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Marcel Dekker, Inc. New York
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Basel
FUNDAMENTALS OF
ONCOLOGY
FOURTH EDITION, REVISED AND EXPANDED
Henry C. Pitot
McArdle Laboratory for Cancer Research
University of Wisconsin Medical School
Madison, Wisconsin
With a Contribution by
Daniel D. Loeb
McArdle Laboratory for Cancer Research
University of Wisconsin Medical School
Madison, Wisconsin
Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.
ISBN: 0-8247-0650-1
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To Mary
Julie and Beth
Anita
Jeanne
Cathy
Henry
Michelle
Lisa
Patrice
Mom, Dad, and Big Anita
I am a cancer cell.
Of my earliest ancestry no evidence remains.
When the earth’s first creatures stirred the
ancient seas, when the Pharaohs wrought
the pyramids, when the medieval scribes
laboriously recorded their philosophies, I was
there. The ingenious Virchow, who recognized
my stamp, marshaled the forces of science
against me. Malicious, relentless, insidious I
am, full of destruction, ripe for carnage, yet in
my enduring frame I carry the secret of life.
Study me, and you will bring into the light of

day precious urns of wisdom long buried in
the tomb of ignorance. For you I shall tell a
wondrous tale of the beginning of things that
are and are to be. Study me, know me, and
you will hold the world in fief. Neglect me, and
as surely as the fingers of the dawn grasp first
the temples of the East, I will strike you dead.
v
Preface to the Fourth Edition
It has been some 15 years since the third edition of this text was published. The original purpose
of the book was to replace notes in a course, “Introduction to Experimental Oncology,” which
has been given in the Department of Oncology at the University of Wisconsin–Madison for more
than 25 years. The course has evolved from being primarily directed towards graduate students
to one that includes more than 80% undergraduates, usually juniors and seniors in various sci-
ences. The course has always been offered for two credits, but with the enormous increase in
information in the field of oncology, it will likely be increased to three credits.
In this revision, four new chapters have been added and the other chapters significantly
expanded. The genetics of neoplasia is now covered in two chapters, as is the stage of progres-
sion. Discussion of carcinogenesis in humans has also been expanded to two full chapters in
addition to the chapter on the evaluation of risk of carcinogenic environmental agents. Finally,
another chapter has been added in the area of host–tumor relationships, covering endocrine and
stromal responses. Of necessity, the glossary has been somewhat expanded, as have the number
of figures and tables. (We are very grateful to the authors and publishers who gave us permission
to incorporate their work in this text. In addition, for instructors wishing to use this text in
classes in oncology, we have developed an extended series of slide illustrations that may be
found at our web site: Click on “Courses” and scroll
down to “Oncology 401.”)
As in the third edition, I have again cited references in the text. Although some of the third
edition’s references have been retained because of their usefulness, a larger number of new refer-
ences have been added since the last edition than were in the third edition itself. Still, this funda-

mental text is not exhaustive in its treatment of the literature (although some students may think
it is), but it presents reasonably representative samples of each of the topics and areas covered.
My sincere apologies are extended to any colleagues whose work was not specifically cited. If
there are other subjects in the field of oncology that should be covered in a basic text such as
this, I would certainly appreciate receiving such information.
I would like to express my sincere appreciation to my colleague Dr. Daniel Loeb, who,
after some arm-twisting, agreed to write the vast majority of Chapter 4, on viruses and cancer.
This field has become much more complex since the third edition, and I felt need of an expert in
the area. I am also grateful to other colleagues who read and made critical comments on the
manuscript, especially Drs. Norman Drinkwater, the late Dr. James Miller, and Bill Sugden of
the McArdle Laboratory; Dr. Lynn Allen-Hoffmann of the Department of Pathology at the Uni-
vi Preface to the Fourth Edition
versity of Wisconsin–Madison; my son, Dr. Henry C. Pitot IV, and his colleagues in the Depart-
ment of Oncology of the Mayo Clinic, Rochester, Minnesota; and Dr. Peter Duesberg of the
University of California, Berkeley. In particular, I express my deepest thanks to Dr. Ilse Riegel
for her invaluable help in editing and correcting the manuscript throughout all its stages. Our
special appreciation and thanks go to Mrs. Mary Jo Markham and Mrs. Kristen Adler for their
patient, enduring, and expert transcribing and typing of the manuscript and indexing the entire
book. A special thanks is given to my colleague Dr. Yi-hua Xu, who aided us immensely in
developing and digitizing figures.
Perhaps the greatest debt of gratitude in developing the fourth edition of this text is owed
my wife and our children, who have endured the constant “working on the book” that kept me
from spending more time with them. As the final corrections were being made to the text, our
oldest daughter was diagnosed with metastatic breast cancer. Several years ago she gave me a
small blackboard on which was written, “A teacher affects eternity; they can never tell where
their influence stops.” I can only hope and pray that these words are prophetic and that this text
may play a small role in the ultimate control of cancer.
Henry C. Pitot
vii
Preface to the Third Edition

Since the manuscript for the second edition of this text was completed, information regarding
the science of oncology, in the human and the experimental animal as well as in the plant king-
dom, has expanded in an astounding manner. The prediction of an earlier reviewer that this test
would require constant updating has proven true many times over. Furthermore, for the sake of
our students—the prime motivation for writing this text—a reasonably succinct survey of the
field of experimental oncology and its applications to humans continues to be of primary impor-
tance in our basic instructional program.
In this revision of the text, a number of new chapters have been added. A new Chapter 5,
concerned with hereditary factors in the causation of cancer, has been included. The discussion
of human cancer has been divided into two chapters: Chapter 9 is concerned with the direct
known causes and Chapter 10 with the scientific and societal considerations of human cancer.
Finally, the chapter on the biochemistry of neoplasia (Chapter 10 in the second edition) has also
been divided into two chapters, one dealing with the biochemistry of the neoplastic transforma-
tion in vivo (Chapter 12), the other with the biochemistry and molecular biology of the neoplas-
tic transformation in vitro (Chapter 13).
At the suggestion of one of the reviewers of the second edition, we have cited the refer-
ences in the text for the convenience of the reader. This has the disadvantage of a somewhat
more formal presentation, but we hope that it will be useful to the student who wishes to study
the field of experimental oncology in greater depth. This fundamental text is not exhaustive in its
treatment of the literature but presents representative examples of each of the topics and areas
covered. My apologies to any colleagues whose work was not specifically cited. If anyone feels
strongly that additional references are needed, please communicate your suggestions to the
author.
Again I would like to express my sincere appreciation to my colleagues at the McArdle
Laboratory who read and made critical comments on the manuscript, especially Doctors Nor-
man Drinkwater, Janet Mertz, James and Elizabeth Miller, Gerald C. Mueller, Van R Potter, Rex
Risser, Jeffrey Ross, Bill Sugden, and Howard M. Temin, and to Dr. Paul Carbone of the
viii Preface to the Third Edition
Wisconsin Clinical Cancer Center. In particular I would like to express my thanks to Dr. Ilse
Riegel and Bette Sheehan for their invaluable help in editing and correcting the manuscript

throughout all of its stages and my appreciation to Mary Jo Markham and Karen Denk for their
patient and expert transcribing and typing. Finally, my thanks are extended to Carol Dizack for
her expert artistry in drawing the figures added to this edition of the text and to Terrill P. Stewart
for his photographic skills.
Henry C. Pitot
ix
Preface to the Second Edition
In the few short years since the publication of the first edition of this text, a number of signifi-
cant facts have been uncovered in the science of oncology. Many of these findings have been
incorporated into the teaching of our basic course in experimental oncology through additional
notes and lectures, and the revision of this text became a clear necessity.
In this revision we have maintained the same format as in the first edition but have altered
the contents of most of the chapters, adding both figures and tables. In addition, the pathogenesis
of cancer and the natural history of cancer in vivo have been divided into Chapters 6 and 8 re-
spectively. Finally, Chapter 13 has been added to present some aspects of the basis for cancer
chemotherapy. Although this chapter is not an attempt to discuss the various treatment modali-
ties used in cancer therapy, the subject matter does introduce the student to the experimental
basis for chemotherapy and also briefly discusses the methodology and rationale for the chemi-
cal therapies used today.
We have continued to utilize illustrative slides to supplement the lectures and text. Lec-
tures by several of my clinical colleagues on the diagnosis, therapy, and psychosocial aspects of
cancer continue to be significant components of our course.
Again I would like to express my sincere appreciation to a number of my colleagues at the
McArdle Laboratory, especially Doctors Roswell Boutwell, James and Elizabeth Miller, Van R.
Potter, Rex Risser, Bill Sugden, and Howard Temin, as well as others who have read and made
critical comments on the manuscript. In particular, I would like to express my thanks to Dr. Ilse
Riegel and Ms. Bette Sheehan for their invaluable help in collating, editing, and correcting the
manuscript throughout all of its stages, and my appreciation to Ms. Karen Denk for her patient
and expert typing. Finally, my thanks are again extended to Mr. John L. Shane for his continued
artistic aid in drawing the new figures for this text.

Henry C. Pitot
x
Preface to the First Edition
The sensationalism and publicity directed toward the investigation, diagnosis, and treatment of
cancer as a disease in the human being have reached a dramatic level in the United States. In part
this is a result of the decision by the political administration of Richard M. Nixon to make the
conquest of cancer a major goal of his office. Although it is not my desire nor is this the place to
consider the ramifications of this decision and the subsequent difficulties that have arisen in its
implementation, it is clear that cancer research received a “shot in the arm” of international pro-
portions by political decisions at the beginning of this decade. The U.S. public, who have sup-
ported the National Cancer Plan through their taxes, have been repeatedly apprised of its
existence and progress since its inception in 1970. Much has been written on the subject of can-
cer in the scientific literature as a direct result of the financial impetus given to research in oncol-
ogy over the past decade. A variety of books and monographs on the general subject of cancer in
humans and animals for both the scientist and the layman have appeared during this same
period.
This text is not meant to be a popular account of the cancer problem. More than two de-
cades ago, the Department of Oncology, which comprises the McArdle Laboratory for Cancer
Research of the University of Wisconsin at Madison, initiated a graduate course in oncology.
This course consisted of a series of lectures covering a variety of aspects of experimental oncol-
ogy including chemical and biological carcinogenesis, host-tumor relationships, the natural his-
tory of cancer, and the biochemistry of cancer. In addition, within a few years of its inception,
several lectures were given on the diagnosis and therapy of cancer in the human patient. The
course was and always has been oriented primarily toward the graduate student in oncology
rather than specifically for the medical student or postgraduate physician. In part as a result of
the increased interest in cancer research by both graduate and undergraduate students and as part
of the mechanism of self-evaluation of teaching programs, several years ago the McArdle Labo-
ratory expanded its original course into three separate courses in experimental oncology. The
first course in this series is open to all students and fellows at the University of Wisconsin, and
the notes given to the students comprise the basis for this short text on the fundamentals of

oncology.
During the course period, these notes are supplemented by several sessions in which slides
are shown depicting a variety of examples both from human and animal neoplasms to illustrate
many of the specific points presented in the text. A list of these slides can be made available to
anyone interested, on written request to the author. In addition, at the end of the course several
Preface to the First Edition xi
lectures are given to the students on the diagnosis and therapy of human cancer as well as on the
psychosocial aspects and bioethics of human oncology.
It is the hope of those of us in the McArdle Laboratory involved in the teaching of this
course that we can instill in our students the basic concepts of the science of this disease and
thereby interest them in learning more about the mechanisms of neoplastic disease and the use
of such knowledge toward the ultimate control of cancer in the human patient.
In particular, I would like to express my appreciation to my colleagues in the McArdle
Laboratory, especially Drs. James and Elizabeth Miller, Van R. Potter, Ilse L. Riegel, Bill Sug-
den, Howard M. Temin, and others who have read and made critical comments on this manu-
script at its earlier stages. My thanks also go to the several outside reviewers of the manuscript
whose suggestions resulted in an increased number of illustrations and the addition of the epi-
logue, and to Mr. John L. Shane, whose artistic skill produced the drawings of the figures.
Henry C. Pitot
xiii
Contents
Preface to the Fourth Edition v
Preface to the Third Edition vii
Preface to the Second Edition ix
Preface to the First Edition x
1. Cancer: Yesterday and Today 1
2. The Language of Oncology 27
3. The Etiology of Cancer: Chemical and Physical Agents 41
4. The Etiology of Cancer as an Infectious Disease 107

5. The Etiology of Cancer: Germline Genetic Factors 133
6. The Etiology of Cancer: Somatic Cell Genetics 189
7. The Natural History of Neoplastic Development: Initiation and Promotion 223
8. The Natural History of Neoplastic Development: Host Effects During
Carcinogenesis 273
9. The Natural History of Neoplastic Development: Progression 335
10. Consequences of the Stage of Progression 373
11. Environmental Factors in the Etiology of Human Cancer—Chemical Agents
and Processes 423
12. Environmental Factors in the Etiology of Human Cancer—Physical and
Biological Agents 491
13. Evaluation of Toxic and Carcinogenic Environmental Agents: Scientific and
Societal Considerations and Their Role in Cancer Prevention 547
14. The Natural History of the Development of Neoplasia in Cultured Cells
and Tissues 593
15. The Cellular and Molecular Biology of Neoplasia in Vivo 643
16. Cellular and Molecular Biology of Neoplastic Transformation in Vitro 697
17. The Host–Tumor Relationship—Nutritional Factors and Biomarkers 743
18. The Host–Tumor Relationship—Endocrine Factors and Stromal Reaction 783
19. Immunobiology of the Host–Tumor Relationship 817
20. Some Basic and Applied Principles of Cancer Chemotherapy 901
Epilogue: Cancer: Tomorrow and the Future 947
Glossary 951
Index 963
1
1
Cancer: Yesterday and Today
History tells us that disease has been a part of the living process on this planet for eons. In fact, it
is clear that life as we know it, by its very nature, requires that disease processes exist. It is

natural, then, that a thinking, reasoning human organism should concern itself with disease and
its effects on individuals as well as populations. Diseases that are self-limiting and readily con-
trolled by natural life processes present no major problem for humans, animals, or plants. Our
concern is with diseases that are potentially life-threatening or morbidly debilitating.
Since the dawn of civilization there have always been a few disease entities of great con-
cern to humans. As evidenced by biblical writings, the disease most feared and abhorred by the
population of the western civilized world at that time was leprosy. Later, in the Middle Ages and
the Renaissance in Europe, the dreaded disease was the bubonic plague, or “black death.” Dur-
ing the last century, a major killer associated with considerable human suffering was the “white
death,” or tuberculosis. With the effective antimicrobial therapy developed in the twentieth cen-
tury, infectious diseases now play a lesser role in “developed cultures” than in the past, although
in relatively underdeveloped countries of the Third World, infectious diseases such as malaria
and hookworm are still of paramount importance and concern. In modern times, however, espe-
cially during the last half of the twentieth century, the most feared disease is cancer. One of the
more succinct descriptions emphasizing the impact of this fear was presented at a symposium on
cancer in 1936 by Glenn Frank, President of the University of Wisconsin.
But not all these tragic consequences together are the worst evil wrought by cancer. For
every-
body
that is
killed
by the
fact
of cancer, multiplied thousands of
minds
are
unnerved
by the
fear
of cancer. What cancer, as an unsolved mystery, does to the morale of millions who may

never know its ravages is incalculable. This is an incidence of cancer that cannot be reached
by the physician’s medicaments, the surgeon’s knife, or any organized advice against panic.
Nothing but the actual conquest of cancer itself will remove this sword that today hangs over
every head.*
Although the United States was not the first country to proclaim the conquest of cancer as
a national effort, the government’s financial backing of cancer research during the 1970s pro-
vided the greatest single impetus in the history of this country to the scientific search for knowl-
edge and understanding to control and eliminate cancer. In 1970, a special panel of consultants
called together by the U.S. Senate submitted a “Report of the National Board of Consultants on
the Conquest of Cancer” (1971); at that time, this was perhaps the best summary of the status of
*Quoted from the welcome by President Glenn Frank to participants in “A Symposium on Cancer,” Uni-
versity of Wisconsin School of Medicine, Madison, Wisconsin, September 7–9, 1936. University of Wis-
consin Press, Madison, 1938.
2 Chapter 1
cancer as a disease and of cancer research in this country. This report showed that cancer is the
primary health concern of the people of the United States. In several polls, approximately two-
thirds of those questioned admitted fearing cancer more than any other disease. Of 200 million
Americans living in 1970, some 50 million were destined to develop cancer, and approximately
34 million would die of the disease. According to the American Cancer Society (1993), about 85
million Americans living in 1993 will eventually develop cancer. About one-half of all deaths
due to cancer occur prior to the age of 65, and cancer causes more deaths among children aged 1
to 14 than any other disease. About 20% of all deaths in this country are caused by cancer; it is
second only to cardiovascular disease as the greatest killer of our population.
The committee of consultants that was convened in 1970 pointed out that in 1969 the bud-
get of this country, on a per capita basis, provided $410 for national defense; $125 for the war in
Vietnam; $19 for the space program; $19 for foreign aid; but only 89 cents for cancer research.
During the same year, deaths from cancer were eight times the number of lives lost in all 6 years
of the Vietnam War up to that time, 5
¹⁄₂
times the number of people killed in automobile acci-

dents in that year, and greater than the number of American servicemen killed in battle in all 4
years of World War II. Hodgson and Rice (1995) have indicated that the yearly cost to this na-
tion’s economy because of cancer is nearly $73 billion, with the cost of medical care of cancer
patients being more than $18 billion per year. These figures do not take into account the costs in
suffering, mental anguish, and psychosocial trauma that haunt both cancer patients and their
families.
We do not yet understand the basic nature of cancer; however, we know a great deal more
about the disease today than we did 50 years ago. In 1930, the medical cure rate for those af-
flicted with cancer was about one in five. Today, approximately two in five are cured, and the
panel’s findings and subsequent studies have demonstrated that this could be improved to almost
one in two simply by better application of the knowledge that exists today. In fact, in 1982, the
National Cancer Institute’s SEER Program (see below) presented data to indicate that nearly
50% of white patients with cancer, excluding nonmelanoma skin cancer and carcinoma in situ
(see Chapter 9), will survive to die of other diseases. Certain specific types of cancers that were
100% fatal prior to 1960 can now be cured in as many as 70% of the cases (see Chapter 16).
CANCER: YESTERDAY
In all likelihood, all multicellular organisms are afflicted or have the potential to be afflicted
with the disease we call cancer. Paleopathologists have shown that cancerous lesions occurred in
dinosaur bones long before the advent of
Homo sapiens
(Bett, 1957). In view of the numerous
reports of spontaneous and induced cancers in plants and animals, vertebrates as well as inverte-
brates, it is probable that cancer has been with us for much of the evolutionary period of life on
earth. Ancient Egyptians knew of the existence of cancer in humans, and in one papyrus, the
Edwin Smith papyrus, a glyph clearly refers to a clinical cancer of the breast (Fig. 1.1). In addi-
tion, autopsies of mummies have shown the existence of bone tumors and the probability of
other cancerous processes.
By the era of Hippocrates in the fourth century
B
.

C
., many types of cancers were clinically
recognized and described, such as cancer of the stomach or uterus. Hippocrates felt that in many
instances little could be done for the cancer patient and, more importantly, that it was to this
disease that one of his cardinal rules,
Primum non nocere
(first do no harm), applied. Hippo-
crates coined the term
carcinoma
, which referred to tumors that spread and destroyed the pa-
tient. This was in contrast to the group he termed
carcinos
, which included benign tumors,
hemorrhoids, and other chronic ulcerations. He proposed that cancer was a disease of an excess
Cancer: Yesterday and Today 3
of black bile, which was manufactured by both the spleen and stomach but not the liver. This
concept of the causation of cancer remained the predominant theory for almost 2000 years.
Hippocrates as well as other physicians during the next two millennia tended not to treat ulcer-
ated or deep-seated cancers, because “if treated, the patients die quickly; but if not treated, they
hold out for a long time.”
Almost 600 years later, Galen distinguished “tumors according to nature,” such as en-
largement of the breast with normal female maturation; “tumors exceeding nature,” which in-
cluded the bony proliferation occurring during the reuniting of a fracture; and “tumors contrary
to nature,” which today we may define as benign or malignant tumors (Chapter 2). This distinc-
tion, proposed some 1800 years ago, is still reasonably correct. Galen also suggested the similar-
ity in gross outline between a crab and the disease we know today as cancer.
The concepts of Hippocrates and Galen dominated medical practice during the Middle
Ages. With the advent of the Renaissance and during the seventeenth and eighteenth centuries,
the “black bile” theory of the causation of cancer was disputed by a number of physicians (in-
cluding Ramazzini), and the surgery of neoplasms became somewhat more extensive. Several

treatises on mastectomies for breast cancer, including dissection of regional lymph nodes, were
written. Ramazzini attributed the high occurrence of breast cancer among nuns to the celibate
life of these women. This was the first example of occupation-associated cancer, an observation
that has withstood the test of time. In addition, in 1761, John Hill of London suggested that
tobacco in the form of snuff was a cause of nasal tumors or polyps.
It was not until the nineteenth century, however, that physicians and scientists began to
study cancer systematically and intensively. The anatomist Bichat extended the principles of Ga-
len, which had reigned supreme for more than 1600 years. Bichat (1821) described the anatomy
of many neoplasms in the human and suggested that cancer was an “accidental formation” of
tissue built up in the same manner as any other portion of the organism. Seventeen years later,
Johannes Müller (1838) extended the findings of Bichat through the use of the microscope. Al-
though the cellular theory was just being formulated during this period, Müller independently
demonstrated that cancer tissue was made up of cells. At the time little was known about cell
Figure 1.1
The hieroglyphic symbol for the word
tumor
, referring to the surgical treatment of cancer o
f
the breast as described in the Edwin Smith papyrus, dated earlier than 1600
B
.
C
. The reader is referred to
Breasted’s translation (1930) of the document for further information.
4 Chapter 1
division, and Pasteur and others had not yet demonstrated the doctrine
Omnis cellula e cellula
,
that is, “Every cell from a cell.”
A student of Müller, Rudolf Virchow (1863), dramatically extended our descriptive

knowledge of cancer; although he proposed a number of theories that were later disproved, he
was the first to point out a relation between chronic irritation and some cancers.
Early in this rapid advance of our knowledge of cancer, two possible pathogenetic bases
for the origin of cancer were proposed—that normal cells are converted to cancer cells, or that
cancer cells exist from embryonic life but do not express themselves until later in the organism’s
existence. Müller (1838) supported the latter concept, as did Julius Cohnheim, who in 1877 ad-
vanced the “embryonal rest theory” of cancer. On the other hand, many pathologists, such as
Laënnec, argued that a number of cancers resemble the normal tissues of the body and that
“there are as many varieties of these as there are kinds of normal tissues.” Laënnec did, however,
recognize that a number of tumors bore no direct resemblance to any normal tissue found in the
adult organism. Laënnec’s studies supported the cellular theory (see above) and actually added
to it the words
ejusdem naturae
, which, combined with the original statement, may be translated
as “Every cell arises from a cell
of the same kind
” (cf. Shimkin, 1977).
In 1829, Recamier published
Recherches du Cancer
, in which he specifically introduced
the term
metastases
and described clearly how cancer spreads by this method (Chapter 2). An-
other major advance was the demonstration by Waldeyer (1872) that metastases were the result
of cell emboli. In addition, he was able to show that cells from primary cancers infiltrated blood
and lymphatic vessels.
After major advances had been made in the knowledge of the biology of human cancer,
experimental oncology emerged as a separate area of study. The first example of the successful
transplantation of an experimental tumor was reported by Novinsky (1877), who succeeded in
transplanting a nasal cancer from an adult dog to several puppies and then maintained the cancer

in vivo for at least one or two generations. By 1900, some animal neoplasms had been carried
through many generations of grafts with few alterations in the microscopic appearance of the
cancers.
Students interested in a more detailed and readable discussion of some aspects of the his-
tory of the science of oncology are referred to Shimkin’s
Contrary to Nature
(1977), which
shows by extensive illustration and relatively complete documentation the development of on-
cology from ancient times to many of the major discoveries through 1975.
During the nineteenth century, many hypotheses of the origin and development of cancer
were presented. In general, these hypotheses may be categorized as follows:
1. The irritation hypothesis
2. The embryonal hypothesis
3. The parasitic hypothesis
The first hypothesis encompassed what little was known at the time of the effects of chem-
ical agents, mostly crude, and of radiation in the genesis of cancer. The relation of some ulcer-
ations, both internal and external, to cancer appeared to support and strengthen this hypothesis.
Cancers arising in old scars and those occurring after both acute and chronic injury were also
cited in support of the irritation hypothesis.
Perhaps the most common example in support of the embryonal hypothesis is the nevus, or
common mole of the skin. In most instances nevi are present from birth, and a very small per-
centage of such structures become cancerous. Many cancers that appear to resemble embryonic
tissue, such as the teratoma (Chapter 2) occurring in the adult, also support this hypothesis.
Prior to the nineteenth century, Hippocrates’ “black bile” theory of cancer causation
served to inhibit any concepts of an infectious etiology of cancer. However, in view of the rapid
Cancer: Yesterday and Today 5
advances in our understanding of infectious disease during the last century by Pasteur and nu-
merous others, physicians and scientists have searched for an infectious origin of cancer during
the last 100 years. Several reports appeared at the end of the nineteenth century, including that of
Doven, who described a bacterium,

Micrococcus neoformans
, which he isolated from several
neoplasms and believed to be the cause of all types of cancer (cf. Bett, 1957; Oberling, 1952).
As it turned out, this organism was merely a common staphylococcus. It was not until the twen-
tieth century that the infectious hypothesis became scientifically sound. Even with the dawn of
this century, more than 50 years were to pass before proper scientific recognition was given to
the parasitic hypothesis (see Chapter 4).
CANCER: TODAY
Today the demographics and statistics of cancer in the human race have become topics of great
popular concern and study. An interesting prelude to the extensive statistical and epidemiologic
investigations (Chapters 11 and 12) of human cancer was the book
The Mortality from Cancer
Throughout the World
, by F. L. Hoffman (1915), which in part comprised a report to the Pruden-
tial Insurance Company of America on the “statistics” of cancer and its application to the life
insurance industry. A number of the points raised by Hoffman in relation to the increase in can-
cer incidence seen in the world at that time, the mortality from cancer in different occupations,
and the geographical consideration of cancer statistics have all proved to be major factors in our
understanding of cancer as a disease in the human race today.
Incidence
The incidence of cancer in the human population may be defined as the rate of diagnosis of the
disease in the human population. This can be expressed in a variety of ways, as demonstrated by
several tables and figures in this chapter. For the student it is important to gain a clear under-
standing of the distinction between cancer incidence rates and cancer mortality rates, the latter
being discussed later in this chapter. Cancer survival rates are related to cancer mortality rates by
the success or failure of the therapy of the disease.
Table 1.1 lists the ten most common cancers in the world (excepting nonmelanotic skin
cancer) in 1985 on the basis of estimates by the International Agency for Research on Cancer
(Parkin et al., 1993; Pisani et al., 1993). The basis of these studies was an investigation of cancer
incidence and mortality patterns in 23 geographical areas of the world, as depicted in Figure 1.2.

In this worldwide survey, the crude cancer incidence rates (see below) for all (or most) of the
countries in a given area were estimated and then the weighted average was calculated, where the
weights are the populations of the individual countries as determined in 1985. Wherever possible,
incidence rates were derived from population-based cancer registries or other reliable sources
(Parkin et al., 1993). In countries in which no incidence data were available but mortality rates
from cancer could be obtained, estimates of incidence were determined with a set of conversion
factors (Parkin et al., 1993). Similarly, for countries or regions in which valid cause-specific mor-
tality information is not available, mortality rates have been estimated from incidence data. For a
given cancer site, mortality is empirically related to incidence by the following relationship:
M = I [k – S
i
]
where S
i
is the relative survival at year i of follow-up, while k is a constant depending on i. M
and I are the mortality and incidence rates respectively (Pisani et al., 1993). Muir (1990) has also
6 Chapter 1
Table 1.1
The Most Frequent Cancers Worldwide, 1985
Males
Females
Both Sexes
Number
a
a
In thousands of cases.
Number
a
Number
a

New Cases Deaths
New Cases Deaths
New Cases Deaths
1. Lung
677 600 1. Breast
719 308 1. Lung
896 785
2. Stomach
472 384 2. Cervix
437 203 2. Stomach
755 620
3. Colon/rectum 331 191 3. Colon/rectum
347 203 3. Breast
719 308
4. Prostate
270 166 4. Stomach
283 236 4. Colon/rectum 678
394
5. Mouth/pharynx 291 149 5. Lung
162 106 5. Cervix
437 203
6. Liver
195 187 6. Ovary
143 96 6. Mouth/pharynx 413
272
7. Esophagus
214 212 7. Mouth/pharynx 140
55 7. Lymphoma
302 287
8. Bladder

182 82 8. Corpus uteri 219 185
8. Liver
315 312
9. Lymphoma
181 109 9. Esophagus
107 100 9. Esophagus
316 188
10. Leukemia
121 99 10. Lymphoma
135 79 10. Prostate
291 149
11. Larynx
121 62 11. —
— — 11. Bladder
243 113
12. —
— — 12. —
— — 12. Leukemia
217 178
Adapted from Pisani et al., 1993.
Cancer: Yesterday and Today 7
1 Eastern Africa
2 Middle Africa
3 Northern Africa
4 Southern Africa
5 Western Africa
6 Caribbean
7 Central America
8 South America (Temperate)
9 South America (Tropical)

10 Northern America
11 China
12 Japan
13 Other Eastern Asia
14 South-Eastern Asia
15 South-Central Asia
16 Western Asia
17 Eastern Europe
18 Northern Europe
19 Southern Europe
20 Western Europe
21 Australia/New Zealand
22 Melanesia
23 Micronesia/Polynesia
10
6
9
8
7
18
18
18
20
19
17
15
13
11
16
3

5
2
1
4
12
13
14
22
23
21
Figure 1.2
Map showing the 24 world areas studied by the International Agenc
y for Research on Cancer (IARC) to obtain the data of Table 1.
1.
(Adapted from Pisani et al., 1999, with permission of authors and publisher
.)
8 Chapter 1
indicated that the expected increase in cancer in the world each year is approximately 6.4 mil-
lion new cases. This number is almost equally divided between Third World countries and those
that are more developed.
In the United States, the most accurate cancer incidence rates are those of the National
Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, now covering
12 geographic areas with population-based registries. These include the metropolitan areas of
Atlanta, Detroit, New Orleans, Seattle–Puget Sound, and Oakland–San Francisco as well as the
states of Connecticut, Iowa, New Jersey, New Mexico, Utah, and Hawaii and the Common-
wealth of Puerto Rico. Several more population areas are due to be added to the SEER program
in the near future. This program involves a sample of approximately 10% of the U.S. population
and thus has a base analogous to that of the world incidence study seen in Table 1.1. While this
is a very large sample of the U.S. population and has been shown to reflect trends in cancer
statistics for the entire country, some race-, sex-, and site-specific differences in the magnitude

of trends and levels of mortality occur in the SEER data as compared with those from the entire
U.S. population (Frey et al., 1992).
On the basis of previous data from the SEER program, the American Cancer Society esti-
mated that, in the United States in 1993, approximately 1.17 million new cases of cancer, ex-
cluding nonmelanoma skin cancer, would occur, essentially equally divided between males and
females. For a child born in 1985, the probability at birth of developing cancer (excluding non-
melanotic skin cancer) at some time during its life span is about 33%. The probability for that
individual of eventually dying of cancer is about 20% (Centers for Disease Control, 1986). In
general, males have a higher age-specific incidence of cancer than females when all sites com-
bined are considered. Even in the best-controlled epidemiological studies as exemplified by the
SEER program, these data may be incomplete, since some cases of cancer are never diagnosed.
The failure to diagnose cancer is related not only to the lack of contact of an individual with a
physician but also to the frequent lack of interaction of a patient with the best methods of cancer
diagnosis, found only in modern hospitals. Earlier studies (cf. Bauer et al., 1973) demonstrated
that the likelihood of discovering an undiagnosed or incorrectly diagnosed case of cancer in-
creases dramatically as the number of hospital admissions increases. Thus, as medical care for
the U.S. population improves in efficiency and availability, it is hoped that the patient who seeks
medical advice and has undiagnosed cancer will become a relative rarity in our society.
Except for cancer of the skin—the most common and, in most cases, the most curable of
human cancers—75% of all cancers in humans in the United States occur in only ten anatomic
sites: colon and rectum, breast, lung and bronchus, prostate, uterus, lymph organs, bladder,
stomach, blood, and pancreas. In the U.S. male, one of the most common sites is the lung, ac-
counting for 17% of such cancers in 1993 (American Cancer Society, 1993). A similarly com-
mon site of cancer incidence in the U.S. male is the prostate, which accounts for 27% of the 10
most common cancers. In the U.S. female, cancer of the breast accounts for 32% of these can-
cers; in both males and females in the United States, the incidence of cancer of the colon and
rectum is approximately 13% of all cancers.
The age-specific incidence of cancer at the four most frequent sites for males and females
as reported by the most recent SEER publication (Miller et al., 1992) is seen in Figure 1.3. In the
male, the incidence of these cancers increases dramatically after age 40 and continues through-

out life except for cancer of the lung and bronchus. The reason for this decline in men over age
80 has been speculated to be the result of either (1) the relatively low incidence of smoking in
this group as young individuals, since smoking became most popular after the 1930s, or (2) the
lethality of the disease and its greater incidence in the 60- to 80-year-old age range. The former
explanation does not coincide with the study by Harris (1983), who reported that, in a represen-
tative sample of the U.S. population, maximum exposure to cigarette smoking probably oc-
Cancer: Yesterday and Today 9
Figure 1.3A Age-specific cancer incidence in U.S. males of all races based on incidence rates
(1986–1988). Data obtained from the SEER study. (Miller et al., 1992.)
Figure 1.3B Age-specific cancer incidence in U.S. females of all races based on incidence rates
(1986–1988). Data obtained from the SEER study. (Miller et al., 1992.)
10 Chapter 1
curred among men now in their seventh and eighth decades. In that study it was also postulated
that the peak exposure to smoking probably occurred in women presently in their fifth and sixth
decades; this would also conform with the decreasing incidence of lung cancer in females over
age 70. Today, deaths from lung cancer exceed those from breast cancer in women (see below).
The reason for the slight decrease in breast cancer and in cancer of the uterus at older ages is not
readily apparent.
On a worldwide basis, the incidence of various types of potentially fatal cancers is some-
what different from that in the United States, as noted in Table 1.1, when compared with Figure
1.3. As in the United States, the total cancer burden in the world includes cancer of the lung and
cancer of the breast as exhibiting the highest incidences in males and females, respectively.
When all areas were considered together for both sexes, the most frequent cancer worldwide in
1980 was cancer of the lung (Table 1.1). Stomach cancer remains the most common cancer in
some parts of the world, including Japan, China, other east Asian countries, and the former So-
viet Union, and incidence rates still remain relatively high in both Europe and Latin America.
Nevertheless, stomach cancer is declining in frequency almost everywhere in the world, with the
estimated number of cases decreasing by 1.9% since the previous estimates in 1975. This is es-
pecially noteworthy since a population increase of 9.4% occurred during the same period. Un-
like stomach cancer, lung cancer has been increasing in incidence between 1975 and 1980, by

11.8% in males and 16% in females worldwide. Thus, lung cancer is the most common fatal
cancer in the human race as we approach the twenty-first century. Another striking finding from
these data is that cancers of the breast and cervix, both limited to females, have a higher inci-
dence than the two most common cancers in males—lung and stomach. Although it is possible
that the increasing incidence of breast cancer worldwide may be the result of changes in the way
the estimates are calculated (Parkin et al., 1993), cancer of the uterine cervix is also increasing,
especially in underdeveloped nations, in which methods for early diagnosis are not as well de-
veloped as in the “developed” areas of the world.
In the United States, the most dramatic changes in the incidence of cancer also reflect
those seen in the world. This is exemplified in Figure 1.4, showing the change in incidence of
specific cancer types during the period 1950–1989. As seen from the figure, the most striking
differences are again seen in cancer of the lung and bronchus, with the percentage change being
greatest in females during this period. Among other cancers that increased dramatically during
this period, non-Hodgkin’s lymphomas, melanomas, and cancers of the kidney, testes, and pros-
tate increased by more than 100%. The incidence of cancer of the breast, while increasing mark-
edly during this period, has not seen a dramatic change like those indicated above. Not listed in
the figure is the recent finding of the dramatic increases seen in the incidence of brain cancers in
the period 1973–1985. The most dramatic increases during this period were noted for persons
aged 75 to 79, 80 to 84, and 85 years and older, where the relative increases were 187%, 394%,
and 501% respectively (Greig et al., 1990).
There are even more striking differences in the incidences of specific cancers in certain
areas and countries of the world. The rates for a variety of cancers in the highest- and lowest-
incidence areas are shown in Table 1.2. The incidence rates of some cancers may vary as much
as 300-fold in different areas of the world. Such variability led some epidemiologists more than
two decades ago, when this information first became available, to suggest that most cancers in
humans are the result of environmental factors, since inherent genetic and related factors could
not explain such large differences in incidence of specific cancers in various parts of the world
(cf. Wynder and Gori, 1977).
Changes in the incidence of cancer may be due either to an absolute change in the inci-
dence—resulting, for example, from some alteration in the environment or to better diagnostic

methods—which give rise to an apparent increase in the incidence of a specific cancer. One ex-