplification

(i.e., number of gene copies that are made), and altering

intercellular communication.

Exposure to many carcinogens, such as those con-

tained in cigarette smoke, is associated with a lifestyle

risk for development of cancer. Cigarette smoke con-

tains both procarcinogens and promoters. It is directly

associated with lung and laryngeal cancer and has been

linked with cancers of the mouth, nasal cavities, phar-

ynx, esophagus, pancreas, liver, kidney, uterus, cervix,

and bladder and myeloid leukemias. Not only is the

smoker at risk, but others passively exposed to cigarette

smoke are at risk. Chewing tobacco increases the risk of

cancers of the oral cavity and esophagus.

Occupational exposure to industrial chemicals is

another significant risk factor for cancer. These include

polycyclic aromatic hydrocarbons, which are metabo-

lized in the liver.5

For example, long-term exposure to

vinyl chloride, the simple two-carbon molecule that is

widely used in the plastics industry, increases the risk for

hepatic angiosarcoma.3

There is also strong evidence that certain elements in

the diet contain chemicals that contribute to cancer risk.

Most known dietary carcinogens occur either naturally

in plants (e.g., aflatoxins) or are produced during food

preparation.2

The polycyclic aromatic hydrocarbons are

of particular interest because they are produced during

several types of food preparation, including frying foods

in animal fat that has been reused multiple times; grill-

ing or charcoal-broiling meats; and smoking meats and

fish. Nitrosamines, which are powerful carcinogens, are

formed in foods that are smoked, salted, cured, or pick-

led using nitrites or nitrates as preservatives. Formation

of these nitrosamines may be inhibited by the presence

of antioxidants such as vitamin C found in fruits and

vegetables. Cancer of the colon has been associated with

high dietary intake of fat and red meat and a low intake

of dietary fiber.28 A high-fat diet is thought to be car-

cinogenic because it increases the flow of primary bile

acids that are converted to secondary bile acids in the

presence of anaerobic bacteria in the colon, producing

carcinogens or promoters.

Heavy or regular alcohol consumption is associ-

ated with a variety of cancers. The first and most toxic

metabolite of ethanol is acetaldehyde, a known car-

cinogen that interferes with DNA synthesis and repair

and that causes point mutations in some cells.28,29 The

carcinogenic effect of cigarette smoke can be enhanced

CHART 7-1 Major Chemical Carcinogens2 , 3

Direct-Acting Alkylating Agents

■ Anticancer drugs (e.g., cyclophosphamide, cisplatin,

busulfan)

Polycyclic and Heterocyclic Aromatic

Hydrocarbons

■ Tobacco combustion (cigarette smoke)

■ Animal fat in broiled and smoked meats

■ Benzo(a)pyrene

■ Vinyl chloride

Aromatic Amines and Azo Dyes

■ β-Naphthylamine

■ Aniline dyes

Naturally Occurring Carcinogens

■ Aflatoxin B1

■ Griseofulvin

■ Betel nuts

Nitrosamines and Amides

■ Formed in gastrointestinal tract from nitro-stable

amines and nitrates used in preserving processed

meats and other foods

Miscellaneous Agents

■ Asbestos

■ Chromium, nickel, and other metals when volatilized

and inhaled in industrial settings

■ Insecticides, fungicides

■ Polychlorinated biphenyls

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Chap ter 7 Neoplasia 143

by concomitant consumption of alcohol; persons who

smoke and drink considerable amounts of alcohol are

at increased risk for development of cancer of the oral

cavity, larynx and esophagus.

The effects of carcinogenic agents usually are dose

dependent—the larger the dose or the longer the dura-

tion of exposure, the greater the risk that cancer will

develop. Some chemical carcinogens may act in concert

with other carcinogenic influences, such as viruses or

radiation, to induce neoplasia. There usually is a time

delay ranging from 5 to 30 years from the time of chem-

ical carcinogen exposure to the development of overt

cancer. This is unfortunate because many people may

have been exposed to the agent and its carcinogenic

effects before the association was recognized.

Radiation

The effects of ionizing radiation in carcinogenesis have

been well documented in atomic bomb survivors, in

patients diagnostically exposed, and in industrial work-

ers, scientists, and physicians who were exposed dur-

ing employment. Malignant epitheliomas of the skin

and leukemia were significantly elevated in these popu-

lations. Between 1950 and 1970, the death rate from

leukemia alone in the most heavily exposed population

groups of the atomic bomb survivors in Hiroshima and

Nagasaki was 147 per 100,000 persons, 30 times the

expected rate.30

The type of cancer that developed depended on the

dose of radiation, the sex of the person, and the age at

which exposure occurred. The length of time between

exposure and the onset of cancer is related to the age

of the individual. For example, children exposed to

ionizing radiation in utero have an increased risk for

developing leukemias and childhood tumors, particu-

larly 2 to 3 years after birth. Therapeutic irradiation to

the head and neck can give rise to thyroid cancer years

later. The carcinogenic effect of ionizing radiation is

related to its mutagenic effects in terms of causing chro-

mosomal breakage, translocations, and, less frequently,

point mutations.2

The association between sunlight and the develop-

ment of skin cancer (see Chapter 46) has been reported

for more than 100 years. Ultraviolet radiation emits

relatively low-energy rays that do not deeply penetrate

the skin. The evidence supporting the role of ultra-

violet radiation in the cause of skin cancer includes

skin cancer that develops primarily on the areas of

skin more frequently exposed to sunlight (e.g., the

head and neck, arms, hands, and legs), a higher inci-

dence in light-complexioned individuals who lack the

ultraviolet-filtering skin pigment melanin, and the fact

that the intensity of ultraviolet exposure is directly

related to the incidence of skin cancer, as evidenced by

higher rates occurring in Australia and the American

Southwest. There also are studies that suggest that

intense, episodic exposure to sunlight, particularly dur-

ing childhood, is more important in the development

of melanoma than prolonged low-intensity exposure.

As with other carcinogens, the effects of ultraviolet

radiation usually are additive, and there usually is a

long delay between the time of exposure and the time

that cancer can be detected.

Viral and Microbial Agents

An oncogenic virus is one that can induce cancer. Many

DNA and RNA viruses have proved to be oncogenic in

animals. However, only four DNA viruses have been

implicated in human cancers: the human papilloma

virus (HPV), Epstein-Barr virus (EBV), hepatitis B virus

(HBV), and human herpesvirus 8 (HHV-8).2,4,31 HHV-8,

which causes Kaposi sarcoma in persons with AIDS, is

discussed in Chapter 16. There is also an association

between infection with the bacterium Helicobacter

pylori and gastric adenocarcinoma and gastric lympho-

mas2,3

(discussed in Chapter 29).

There are over 70 genetically different types of HPV.2

Some types (i.e., types 1, 2, 4, 7) have been shown to

cause benign squamous papillomas (i.e., warts). By con-

trast, high-risk HPVs (e.g., types 16 and 18) are impli-

cated in the pathogenesis of squamous cell carcinoma of

the cervix and anogenital region.2,3

Thus, cervical cancer

can be viewed as a sexually transmitted disease, caused

by transmission of HPV. In addition, at least 20% of

oropharyngeal cancers are associated with high-risk

HPVs.2

A vaccine to protect against HPV types 6, 11,

16, and 18 is now available32 (see Chapter 40).

Epstein-Barr virus is a member of the herpesvirus fam-

ily. It has been implicated in the pathogenesis of several

human cancers, including Burkitt lymphoma, a tumor of

B lymphocytes. In persons with normal immune func-

tion, the EBV-driven B-cell proliferation is readily

controlled and the person becomes asymptomatic or

experiences a self-limited episode of infectious mono-

nucleosis (see Chapter 11). However, in regions of the

world where Burkitt lymphoma is endemic, such as

parts of East Africa, concurrent malaria or other infec-

tions cause impaired immune function, allowing sus-

tained B-lymphocyte proliferation. Epstein-Barr virus

is also associated with B-cell lymphomas in immuno-

suppressed individuals, such as those with AIDS or

with drug-suppressed immune systems (e.g., individu-

als with transplanted organs).

There is strong epidemiologic evidence linking chronic

HBV and hepatitis C virus (HCV) infection with hepa-

tocellular carcinoma (discussed in Chapter 30). It has

been estimated that 70% to 85% of hepatocellular can-

cers worldwide are due to infection with HBV or HCV.2

The precise mechanism by which these viruses induce

hepatocellular cancer has not been fully determined. It

seems probable that the oncogenic effects are multifac-

torial, with immunologically mediated chronic inflam-

mation leading to persistent liver damage, regeneration,

and genomic damage. The regeneration process is medi-

ated by a vast array of growth factors, cytokines, che-

mokines, and bioactive substances produced by immune

cells that promote cell survival, tissue remodeling, and

angiogenesis.

Although a number of retroviruses (RNA viruses)

cause cancer in animals, human T-cell leukemia virus-1

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144 UNIT 1 Cell and Tissue Function

(HTLV-1) is the only known retrovirus to cause cancer in

humans. Human T-cell leukemia virus-1 is associated with

a form of T-cell leukemia that is endemic in certain parts

of Japan and some areas of the Caribbean and Africa,

and is found sporadically elsewhere, including the United

States and Europe.2

Similar to the AIDS virus, HTLV-1 is

attracted to the CD4+

T cells, and this subset of T cells is

therefore the major target for malignant transformation.

The virus requires transmission of infected T cells by way

of sexual intercourse, infected blood, or breast milk.

Clinical Manifestations

There probably is not a single body function left unaf-

fected by the presence of cancer. Even the presenting

signs and symptoms may be localized or widespread.

Local and Regional Manifestations

Because tumor cells replace normally functioning paren-

chymal cells, the initial manifestations of cancer usually

reflect the function of the primary site of involvement.

For example, lung cancer initially produces impairment

of respiratory function; as the tumor grows and metas-

tasizes, other body structures become affected.

Cancer has no regard for normal anatomic bound-

aries; as it grows, it invades and compresses adjacent

structures. Abdominal cancer, for example, may com-

press the viscera and cause bowel obstruction. Growing

tumors may also compress and erode blood vessels,

causing ulceration and necrosis along with frank bleed-

ing and sometimes hemorrhage.

The development of effusions (i.e., fluid) in the pleu-

ral, pericardial, or peritoneal spaces may be the present-

ing sign of some tumors. Direct involvement of the serous

surface seems to be the most significant inciting factor,

although many other mechanisms such as obstruction of

lymphatic flow may play a role. Most persons with pleu-

ral effusions are symptomatic at presentation with chest

pain, shortness of breath, and cough. More than any

other malignant neoplasms, ovarian cancers are asso-

ciated with the accumulation of fluid in the peritoneal

cavity. Complaints of abdominal discomfort, swelling

and a feeling of heaviness, and increase in abdominal

girth, which reflect the presence of peritoneal effusions

or ascites, are the most common presenting symptoms in

ovarian cancer, occurring in up to 65% of women with

the disease.33

Systemic Manifestations

Cancer also produces systemic manifestations such as

anemia, anorexia and cachexia, and fatigue and sleep dis-

orders. Many of these manifestations are compounded

by the side effects of methods used to treat the disease. In

its late stages, cancer often causes pain (see Chapter 35).

Pain is probably one of the most dreaded aspects of can-

cer, and pain management is one of the major treatment

concerns for persons with incurable cancers. Although

research has produced amazing insights into the causes

and cures for cancer, only recently have efforts focused

on the associated side effects of the disease.

Anemia

Anemia is common in persons with various types of

cancers. It may be related to blood loss, iron deficiency,

hemolysis, impaired red cell production, or treatment

effects.34–36 For example, drugs used in treatment of

cancer are cytotoxic and can decrease red blood cell

production. Also, there are many mechanisms through

which erythrocyte production can be impaired in

persons with malignancies including nutritional defi-

ciencies, bone marrow failure, a blunted erythro-

poietin response to hypoxia, and an iron deficiency.

Inflammatory cytokines generated in response to

tumors decrease erythropoietin synthesis, resulting in a

decrease in erythrocyte production. Iron deficiency may

SUMMARY CONCEPTS

■ The etiology of cancer is highly complex,

encompassing both molecular and cellular

origins, and external and contextual factors

such as heredity and environmental agents that

influence its inception and growth. It is likely that

multiple factors interact at the molecular and

cellular level to transform normal cells into cancer

cells.

■ The molecular pathogenesis of cancer is

thought to have its origin in genetic damage or

a mutation that changes the cell’s physiology

and transforms it into a cancer cell. The types of

genes involved in cancer are numerous, but two

main groups are the proto-oncogenes, which

control cell growth and replication, and tumor-

suppressor genes, which are growth-inhibiting

regulatory genes.

■ Genetic and molecular mechanisms that increase

susceptibility to cancer and/or facilitate cancer

include defects in DNA repair mechanisms,

defects in growth factor signaling pathways,

evasion of apoptosis, development of sustained

angiogenesis, invasion, and metastasis. Genetic

and epigenetic damage may be the result of

interactions between multiple risk factors or

repeated exposure to a single carcinogenic

(cancer-producing) agent.

■ Among the external and contextual risk factors

that have been linked to cancer are heredity,

hormonal factors, obesity, immunologic

mechanisms, and environmental agents such as

chemicals, radiation, and cancer-causing viruses

and microbes.

0002114681.INDD 144 7/7/2014 9:55:05 AM

Chap ter 7 Neoplasia 145

be due, in part, to a dysregulation of iron metabolism,

leading to a functional iron deficiency.37

Cancer-related anemia is associated with reduced

treatment effectiveness, increased mortality, increased

transfusion requirements, and reduced performance

and quality of life. Hypoxia, a characteristic feature of

advanced solid tumors, has been recognized as a critical

factor in promoting tumor resistance to radiotherapy

and some chemotherapeutic agents.

Cancer-related anemia is often treated with iron

supplementation and recombinant human erythropoi-

etin (rHuEPO, epoetin alfa).37 Since iron deficiency

may result in failure to respond to erythropoietin, it

has been suggested that iron parameters be measured

before initiation of erythropoietin therapy. When treat-

ment with supplemental iron is indicated, it has been

suggested that it be given intravenously, since oral iron

has been shown to be largely ineffective in persons with

cancer.37

Anorexia and Cachexia

Many cancers are associated with weight loss and wasting

of body fat and muscle tissue, accompanied by profound

weakness, anorexia, and anemia. This wasting syndrome

is often referred to as the cancer anorexia–cachexia syn-

drome.

38–40 It is a common manifestation of most solid

tumors with the exception of breast cancer. The condi-

tion is more common in children and elderly persons

and becomes more pronounced as the disease progresses.

Persons with cancer cachexia also respond less well to

chemotherapy and are more prone to toxic side effects.

The cause of the cancer anorexia–cachexia syn-

drome is probably multifactorial, resulting from a

persistent inflammatory response in conjunction with

production of specific cytokines and catabolic factors

by the tumor. Although anorexia, reduced food intake,

and abnormalities of taste are common in people

with cancer and often are accentuated by treatment

methods, the extent of weight loss and protein wast-

ing cannot be explained in terms of diminished food

intake alone. There also is a disparity between the size

of the tumor and the severity of cachexia, which sup-

ports the existence of other mediators in the develop-

ment of cachexia. It has been demonstrated that tumor

necrosis factor (TNF)-α and other cytokines including

interleukin-1 (IL-1) and IL-6 can produce the wast-

ing syndrome in experimental animals.3

High serum

levels of these cytokines have been observed in per-

sons with cancer, and their levels appear to correlate

with progress of the tumor. Tumor necrosis factor-α,

secreted primarily by macrophages in response to

tumor cell growth or gram-negative bacterial infec-

tions, was the first identified cytokine associated with

cachexia and wasting. It causes anorexia by suppressing

satiety centers in the hypothalamus and increasing the

synthesis of lipoprotein lipase, an enzyme that facili-

tates the release of fatty acids from lipoproteins so that

they can be used by tissues. IL-1 and IL-6 share many

of the features of TNF-α in terms of the ability to initi-

ate cachexia.

Fatigue and Sleep Disorders

Fatigue and sleep disturbances are two of the side effects

most frequently experienced by persons with cancer.41–45

Cancer-related fatigue is characterized by feelings of

tiredness, weakness, and lack of energy and is distinct

from the normal tiredness experienced by healthy indi-

viduals in that it is not relieved by rest or sleep. It occurs

both as a consequence of the cancer itself and as a side

effect of cancer treatment. Cancer-related fatigue may

be an early symptom of malignant disease and has been

reported by as many as 40% of patients at the time of

diagnosis.42 Furthermore, the symptom often remains

for months or even years after treatment.

The cause of cancer-related fatigue is largely unknown

but is probably multifactorial and involves the dysregu-

lation of several interrelated physiologic, biochemical,

and psychological systems. The basic mechanisms of

fatigue have been broadly categorized into two compo-

nents: peripheral and central. Peripheral fatigue, which

has its origin in the neuromuscular junction and muscles,

results from the inability of the peripheral neuromus-

cular apparatus to perform a task in response to cen-

tral stimulation. Mechanisms implicated in peripheral

fatigue include a lack of adenosine triphosphate (ATP)

and the buildup of metabolic by-products such as lactic

acid. Central fatigue arises in the central nervous system

(CNS) and is often described as the difficulty in initiat-

ing or maintaining voluntary activities. One hypothesis

proposed to explain cancer-related fatigue is that cancer

and cancer treatments result in dysregulation of brain

serotonin (5-HT) levels or function. There is also evi-

dence that proinflammatory cytokines, such as TNF-α,

can influence 5-HT metabolism.

Paraneoplastic Syndromes

In addition to signs and symptoms at the sites of primary

and metastatic disease, cancer can produce manifesta-

tions in sites that are not directly affected by the disease.

Such manifestations are collectively referred to as para-

neoplastic syndromes.46,47 Some of these manifestations

are caused by the elaboration of hormones by cancer

cells, and others result from the production of circulat-

ing factors that produce hematopoietic, neurologic, and

dermatologic syndromes (Table 7-3). These syndromes

are most commonly associated with lung, breast, and

hematologic malignancies.2

A variety of peptide hormones are produced by both

benign and malignant tumors. Although not normally

expressed, the biochemical pathways for the synthesis and

release of peptide hormones are present in most cells.47

The three most common endocrine syndromes associated

with cancer are the syndrome of inappropriate antidi-

uretic hormone (ADH) secretion (see Chapter 8), Cushing

syndrome due to ectopic adrenocorticotropic hormone

(ACTH) production (see Chapter 32), and hypercalcemia

(see Chapter 8). Hypercalcemia also can be caused by

osteolytic processes induced by cancer such as multiple

myeloma or bony metastases from other cancers.

Some paraneoplastic syndromes are associated with

the production of circulating mediators that produce

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146 UNIT 1 Cell and Tissue Function

hematologic complications.47 For example, a variety

of cancers may produce procoagulation factors that

contribute to an increased risk for venous thrombosis

and nonbacterial thrombotic endocarditis. Sometimes,

unexplained thrombotic events are the first indication

of an undiagnosed malignancy. The precise relation-

ship between coagulation disorders and cancer is still

unknown. Several malignancies, such as mucin-producing

adenocarcinomas, release thromboplastin and other

substances that activate the clotting system.

The symptomatic paraneoplastic neurologic dis-

orders are relatively rare with the exception of the

Lambert-Eaton myasthenic syndrome, which affects

about 3% of persons with small cell lung cancer, and

myasthenia gravis, which affects about 15% of people

with thymoma.48,49 The Lambert-Eaton syndrome, or

reverse myasthenia gravis, is seen almost exclusively in

small cell lung cancer. It produces muscle weakness in

the limbs rather than the initial mouth and eye muscle

weakness seen in myasthenia gravis. The origin of para-

neoplastic neurologic disorders is thought to be immune

mediated. The altered immune response is initiated by

the production of onconeural antigens (e.g., antigens

normally expressed in the nervous system) by the can-

cer cells. The immune system, in turn, recognizes the

onconeural antigens as foreign and mounts an immune

response. In many cases, the immune attack controls the

growth of the cancer.

The paraneoplastic syndromes may be the earliest

indication that a person has cancer, and should be

regarded as such. They may also represent significant

clinical problems, may be potentially lethal in persons

with cancer, and may mimic metastatic disease and con-

found treatment. Diagnostic methods focus on both

identifying the cause of the disorder and locating the

malignancy responsible. Techniques for precise identifi-

cation of minute amounts of polypeptides may allow for

early diagnosis of curable malignancies in asymptomatic

individuals. The treatment of paraneoplastic syndromes

involves concurrent treatment of the underlying cancer

and suppression of the mediator causing the syndrome.

TABLE 7-3 Common Paraneoplastic Syndromes

Type of Syndrome Associated Tumor Type Proposed Mechanism

Endocrinologic

Syndrome of inappropriate ADH Small cell lung cancer, others Production and release of ADH by tumor

Cushing syndrome Small cell lung cancer, bronchial

carcinoid cancers

Production and release of ACTH by tumor

Hypercalcemia Squamous cell cancers of the lung,

head, neck, ovary

Production and release of polypeptide

factor with close relationship to PTH

Hematologic

Venous thrombosis Pancreatic, lung, other cancers Production of procoagulation factors

Nonbacterial thrombolytic

endocarditis

Advanced cancers

Neurologic

Eaton-Lambert syndrome Small cell lung cancer Autoimmune production of antibodies to

motor end-plate structures

Myasthenia gravis Thymoma

Dermatologic

Acanthosis nigricans Gastric carcinoma Possibly caused by production of growth

factors (epidermal) by tumor cells

ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; PTH, parathyroid hormone.

SUMMARY CONCEPTS

■ There probably is no single body function left

unaffected by the presence of cancer. Because

tumor cells replace normally functioning

parenchymal tissue, the initial manifestations

of cancer usually reflect the primary site of

involvement.

■ Cancer compresses blood vessels, obstructs

lymph flow, disrupts tissue integrity, invades

serous cavities, and compresses visceral organs.

It may result in development of effusions (i.e.,

fluid) in the pleural, pericardial, or peritoneal

spaces.

■ Systemic manifestations of cancer include

anorexia and cachexia; fatigue and sleep

disorders; and anemia.

■ Cancer may also produce paraneoplastic

syndromes that arise from the ability of

neoplasms to elaborate hormones and other

chemical mediators to produce endocrine,

hematopoietic, neurologic, and dermatologic

syndromes. Many of these manifestations are

compounded by the side effects of methods used

to treat the disease.

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Chap ter 7 Neoplasia 147

Screening, Diagnosis, and

Treatment

Advances in the screening, diagnosis, and treatment

of cancer have boosted 5-year survival rates to nearly

64%. When treatment cannot cure the disease, it may be

used to slow its progression or provide palliative care.

Screening

Screening represents a secondary prevention measure

for the early recognition of cancer in an otherwise

asymptomatic population.50,51 Screening can be achieved

through observation (e.g., skin, mouth, external genita-

lia), palpation (e.g., breast, thyroid, rectum and anus,

prostate, lymph nodes), and laboratory tests and pro-

cedures (e.g., Papanicolaou [Pap] smear, colonoscopy,

mammography). It requires a test that will specifically

detect early cancers or premalignancies, is cost effective,

and results in improved therapeutic outcomes. For most

cancers, stage at presentation is related to curability,

with the highest rates reported when the tumor is small

and there is no evidence of metastasis. For some tumors,

however, metastasis tends to occur early, even from a

small primary tumor. Unfortunately, no reliable screen-

ing methods are currently available for many cancers.

Cancers for which current screening or early detection

has led to improvement in outcomes include cancers of

the breast (breast self-examination and mammography,

discussed in Chapter 40), cervix (Pap smear, Chapter 40),

colon and rectum (rectal examination, fecal occult

blood test, and flexible sigmoidoscopy and colonoscopy,

Chapter 29), prostate (prostate-specific antigen test-

ing and transrectal ultrasonography, Chapter 39), and

malignant melanoma (self-examination, Chapter 46).

While not as clearly defined, it is recommended that

screening for other types of cancers such as cancers of

the thyroid, testicles, ovaries, lymph nodes, and oral cav-

ity be done at the time of periodic health examinations.

Diagnostic Methods

The methods used in the diagnosis and staging of can-

cer are determined largely by the location and type of

cancer suspected. They include blood tests for tumor

markers, cytologic studies, tissue biopsy, and gene pro-

filing techniques as well as medical imaging, which is

discussed with specific cancers later in this text.

Tumor Markers

Tumor markers are antigens expressed on the surface

of tumor cells or substances released from normal cells

in response to the presence of tumor.2

Some substances,

such as hormones and enzymes, that are normally pro-

duced by the involved tissue become overexpressed as

a result of cancer. Tumor markers are used for screen-

ing, establishing prognosis, monitoring treatment, and

detecting recurrent disease. Table 7-4 identifies some of

the more commonly used tumor markers and summa-

rizes their source and the cancers associated with them.

TABLE 7-4 Tumor Markers

Marker Source Associated Cancers

Oncofetal Antigens

α-Fetoprotein (AFP) Fetal yolk sac and gastrointestinal

structures early in fetal life

Primary liver cancers; germ cell cancer

of the testis

Carcinoembryonic antigen (CEA) Embryonic tissues in gut, pancreas,

and liver

Colorectal cancer and cancers of the

pancreas, lung, and stomach

Hormones

Human chorionic gonadotropin (hCG) Hormone normally produced by placenta Gestational trophoblastic tumors; germ

cell cancer of testis

Calcitonin Hormone produced by thyroid

parafollicular cells

Thyroid cancer

Catecholamines (epinephrine,

norepinephrine) and metabolites

Hormones produced by chromaffin cells

of the adrenal gland

Pheochromocytoma and related tumors

Specific Proteins

Monoclonal immunoglobulin Abnormal immunoglobulin produced

by neoplastic cells

Multiple myeloma

Prostate-specific antigen (PSA) Produced by the epithelial cells lining

the acini and ducts of the prostate

Prostate cancer

Mucins and Other Glycoproteins

CA-125 Produced by müllerian cells of ovary Ovarian cancer

CA-19-9 Produced by alimentary tract epithelium Cancer of the pancreas, and colon

Cluster of Differentiation

CD antigens Present on leukocytes Used to determine the type and level of

differentiation of leukocytes involved

in different types of leukemia and

lymphoma

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148 UNIT 1 Cell and Tissue Function

The serum markers that have proven most useful in

clinical practice are the human chorionic gonadotro-

pin (hCG), prostate-specific antigen (PSA), CA-125,

α-fetoprotein (AFP), CD blood cell antigens, and car-

cinoembryonic antigen (CEA). The hCG is a hormone

normally produced by the placenta. It is used as a marker

for diagnosing, prescribing treatment, and following

the disease course in persons with high-risk gestational

trophoblastic tumors. Prostate-specific antigen (PSA)

is used as a marker in prostate cancer, and CA-125 is

used as a marker in ovarian cancer. Markers for leuke-

mia and lymphomas are grouped by so-called clusters

of differentiation (CD) antigens (see Chapter 15). The

CD antigens help to distinguish among T and B lympho-

cytes, monocytes, granulocytes, and natural killer cells

and immature variants of these cells.2,3

Some cancers express fetal antigens that are nor-

mally present only during embryonal development and

induced to reappear as a result of neoplasia.2

The two

that have proved most useful as tumor markers are alpha

fetoprotein (AFP) and CEA. α-fetoprotein is synthesized

by the fetal liver, yolk sac, and gastrointestinal tract and

is the major serum protein in the fetus. Elevated levels

are encountered in people with primary liver cancers

and have also been observed in some testicular, ovarian,

pancreatic, and stomach cancers. Carcinoembryonic

antigen normally is produced by embryonic tissue in the

gut, pancreas, and liver and is elaborated by a number

of different cancers, including colorectal carcinomas,

pancreatic cancers, and gastric and breast tumors. As

with most other tumor markers, elevated levels of AFP

and CEA are found in other, noncancerous conditions,

and elevated levels of both depend on tumor size so that

neither is useful as an early test for cancer.

As diagnostic tools, tumor markers have limitations.

Nearly all markers can be elevated in benign conditions,

and most are not elevated in the early stages of malignancy.

Furthermore, they are not in themselves specific enough

to permit a diagnosis of a malignancy, but once a malig-

nancy has been diagnosed and shown to be associated

with elevated levels of a tumor marker, the marker can be

used to assess progress of the disease. Extremely elevated

levels of a tumor marker can indicate a poor prognosis or

the need for more aggressive treatment. Perhaps the great-

est value of tumor markers is in monitoring therapy in

people with widespread cancer. The level of most cancer

markers tends to decrease with successful treatment and

increase with recurrence or spread of the tumor.

Cytologic, Histologic, and Gene-Profiling

Methods

Cytologic and histologic studies are laboratory meth-

ods used to examine tissues and cells. Several sampling

approaches are available including cytologic smears, tis-

sue biopsies, and needle aspiration.2

Papanicolaou Smear. The Pap smear is a cytologic

method that consists of a microscopic examination of a

properly prepared slide by a cytotechnologist or patho-

logist for the purpose of detecting the presence of abnor-

mal cells. The usefulness of the Pap smear relies on the

fact that cancer cells lack the cohesive properties and

intercellular junctions that are characteristic of normal

tissue; without these characteristics, cancer cells tend to

exfoliate and become mixed with secretions surround-

ing the tumor growth. Although the Pap smear is widely

used as a screening test for cervical cancer, it can be per-

formed on other body secretions, including nipple drain-

age, pleural or peritoneal fluid, and gastric washings.

Tissue Biopsy. Tissue biopsy involves the removal of

a tissue specimen for microscopic study. It is of criti-

cal importance in designing the treatment plan should

cancer cells be found. Biopsies are obtained in a number

of ways, including needle biopsy; endoscopic methods,

such as bronchoscopy or cystoscopy, which involve the

passage of an endoscope through an orifice and into the

involved structure; and laparoscopic methods.

Fine needle aspiration involves withdrawing cells and

attendant fluid with a small-bore needle. The method

is most widely used for assessment of readily palpable

lesions in sites such as the thyroid, breast, and lymph

nodes. Modern imaging techniques have also enabled

the method to be extended to deeper structures such as

the pelvic lymph nodes and pancreas.

In some instances, a surgical incision is made from

which biopsy specimens are obtained. Excisional biop-

sies are those in which the entire tumor is removed. The

tumors usually are small, solid, palpable masses. If the

tumor is too large to be completely removed, a wedge

of tissue from the mass can be excised for examination.

A quick frozen section may be done and examined by a

pathologist to determine the nature of a mass lesion or

evaluate the margins of an excised tumor to ascertain

that the entire neoplasm has been removed.3

Immunohistochemistry. Immunohistochemistry inv-

olves the use of monoclonal antibodies to facilitate

the identification of cell products or surface markers.3

For example, certain anaplastic carcinomas, malignant

lymphomas, melanomas, and sarcomas look very simi-

lar under the microscope, but must be accurately iden-

tified because their treatment and prognosis are quite

different.

Immunohistochemistry can also be used to determine

the site of origin of metastatic tumors. Many cancer

patients present with metastasis. In cases in which the ori-

gin of the metastasis is obscure, immunochemical detec-

tion of tissue-specific or organ-specific antigens can often

help to identify the tumor source. Immunochemistry can

also be used to detect molecules that have prognostic or

therapeutic significance. For example, detection of estro-

gen receptors on breast cancer cells is of prognostic and

therapeutic significance because these tumors respond to

antiestrogen therapy.

Microarray Technology. Microarray technology has

the advantage of analyzing a large number of molecu-

lar changes in cancer cells to determine overall patterns

of behavior that would not be available by conventional

means. The technique uses “gene chips” that can perform

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Chap ter 7 Neoplasia 149

miniature assays to detect and quantify the expression of

large numbers of genes at the same time.2

DNA arrays

are now commercially available to assist in making clini-

cal decisions regarding breast cancer treatment. In addi-

tion to identifying tumor types, microarrays have been

used for predicting prognosis and response to therapy,

examining tumor changes after therapy, and classifying

hereditary tumors.2

Staging and Grading of Tumors

The two basic methods for classifying cancers are grad-

ing according to the histologic or cellular characteristics

of the tumor and staging according to the clinical spread

of the disease. Both methods are used to determine the

course of the disease and aid in selecting an appropriate

treatment or management plan.

Grading of tumors involves the microscopic exami-

nation of cancer cells to determine their level of dif-

ferentiation and the number of mitoses. The closer the

tumor cells resemble comparable normal tissue cells,

both morphologically and functionally, the lower the

grade. Accordingly, on a scale ranging from grade I

to IV, grade I neoplasms are well differentiated and

grade IV are poorly differentiated and display marked

anaplasia.2,3

The clinical staging of cancers uses methods to deter-

mine the extent and spread of the disease. It is useful

in determining the choice of treatment for individual

patients, estimating prognosis, and comparing the results

of different treatment regimens. The significant criteria

used for staging that vary with different organs include

the size of the primary tumor, its extent of local growth

(whether within or outside the organ), lymph node

involvement, and presence of distant metastasis.2,3

This

assessment is based on clinical and radiographic exami-

nation (CT and MRI) and, in some cases, surgical explo-

ration. Two methods of staging are currently in use: the

TNM system (T for primary tumor, N for regional lymph

node involvement, and M for metastasis), which was

developed by the Union for International Cancer Control,

and the American Joint Committee (AJC) system.2

In the

TNM system, T1, T2, T3, and T4 describe tumor size,

N0, N1, N2, and N3, lymph node involvement; and M0

or M1, the absence or presence of metastasis. In the AJC

system, cancers are divided into stages 0 to IV incorpo-

rating the size of the primary lesions and the presence of

nodal spread and distant metastasis.

Cancer Treatment

The goals of cancer treatment methods fall into three

categories: curative, control, and palliative. The most

common modalities are surgery, radiation, chemother-

apy, hormonal therapy, and biotherapy. The treatment

of cancer involves the use of a carefully planned pro-

gram that combines the benefits of multiple treatment

modalities and the expertise of an interdisciplinary team

of specialists including medical, surgical, and radiation

oncologists; clinical nurse specialists; nurse practitio-

ners; pharmacists; and a variety of ancillary personnel.

Surgery

Surgery is used for diagnosis, staging of cancer, tumor

removal, and palliation (i.e., relief of symptoms) when

a cure cannot be achieved.52 The type of surgery to be

used is determined by the extent of the disease, the loca-

tion and structures involved, the tumor growth rate and

invasiveness, the surgical risk to the patient, and the

quality of life the patient will experience after the sur-

gery. If the tumor is small and has well-defined margins,

the entire tumor often can be removed. If, however, the

tumor is large or involves vital tissues, surgical removal

may be difficult if not impossible.

Radiation Therapy

Radiation can be used as the primary method of treat-

ment, as preoperative or postoperative treatment, with

chemotherapy, or along with chemotherapy and sur-

gery.53–57 It can also be used as a palliative treatment

to reduce symptoms in persons with advanced can-

cers. It is effective in reducing the pain associated with

bone metastasis and, in some cases, improves mobility.

Radiation also is used to treat several oncologic emer-

gencies, such as spinal cord compression, bronchial

obstruction, and hemorrhage.

Radiation therapy exerts its effects through ioniz-

ing radiation, which affects cells by direct ionization of

molecules or, more commonly, by indirect ionization.

Indirect ionization produced by x-rays or gamma rays

causes cellular damage when these rays are absorbed

into tissue and give up their energy by producing fast-

moving electrons. These electrons interact with free or

loosely bonded electrons of the absorber cells and sub-

sequently produce free radicals that interact with criti-

cal cell components (see Chapter 2). It can immediately

kill cells, delay or halt cell cycle progression, or, at dose

levels commonly used in radiation therapy, cause dam-

age to the cell nucleus, resulting in cell death after rep-

lication. Cell damage can be sublethal, in which case

a single break in the strand can repair itself before the

next radiation insult. Double-stranded breaks in DNA

are generally believed to be the primary damage that

leads to cell death. Cells with unrepaired DNA damage

may continue to function until they undergo cell mito-

sis, at which time the genetic damage causes cell death.

The therapeutic effects of radiation therapy derive

from the fact that the rapidly proliferating and poorly

differentiated cells of a cancerous tumor are more likely

to be injured by radiation therapy than are the more

slowly proliferating cells of normal tissue. To some

extent, however, radiation is injurious to all rapidly

proliferating cells, including those of the bone marrow

and the mucosal lining of the gastrointestinal tract. This

results in many of the common adverse effects of radia-

tion therapy, including infection, bleeding, and anemia

due to loss of blood cells, and nausea and vomiting due

to loss of gastrointestinal tract cells. In addition to its

lethal effects, radiation also produces sublethal injury.

Recovery from sublethal doses of radiation occurs in the

interval between the first dose of radiation and subse-

quent doses. This is why large total doses of radiation

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150 UNIT 1 Cell and Tissue Function

can be tolerated when they are divided into multiple

smaller, fractionated doses. Normal tissue is usually able

to recover from radiation damage more readily than is

cancerous tissue.

Therapeutic radiation can be delivered in one of three

ways: external beam or teletherapy, with beams gener-

ated by a linear accelerator or cobalt-60 machine at a

distance and aimed at the patient’s tumor; brachyther-

apy, in which a sealed radioactive source is placed close

to or directly in the tumor site; and systemic therapy, in

which radioisotopes with a short half-life are given by

mouth or injected into the tumor site.

Chemotherapy

Cancer chemotherapy has evolved as one of the major

systemic treatment modalities.58,59 Unlike surgery and

radiation, cancer chemotherapy is a systemic treatment

that enables drugs to reach the site of the tumor as well

as distant sites. Chemotherapeutic drugs may be used as

the primary form of treatment, or they may be used as

part of a multimodal treatment plan. Chemotherapy is

the primary treatment for most hematologic and some

solid tumors, including choriocarcinoma, testicular can-

cer, acute and chronic leukemia, Burkitt lymphoma,

Hodgkin disease, and multiple myeloma.

Most cancer drugs are more toxic to rapidly prolif-

erating cells than to those incapable of replication or in

phase G0 of the cell cycle. Because of their mechanism

of action, they are more effective against tumors with a

high growth fraction. By the time many cancers reach a

size that is clinically detectable, the growth fraction has

decreased considerably. In this case, reduction in tumor

size through the use of surgical debulking procedures or

radiation therapy often causes tumor cells residing in G0

to reenter the cell cycle. Thus, surgery or radiation ther-

apy may be used to increase the effectiveness of chemo-

therapy, or chemotherapy may be given to patients with

no overt evidence of residual disease after local treat-

ment (e.g., surgical resection of a primary breast cancer).

For most chemotherapy drugs, the relationship

between tumor cell survival and drug dose is exponen-

tial, with the number of cells surviving being propor-

tional to drug dose, and the number of cells at risk for

exposure being proportional to the destructive action

of the drug. Exponential killing implies that a propor-

tion or percentage of tumor cells is killed, rather than an

absolute number (Fig. 7-10). This proportion is a con-

stant percentage of the total number of cells. For this

reason, multiple courses of treatment are needed if the

tumor is to be eradicated.

A major problem in cancer chemotherapy is the

development of cellular resistance. Acquired resistance

develops in a number of drug-sensitive tumor types.59

Experimentally, drug resistance can be highly specific to

a single agent and is usually based on genetic changes in

a given tumor cell type. In other instances, a multidrug-

resistant phenomenon affecting anticancer drugs with

differing structures occurs. This type of resistance often

involves the increased expression of transmembrane

transporter genes involved in drug efflux.

Cancer chemotherapy drugs may be classified as

either cell cycle specific or cell cycle nonspecific (see

Understanding—The Cell Cycle, Chapter 4).58 Drugs are

cell cycle specific if they exert their action during a spe-

cific phase of the cell cycle. For example, methotrexate,

an antimetabolite, acts by interfering with DNA synthe-

sis and thereby interrupts the S phase of the cell cycle.

Cell cycle–nonspecific drugs exert their effects through-

out all phases of the cell cycle. The alkylating agents,

which are cell cycle nonspecific, act by disrupting DNA

when cells are in the resting state as well as when they are

dividing. The site of action of chemotherapeutic drugs

varies. Chemotherapy drugs that have similar structures

and effects on cell function usually are grouped together,

and these drugs usually have similar side effect profiles.

Because chemotherapy drugs differ in their mechanisms

of action, cell cycle–specific and cell cycle–nonspecific

agents are often combined to treat cancer.

Combination chemotherapy has been found to be

more effective than treatment with a single drug. With

this method, several drugs with different mechanisms

of action, metabolic pathways, times of onset of action

and recovery, side effects, and onset of side effects are

used. Drugs used in combinations are individually

effective against the tumor and synergistic with each

other. The maximum possible drug doses usually are

used to ensure the maximum cell kill within the range

of toxicity tolerated by the host for each drug. Routes

of administration and dosage schedules are carefully

designed to ensure optimal delivery of the active forms

of the drugs to the tumor during the sensitive phase of

the cell cycle.

Chemotherapy Side Effects. Unfortunately, chemo-

therapeutic drugs affect both cancer cells and the rapidly

proliferating cells of normal tissue, producing undesir-

able side effects. Some side effects appear immediately

or after a few days (acute), some within a few weeks

(intermediate), and others months to years after chemo-

therapy administration (long term).

Most chemotherapeutic drugs suppress bone marrow

function and formation of blood cells, leading to anemia,

neutropenia, and thrombocytopenia. With neutropenia,

there is risk for developing serious infections, whereas

thrombocytopenia increases the risk for bleeding. The

availability of hematopoietic growth factors (e.g., gran-

ulocyte colony-stimulating factor [G-CSF]); erythropoi-

etin, which stimulates red blood production; and IL-11,

which stimulates platelet production) has shortened the

period of myelosuppression, thereby reducing the need

for hospitalizations due to infection and decreasing the

need for blood products.

Anorexia, nausea, and vomiting are common prob-

lems associated with cancer chemotherapy.58 The severity

of the vomiting is related to the emetic potential of the

particular drug. These symptoms can occur within min-

utes or hours of drug administration and are thought to

be due to stimulation of the chemoreceptor trigger zone

in the medulla that stimulates vomiting (see Chapter 28).

The chemoreceptor trigger zone responds to the level

of chemicals circulating in the blood. The acute symp-

toms usually subside within 24 to 48 hours and often

can be relieved by antiemetic drugs. The pharmacologic

approaches to prevent chemotherapy-induced nausea and

vomiting have greatly improved over several decades. The

development of serotonin (5-HT3) receptor antagonists

has facilitated the use of highly emetic chemotherapy

drugs by more effectively reducing the nausea and vomit-

ing induced by these drugs.

Alopecia or hair loss results from impaired prolifera-

tion of the hair follicles and is a side effect of a number

of cancer drugs; it usually is temporary, and the hair

tends to regrow when treatment is stopped. The rap-

idly proliferating structures of the reproductive system

are particularly sensitive to the action of cancer drugs.

Women may experience changes in menstrual flow or

have amenorrhea. Men may have a decreased sperm

count (i.e., oligospermia) or absence of sperm (i.e., azo-

ospermia). Many chemotherapeutic agents also may

have teratogenic or mutagenic effects leading to fetal

abnormalities.58

Chemotherapy drugs are toxic to all cells. Because they

are potentially mutagenic, carcinogenic, and teratogenic,

special care is required when handling or administering

the drugs. Drugs, drug containers, and administration

equipment require special disposal as hazardous waste.60

Hormone and Antihormone Therapy

Hormonal therapy consists of administration of drugs

designed to deprive the cancer cells of the hormonal sig-

nals that otherwise would stimulate them to divide. It is

used for cancers that are responsive to or dependent on

hormones for growth and have specific hormone recep-

tors.61 Among the tumors that are known to be respon-

sive to hormonal manipulation are those of the breast,

prostate, and endometrium. Other cancers, such as

Kaposi sarcoma and renal, liver, ovarian, and pancreatic

cancer, are also responsive to hormonal manipulation,

but to a lesser degree.

The therapeutic options for altering the hormonal

environment in the woman with breast cancer or the

man with prostate cancer include surgical and phar-

macologic measures. Surgery involves the removal

of the organ responsible for the hormone produc-

tion that is stimulating the target tissue (e.g., ovaries

in women or testes in men). Pharmacologic methods

focus largely on reducing circulating hormone levels

or changing the hormone receptors so that they no

longer respond to the hormone. Pharmacologic sup-

pression of circulating hormone levels can be effected

through pituitary desensitization, as with the admin-

istration of androgens, or through the administration

of gonadotropin-releasing hormone (GnRH) analogs

that act at the level of the hypothalamus to inhibit

gonadotropin production and release. Another class of

drugs, the aromatase inhibitors, is used to treat breast

cancer; these drugs act by interrupting the biochemi-

cal processes that convert the adrenal androgen andro-

stenedione to estrone.62

Hormone receptor function can be altered by the

administration of pharmacologic doses of exogenous

hormones that act by producing a decrease in hormone

receptors or by antihormone drugs (antiestrogens and

antiandrogens) that bind to hormone receptors, mak-

ing them inaccessible to hormone stimulation. Initially,

patients often respond favorably to hormonal treat-

ments, but eventually the cancer becomes resistant to

hormonal manipulation, and other approaches must be

sought to control the disease.

Biotherapy

Biotherapy involves the use of immunotherapy and

biologic response modifiers as a means of changing a

person’s immune response and modifying tumor cell

biology. It involves the use of monoclonal antibodies,

cytokines, and adjuvants.63

Monoclonal Antibodies. Recent advances in the ability

to manipulate the genes of immunoglobulins have resulted

in the development of a wide array of monoclonal antibod-

ies directed against tumor-specific antigens as well as sig-

naling molecules.64 These include chimeric human-murine

(mouse) antibodies with human constant region and

murine-variable regions (see Chapter 15, Figure 15-10),

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152 UNIT 1 Cell and Tissue Function

humanized antibodies in which the murine regions that

bind antigen have been grafted into human immunoglobu-

lin (Ig) G molecules, and entirely human antibodies derived

from transgenic mice expressing immunoglobulin genes.65

Some monoclonal antibodies are directed to block major

pathways central to tumor cell survival and proliferation,

whereas others are modified to deliver toxins, radioiso-

topes, cytokines, or other cancer drugs.

Currently approved monoclonal antibodies include

rituximab (Rituxan), a chimeric IgG monoclonal anti-

body that targets the CD20 antigen on B cells and is

used in the treatment of nonHodgkin lymphoma; beva-

cozumab (Avastin), a humanized IgG monoclonal anti-

body that targets vascular endothelial growth factor

(VEGF) to inhibit blood vessel growth (angiogenesis)

and is approved for treatment of colorectal, lung, renal,

and breast cancer; and cetuximab (Erbitux), a chimeric

monoclonal antibody that targets the epidermal growth

factor receptor (EGFR) to inhibit tumor cell growth and

is approved for treatment of colorectal cancer and squa-

mous cell cancer of the head and neck.64,65

Cytokines. The biologic response modifiers include

cytokines such as the interferons and interleukins. The

interferons appear to inhibit viral replication and also

may be involved in inhibiting tumor protein synthesis,

prolonging the cell cycle, and increasing the percentage

of cells in the G0 phase. Interferons stimulate NK cells

and T-lymphocyte killer cells. There are three major

types of interferons, alpha (α), beta (β), and gamma (γ),

with members of each group differing in terms of their

cell surface receptors.63 Interferon-γ has been approved

for the treatment of hairy cell leukemia, AIDS-related

Kaposi sarcoma, and chronic myelogenous leukemia,

and as adjuvant therapy for patients at high risk for

recurrent melanoma. Interferon-α has been used to treat

some solid tumors (e.g., renal cell carcinoma, colorectal

cancer, carcinoid tumors, ovarian cancer) and hema-

tologic neoplasms (e.g., B-cell and T-cell lymphomas,

cutaneous T-cell lymphoma, and multiple myeloma).62

Research now is focusing on combining interferons with

other forms of cancer therapy and establishing optimal

doses and treatment protocols.

The interleukins (ILs) are cytokines that provide com-

munication between cells by binding to receptor sites on

the cell surface membranes of the target cells. Of the 18

known interleukins (see Chapter 15), IL-2 has been the

most widely studied. A recombinant human IL-2 (rIL-2,

aldesleukin) has been approved by the U.S. Food and

Drug Administration (FDA) and is currently being used

for the treatment of metastatic renal cell carcinoma and

metastatic melanoma.63

Adjuvants. Adjuvants are substances such as Bacillus

Calmette-Guérin (BCG) that nonspecifically stimulate or

indirectly augument the immune system.63 Instillations

of BCG, an attenuated strain of the bacterium that

causes bovine tuberculosis, are used to treat noninva-

sive bladder cancer after surgical ablation. It is assumed

that BCG acts locally to stimulate an immune response,

thereby decreasing the relapse rate.

Targeted Therapy

Researchers have been working diligently to produce drugs

that selectively attack malignant cells while leaving normal

cells unharmed.66,67 The characteristics and capabilities

of cancer cells have been used to establish a framework

for the development of such targeted therapies, including

those that disrupt molecular signaling pathways, inhibit

angiogenesis, and harness the body’s immune system. The

first targeted therapies were the monoclonal antibodies.

Researchers are now working to design drugs that can dis-

rupt molecular signaling pathways, such as those that use

the protein tyrosine kinases. The protein tyrosine kinases

are intrinsic components of the signaling pathways for

growth factors involved in the proliferation of lymphocytes

and other cell types. Imatinib mesylate is a protein tyro-

sine kinase inhibitor indicated in the treatment of chronic

myeloid leukemia (see Chapter 11). Angiogenesis is also

being explored as a target for targeted cancer therapy.66

One of the newerr antiangiogenic agents, bevacizumab,

targets and blocks VEGF, which is released by many can-

cers to stimulate proliferation of new blood vessels.

SUMMARY CONCEPTS

■ The methods used in the detection and diagnosis

of cancer vary with the type of cancer and its

location. Because many cancers are curable if

diagnosed early, health care practices designed

to promote early detection, such as screening, are

important.

■ Diagnostic methods include laboratory tests for

the presence of tumor markers, cytologic and

histologic studies using cells or tissue specimens,

and gene profiling methods, in addition to

medical imaging.

■ There are two basic methods of classifying

tumors: grading according to the histologic

or tissue characteristics, and clinical staging

according to spread of the disease. The Tumor,

Node, Metastasis (TNM) system for clinical

staging of cancer uses tumor size, lymph node

involvement, and presence of metastasis.

■ Treatment of cancer can include surgery,

radiation, or chemotherapy. Other therapies

include hormonal, immunologic, and biologic

therapies, as well as molecularly targeted agents

that disrupt molecular signaling pathways, inhibit

angiogenesis, and harness the body’s immune

system. Treatment plans that use more than one

type of therapy are providing cures for a number

of cancers that a few decades ago had a poor

prognosis, and are increasing the life expectancy

in other types of cancer.

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Chap ter 7 Neoplasia 153

Childhood Cancers and Late

Effects on Cancer Survivors

Despite progressively improved 5-year survival rates,

from 56% in 1974 to 75% in 2000, cancer remains the

leading cause of disease-related deaths among children

between 1 to 14 years in the United States.68 Leukemia

(discussed in Chapter 11) accounts for one-third of

cases of cancer in children ages 1 to 14 years.1

Cancer

of the brain and other parts of the nervous system are

the second most common, followed by tissue sarcoma,

neuroblastoma, renal cancer (Wilms tumor, discussed

in Chapter 26), and non-Hodgkin and Hodgkin lym-

phoma (discussed in Chapter 11).1

Two young girls with acute lymphocytic leukemia are

receiving chemotherapy (From National Cancer Institute

Visuals. No. AV-8503-3437.)

Incidence and Types

of Childhood Cancers

The spectrum of cancers that affect children differs

markedly from those that affect adults. Although most

adult cancers are of epithelial cell origin (e.g., lung can-

cer, breast cancer, colorectal cancers), childhood cancers

usually involve the hematopoietic system (leukemia),

brain and other parts of the nervous system, soft tissues,

kidneys (Wilms tumor), and bone.1,68

The incidence of childhood cancers is greatest during

the first years of life, decreases during middle childhood,

and then increases during puberty and adolescence.68

During the first 2 years of life, embryonal tumors such

as neuroblastoma, retinoblastoma, and Wilms tumor

are among the most common types of tumors. Acute

lymphocytic leukemia has a peak incidence in children

2 to 5 years of age. As children age, especially after they

pass puberty, bone malignancies, lymphoma, gonadal

germ cell tumors (testicular and ovarian carcinomas),

and various carcinomas such as thyroid cancer and

malignant melanoma increase in incidence.

A number of the tumors of infancy and early child-

hood are embryonal in origin, meaning that they exhibit

features of organogenesis similar to that of embryonic

development. Because of this characteristic, these tumors

are frequently designated with the suffix “-blastoma”

(e.g., nephroblastoma [Wilms tumor], retinoblastoma,

neuroblastoma).2

Wilms tumor (discussed in Chapter 25)

and neuroblastoma are particularly illustrative of this

type of childhood tumor.

Biology of Childhood Cancers

As with adult cancers, there probably is no one cause

of childhood cancer. Although a number of genetic

conditions are associated with childhood cancer, such

conditions are relatively rare, suggesting an interac-

tion between genetic susceptibility and environmental

exposures. The most notable heritable conditions that

impart susceptibility to childhood cancer include Down

syndrome (20- to 30-fold increased risk of acute lym-

phoblastic leukemia),1

neurofibromatosis (NF) type 1

(neurofibromas, optic gliomas, brain tumors), NF type 2

(acoustic neuroma, meningiomas), xeroderma pigmen-

tosum (skin cancer), ataxia-telangiectasia (lymphoma,

leukemia), and the Beckman-Wiedemann syndrome

(Wilms tumor).2,69

While constituting only a small percentage of

childhood cancers, the biology of a number of these

tumors illustrates several important biologic aspects

of neoplasms, such as the two-hit theory of recessive

tumor-suppressor genes (e.g., RB gene mutation in

retinoblastoma); defects in DNA repair; and the histo-

logic similarities between embryonic organogenesis and

oncogenesis. Syndromes associated with defects in DNA

repair include xeroderma pigmentosa, in which there is

increased risk of skin cancers due to defects in repair

of DNA damaged by ultraviolet light. The development

of childhood cancers has also been linked to genetic

imprinting, which is characterized by selective inacti-

vation of one of the two alleles of a certain gene (dis-

cussed in Chapter 5).69 The inactivation is determined

by whether the gene is inherited from the mother or

father. For example, normally the maternal allele for the

insulin-like growth factor-2 (IGF-2) gene is inactivated

(imprinted). The Beckwith-Wiedemann syndrome is an

overgrowth syndrome characterized by organomegaly,

macroglossia (enlargement of the tongue), hemihyper-

trophy (muscular or osseous hypertrophy of one side

of the body or face), renal abnormalities, and enlarged

adrenal cells.2

The syndrome, which reflects changes

in the imprinting of IGF-2 genes located on chromo-

some 11, is also associated with increased risk of Wilms

tumor, hepatoblastoma, rhabdomyosarcoma, and adre-

nal cortical carcinoma.

Diagnosis and Treatment

Because many childhood cancers are curable, early

detection is imperative. In addition, there are several

types of cancers for which less therapy is indicated than

for more advanced disease. Therefore, early detection

often minimizes the amount and duration of treatment

required for cure.

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154 UNIT 1 Cell and Tissue Function

Unfortunately, there are no early warning signs or

screening tests for cancer in children.70,71 Prolonged fever,

persistent lymphadenopathy, unexplained weight loss,

growing masses (especially in association with weight

loss), and abnormalities of central nervous system func-

tion should be viewed as warning signs of cancer in chil-

dren. Because these signs and symptoms of cancer are

often similar to those of common childhood diseases,

they are frequently attributed to other causes.

Diagnosis of childhood cancers involves many of the

same methods that are used in adults. Histologic exami-

nation is usually an essential part of the diagnostic pro-

cedure. Accurate disease staging is especially beneficial

in childhood cancers, in which the potential benefits of

treatment must be carefully weighed against potential

long-term treatment effects.

The treatment of childhood cancers is complex and

continuously evolving. It usually involves appropri-

ate multidisciplinary and multimodal therapy, as well

as the evaluation for recurrent disease and late effects

of the disease and therapies used in its treatment. The

treatment program should include specialized teams of

health care providers.72

Several modalities are frequently used in the treat-

ment of childhood cancer, with chemotherapy being the

most widely used, followed in order of use by surgery,

radiotherapy, and biologic agent therapy. Chemotherapy

is more widely used in treatment of children with cancer

than in adults because children better tolerate the acute

adverse effects, and in general, pediatric tumors are

more responsive to chemotherapy than adult cancers.

Radiation therapy is generally used sparingly in children

because they are more vulnerable to the late adverse

effects. As with care of adults, adequate pain manage-

ment is critical.

Survivors of Childhood Cancers

With improvement in treatment methods, the number

of children who survive childhood cancer is continuing

to increase.73–76 As a result of cancer treatment, almost

80% of children and adolescents with a diagnosis of

cancer become long-term survivors.72 Unfortunately,

radiation and chemotherapy may produce late sequelae,

such as impaired growth, neurologic dysfunction, hor-

monal dysfunction, cardiomyopathy, pulmonary fibro-

sis, and risk for second malignancies (Table 7-5). There

is a special risk of second cancers in children with the

retinoblastoma gene. Thus, one of the growing chal-

lenges is providing appropriate health care to survivors

of childhood and adolescent cancers.

Children reaching adulthood after cancer therapy

may have reduced physical stature because of the ther-

apy they received, particularly radiation, which retards

the growth of normal tissues along with cancer tissue.

The younger the age and the higher the radiation dose, the

greater the deviation from normal growth.

There is concern about the effect that CNS radiation

has on cognition and hormones that are controlled by

the hypothalamic-pituitary axis. Children younger than

6 years of age at the time of radiation and those receiving

TABLE 7-5 Long-term Effects of Childhood Cancer Treatment

System Cancer Treatment Risk

Cardiac Radiation, chemotherapy (anthracyclines) Cardiomyopathy, conduction abnormalities,

valve damage, pericarditis, left ventricular

dysfunction

Pulmonary Radiation, chemotherapy (carmustine,

lomustine, bleomycin)

Reduction in lung volume with exercise

intolerance, restrictive lung disease

Renal/urological Radiation, chemotherapy (platinums,

ifbsfamide and cyclophosphamide,

cyclosporine A), nephrectomy

Kidney hypertrophy or atrophy, renal

insufficiency or failure, hydronephrosis

Endocrine Radiation, chemotherapy (alkylating agents) Pituitary, thyroid, and adrenal dysfunction;

growth failure; ovarian and testicular failure;

delayed secondary sex characteristics;

obesity; infertility

Central nervous system Radiation, intrathecal (injected into

subarachnoid or subdural space)

chemotherapy

Learning disabilities

Musculoskeletal and bone Radiation, chemotherapy (alkylating agents,

topoisomerase II inhibitors), amputation

Disordored limb growth, disorders of

ambulation and limb use

Hematologic and lymphatic

systems

Radiation, chemotherapy (anthracyclines,

alkylating agents, vinca alkyloids,

antimetabolites), and corticosteroid

medications

Leukemia

Lymphoma

Second malignancy Radiation, chemotherapy (alkylating agents,

epipodophylotoxins)

Solid tumors, leukemia, lymphoma, brain

tumors

Information from: Schmidt D, Anderson L, Bingen K, et al. Late effects in adult survivors of childhood cancer:

Considerations for the general practitioner. WMJ. 2010;109(2):98–107; and Henderson TO, Friedman DL, Meadows

AT. Childhood cancer survivors: Transition to adult-focused risk-based care. Pediatrics. 2010;126:127–136.

0002114681.INDD 154 7/7/2014 9:56:03 AM

Chap ter 7 Neoplasia 155

the highest radiation doses are most likely to have

subsequent cognitive difficulties.73–75 Growth hormone

deficiency in adults is associated with increased preva-

lence of dyslipidemia, insulin resistance, and cardiovas-

cular mortality.77 Moderate doses of cranial radiation

therapy (CRT) are also associated with obesity, particu-

larly in female patients. For many years, whole-brain

radiation or cranial radiation was the primary method

of preventing CNS relapse in children with acute lym-

phocytic leukemia. Because of cognitive dysfunction

associated with CRT, other methods of CNS prophy-

laxis are now being used.

Delayed sexual maturation in both boys and girls

can result from chemotherapy with alkylating agents or

from irradiation of the gonads. Cranial irradiation may

result in premature menarche in girls, with subsequent

early closure of the epiphyses and a reduction in final

growth achieved. Data related to fertility and health

of the offspring of childhood cancer survivors is just

becoming available.

Vital organs such as the heart and lungs may be

affected by cancer treatment. Children who received

anthracyclines (i.e., doxorubicin or daunorubicin) may

be at risk for developing cardiomyopathy and conges-

tive heart failure. Pulmonary irradiation may cause lung

dysfunction and restrictive lung disease. Drugs such as

bleomycin, methotrexate, and busulfan also can cause

lung disease.

REVIEW EXERCISES

1. A 30-year-old woman has experienced heavy

menstrual bleeding and is told she has a uterine

tumor called a leiomyoma. She is worried she has

cancer.

A. What is the difference between a leiomyoma and

leiomyosarcoma?

B. How would you go about explaining the

difference to her?

2. Among the characteristics of cancer cells are the

lack of cell differentiation, impaired cell–cell

adhesion, and loss of anchorage dependence.

A. Explain how each of these characteristics

contributes to the usefulness of the Pap smear as

a screening test for cervical cancer.

3. A 12-year-old boy is seen in the pediatric cancer

clinic with osteosarcoma. His medical history

reveals that his father had been successfully treated

for retinoblastoma as an infant.

A. Relate the genetics of the retinoblastoma

(RB) gene and “two hit” hypothesis to the

development of osteosarcoma in this boy.

4. A 48-year-old man presents at his health care

clinic with complaints of leg weakness. He is a

heavy smoker and has had a productive cough for

years. Subsequent diagnostic tests reveal he has a

small cell lung cancer with brain metastasis. His

proposed plan of treatment includes chemotherapy

and radiation therapy.

A. What is the probable cause of the leg weakness

and is it related to the lung cancer?

B. Relate this man’s smoking history to the

development of lung cancer.

C. Explain the mechanism of cancer metastasis.

D. Explain the mechanisms whereby chemotherapy

and irradiation are able to destroy cancer cells

while having less or no effect on normal cells.

5. A 17-year-old girl is seen by a guidance counselor

at her high school because of problems in keeping

up with assignments in her math and science

courses. She tells the counselor that she had

leukemia when she was 2 years old and was given

radiation treatment to her brain. She confides that

she has always had more trouble with learning than

her classmates and thinks it might be due to the

radiation. She also relates that she is shorter than

her classmates and this has been bothering her.

A. Explain the relationship between cranial

radiation therapy and decreased cognitive

function and short stature.

B. What other neuroendocrine problems might this

girl have as a result of the radiation treatment?