Testicular Cancer (The Biology of Cancer)

Testicular
Cancer
Cancer Genetics
Causes of Cancer
Diagnosis and Treatment of Cancer
Leukemia
Myeloma
Prevention of Cancer
Skin Cancer
Stages of Cancer Development
Testicular Cancer
Testicular
Cancer
Kathleen M. Verville, Ph.D.

Consulting Editor,
Donna Bozzone, Ph.D.,
Professor of Biology
Saint Michael’s College
THE Biology of Cancer: TESTICULAR cancer
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Library of Congress Cataloging-in-Publication Data

Verville, Kathleen.
Testicular cancer / Kathleen Verville ; consulting editor, Donna M. Bozzone.
p. cm. — (Biology of cancer)
Includes bibliographical references and index.
ISBN-13: 978-1-60413-166-6 (alk. paper)
ISBN-10: 1-60413-166-7 (alk. paper)
1. Testis—Cancer—Popular works. I. Title. II. Series.
RC280.T4V84 2009
616.99'463—dc22
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Contents
♦
Foreword 6
1 Young Men 11
2 Detection of Testicular Cancer 25
3 Diagnosis of Testicular Cancer 36
4 The Testes 47
5 Germ Cell Cancers 65
6 Non-Germ Cell Testicular Cancers 82
7 Treatment of Testicular Cancer? 87
8 What Causes Testicular Cancer? 110
9 Challenges and Questions for the Future 120
Notes 126
Glossary 128
Bibliography 136
Further Resources 147
Index 149
About the Author 155
About the Consulting Editor 156
Foreword
♦
A pproximately 1,500 people die each day of cancer in the United

States. Worldwide, more than 8 million new cases are diagnosed
each year. In affluent, developed nations such as the United States,
around 1 out of 3 people will develop cancer in his or her lifetime.
As deaths from infection and malnutrition become less prevalent in
developing areas of the world, people live longer and cancer incidence
increases to become a leading cause of mortality. Clearly, few people
are left untouched by this disease, because of either their own illness or
that of loved ones. This situation leaves us with many questions: What
causes cancer? Can we prevent it? Is there a cure?
Cancer did not originate in the modern world. Evidence of humans
afflicted with cancer dates from ancient times. Examinations of bones
from skeletons that are more than 3,000 years old reveal structures that
appear to be tumors. Records from ancient Egypt, written more than
4,000 years ago, describe breast cancers. Possible cases of bone tumors
have been observed in Egyptian mummies that are more than 5,000 years
old. It is even possible that our species’ ancestors developed cancer. In
1932 Louis Leakey discovered a jawbone from either Australopithecus or
Homo erectus, which possessed what appeared to be a tumor. Cancer
specialists examined the jawbone and suggested that the tumor was due
to Burkitt’s lymphoma, a type of cancer that affects the immune system.

Foreword
It is likely that cancer has been a concern for the human lineage for at
least a million years.
Human beings have been searching for ways to treat and cure
cancer since ancient times, but cancer is becoming an even greater
problem today. Because life expectancy increased dramatically in the
twentieth century because of public health successes such as improve-
ments in our ability to prevent and fight infectious disease, more people
live long enough to develop cancer. Children and young adults can
develop cancer, but the chance of developing the disease increases as
a person ages. Now that so many people live longer, cancer incidence
has increased dramatically in the population. As a consequence, the
prevalence of cancer came to the forefront as a public health concern
by the middle of the twentieth century. In 1971 President Richard Nixon
signed the National Cancer Act and thus declared “war” on cancer. The
National Cancer Act brought cancer research to the forefront and pro-
vided funding and a mandate to spur research to the National Cancer
Institute. During the years since that action, research laboratories have
made significant progress toward understanding cancer. Surprisingly,
the most dramatic insights came from learning how normal cells func-
tion, and by comparing that to what goes wrong in cancer cells.
Many people think of cancer as a single disease, but it actually
comprises more than 100 different disorders in normal cell and tissue
function. Nevertheless, all cancers have one feature in common: All are
diseases of uncontrolled cell division. Under normal circumstances,
the body regulates the production of new cells very precisely. In
cancer cells, particular defects in deoxyribonucleic acid, or DNA,
lead to breakdowns in the cell communication and growth control
normal in healthy cells. Having escaped these controls, cancer cells
can become invasive and spread to other parts of the body. As a
testicular Cancer
consequence, normal tissue and organ functions may be seriously

disrupted. Ultimately cancer can be fatal.
Even though cancer is a serious disease, modern research has
provided many reasons to feel hopeful about the future of cancer treat-
ment and prevention. First, scientists have learned a great deal about
the specific genes involved in cancer. This information paves the way for
improved early detection, such as identifying individuals with a genetic
predisposition to cancer and monitoring their health to ensure the earli-
est possible detection. Second, knowledge of both the specific genes
involved in cancer and the proteins made by cancer cells has made it
possible to develop very specific and effective treatments for certain
cancers. For example, childhood leukemia, once almost certainly fatal,
now can be treated successfully in the great majority of cases. Similarly,
improved understanding of cancer cell proteins led to the development
of new anticancer drugs such as Herceptin, which is used to treat certain
types of breast tumors. Third, many cancers are preventable. In fact, it is
likely that more than 50 percent of cancers would never occur if people
avoided smoking, overexposure to sun, a high-fat diet, and a sedentary
lifestyle. People have tremendous power to reduce their chances of
developing cancer by making good health and lifestyle decisions. Even
if treatments become perfect, prevention is still preferable to avoid the
anxiety of a diagnosis and the potential pain of treatment.
The books in the Biology of Cancer series reveal information about
the causes of the disease; the DNA changes that result in tumor forma-
tion; ways to prevent, detect, and treat cancer; and detailed accounts of
specific types of cancers that occur in particular tissues or organs. Books
in this series describe what happens to cells as they lose growth control
and how specific cancers affect the body. The Biology of Cancer also
provides insights into the studies undertaken, the research experiments
foreword
done, and the scientists involved in the development of the present state
of knowledge of this disease. In this way, readers get to see beyond “the
facts” and understand more about the process of biomedical research.
Finally, the books in the Biology of Cancer series provide information to
help readers make healthy choices that can reduce the risk of cancer.
Cancer research is at a very exciting crossroads, affording scientists
the challenge of scientific problem solving as well as the opportunity
to engage in work that is likely to directly benefit people’s health and
well-being. I hope that the books in this series will help readers learn
about cancer. Even more, I hope that these books will capture your inter-
est and awaken your curiosity about cancer so that you ask questions
for which scientists presently have no answers. Perhaps some of your
questions will inspire you to follow your own path of discovery. If so, I
look forward to your joining the community of scientists; after all, there
is still a lot of work to be done.
Donna M. Bozzone, Ph.D.

Professor of Biology
Saint Michael’s College
Colchester, Vermont
1
Young Men
KEY POINTS
♦ Testicular cancer can occur at any age, but most cases occur in men
in their late teens through thirties.
♦ Most testicular cancers form from cells in the testes known as germ
cells. These cells normally produce sperm.
♦ Although testicular cancer is a relatively rare cancer, the number of

cases has increased in recent years.
♦ The causes of testicular cancer are not known, but some risk factors
for the disease have been recognized.
♦ Advances in the treatment of testicular cancer have helped make

testicular cancer one of the most curable types of cancer.
11
12 testicular Cancer
A Typical Testicular Cancer Patient
In 1999, third baseman Mike Lowell, 24 years old and recently married,
had just been traded to the Florida Marlins from the New York Yankees.
During the routine physical examination required of major-league base-
ball players before the start of the season, Lowell’s doctor discovered
a problem: One of Lowell’s testicles felt as if it contained a tumor. The
lump had not caused him pain, so Lowell had not noticed it. Because
most testicular tumors in men Lowell’s age are malignant tumors (can-
cer), the next step was to remove the entire testis, or testicle, in a type
of surgery called an orchiectomy. To do this, his doctor made a small,
shallow incision in Lowell’s lower abdomen, just above the crease of his
leg. The surgeon then pulled the testicle out from the scrotum, the sac
in which the testicles sit, and cut the connections between the testicle
and the body. The testicle was then sent to a laboratory, where another
physician, a pathologist, studied thin slices of it through a microscope.
As expected, the look and arrangement of the tumor cells showed that
the tumor was malignant; Mike Lowell had testicular cancer.
Once the pathologist determined that the tumor was cancerous, the
next step was to determine the type of testicular cancer. This was im-
portant because the type of cancer would determine which treatments
the doctors would use and how likely Lowell would be to survive. The
two main categories of testicular cancer are “germ cell” and “non-germ
cell.” The pathologist determined that Lowell had a type of testicular
cancer called seminoma, which belongs to the germ cell category. In a
testicular germ cell cancer, a germ cell in the testis—a cell that nor-
mally would have divided to produce sperm—acquires cancer-causing
mutations or alterations in its genetic material and divides to produce
Young Men 13
Figure 1.1 Mike Lowell, shown here playing for the

Florida Marlins, survived a type of testicular cancer called a
seminoma. (© CNRI/Photo Researchers, Inc.)
a malignant tumor. Germ cell cancers are the most common type of
testicular cancer.
Because seminomas are sensitive to radiation, Lowell subsequently
underwent three weeks of radiation therapy. Radiation therapy exposes
cells to a focused beam of high-energy radiation. For testicular cancer it
is used to kill any cancer cells that might have metastasized to lymph
nodes. The radiation therapy made him nauseous and tired, yet his ill-
ness did not keep him away from baseball for long. By late May of the
1999 season, Lowell was a starting player for the Florida Marlins. In rec-
ognition of the courage and perseverance he had shown in overcoming
the adversity he had faced, Lowell received baseball’s Tony Conigliaro
Award. In the years since his cancer diagnosis and treatment, Lowell has
been recognized for his undeniable talent with a Rawlings Gold Glove
and multiple All-Star appearances, and he and his wife Bertica have had
two children.
Mike Lowell is not alone in his struggles with testicular cancer. Al-
though testicular cancer is an uncommon form of cancer, the National
Cancer Institute (NCI) estimated that in 2008 there would be 8,090 men
in the United States diagnosed with the disease. For reasons that are
not yet understood, the annual number of cases of testicular germ cell
cancer worldwide has more than doubled since the 1950s.
There are several aspects of Lowell’s case that make him a typical
testicular cancer patient. Although cancer of any type is a rare diagnosis
for a 24-year-old, Lowell’s testicular cancer diagnosis came at an age
that is typical for the disease. The NCI reports that for the years 2000 to
2004, only 2.7 percent of all cancers occurred in the 20 to 34 age group.
However, the numbers are quite different for testicular cancer. Of all of
the testicular cancer cases reported, 46.2 percent occurred in individu-
als who were 20 to 34 years old. An additional 30.3 percent occurred in
Young Men 15
patients between the ages of 35 and 44 years. Of all the types of cancer
diagnosed in men between the ages of 15 and 34, testicular cancer is the
most common. Testicular cancer can occur at any age, but is most often
a disease of young men—some still in high school, others in college,
many just beginning their careers and families.
Lowell’s case is also typical because he survived and was able to return
to a physically demanding career. The NCI reports that 380 testicular cancer
deaths are expected in 2008. While this number is hardly negligible—thanks
to important advances in medicine and the remarkable (but still poorly
understood) sensitivity of testicular cancer cells to chemotherapy and, at
times, radiation—the survival rate for testicular cancer is far better than for
most other types of cancer. For some forms of testicular cancer, such as
Lowell’s, the survival rate is now greater than 99 percent.
It is also not unusual for patients who have survived testicular cancer
to conceive children after treatment, which often involves the removal
of a testicle as well as radiation treatment that could damage the sperm-
producing ability of the remaining testicle. This outcome is particularly
important for patients with testicular cancer, because the disease tends
to occur before many men have completed—or, in many cases, even
contemplated—having a family. Sometimes the man’s sperm is collected
and stored (banked) before the potentially damaging therapy begins.
Detection of Testicular Cancer
Sometimes, as in Lowell’s case, testicular cancer is detected during a

routine physical exam. Physicians might discover that a testicle either
has a lump in it or is enlarged. However, many physicians do not
routinely check male patients for abnormalities of the testicles during
routine checkups.
In other cases, the patient may discover a problem. He might notice

a lump or a firm area in the testicle, or he may notice that the testicle is
enlarged or swollen. Other indications are a feeling of heaviness in the
scrotum or pain, tenderness, discomfort, or a dull ache in the testis or
scrotum. However, many patients do not experience discomfort.
Lumps and other changes in the testicles are most easily noticed
if a man is in the habit of routinely examining himself. A person who
notices a problem should see a physician immediately. Sometimes a
person is embarrassed to talk about his testicles or afraid of the diag-
nosis and therefore delays seeking assistance. The American Urological
Association reports that the average time span between when a man
detects a problem and when it is brought to the attention of a physician
is five months. This is problematic because testicular cancer can quickly
spread to other parts of the body. Although the cancer can often be
effectively treated even after it has spread, the treatment needed at that
point may be more intensive and more extensive.
If an abnormal testicle is not noticed or is ignored, the patient may
notice symptoms that result from the metastasis of the cancer from the
testicle to other areas of the body. If the cancer spreads to certain lymph
nodes of the abdomen, the patient may experience pain in the back or
the abdomen. Figure skater and Olympic gold medalist Scott Hamilton
was diagnosed with testicular cancer in his late thirties. He had pain
in his mid-abdomen that was so severe it prevented him from standing
up straight. Hamilton had a type of germ cell cancer classified as a
nonseminoma that had metastasized to lymph nodes in his abdomen.
Despite the abdominal metastases, Hamilton was successfully treated
with surgeries (one to remove the affected testicle and one to remove
abdominal lymph nodes) and chemotherapy. Sean Kimerling, an Emmy
Award winning sports anchorman and pregame announcer for the New
Young Men 17
York Mets, lost his battle with nonseminoma testicular cancer at the age
of 37—just one month following his diagnosis; he had suffered severe
back pain from the metastases that he had mistakenly attributed to a
physical injury.
Once a problem comes to the attention of a physician, the next step
taken is often an ultrasound exam. Ultrasound technology uses sound
waves to visualize the testis, and can help to rule out other causes as
well as evaluate a tumor. Blood tests are also performed to determine
whether alpha-fetoprotein molecules are present in the blood. Some
types of testicular cancer cells can form these and other molecules.
Because they can indicate the presence in the body of certain types of
cancer cells, these molecules are called tumor markers.
The testicle can be easily accessed in its position outside the main
body cavity, so one might expect that the next step would be a biopsy in
which a small sample of the tumor would be taken by inserting a needle
through the scrotum. However, most testicular tumors in pubescent
males are malignant and obtaining a tissue sample this way risks spread-
ing the cancer cells, so the next step is usually the removal of the entire
testicle, an orchiectomy. After this procedure, the removed testicle is
examined in a pathology laboratory.
The pathologist who evaluates the testicle examines the way the
tumor appears to the naked eye and the way the cells and tissues of
the tumor look under a microscope. The tumor marker information
from the blood tests is also considered. The microscopic analysis and
tumor marker information allows the pathologist to determine whether
the tumor is malignant and, if it is, what type of testicular cancer is
present. Although most testicular tumors are germ cell tumors, there
are other types to consider. And while germ cell tumors are categorized
as seminomas (seminomatous germ cell tumors) or nonseminomas
(nonseminomatous germ cell tumors), these two categories actually en-

compass several different types of tumors. Sometimes germ cell tumors
contain several types of cancer cells and are referred to as mixed germ
cell tumors (MGCTs). Identifying the exact type of cancer is important
because the different types of cancer cells can spread in different ways
within the body and respond differently to the available treatments. For
example, seminomas typically respond well to radiation therapy, but
nonseminomas do not.
Treatment of Testicular Cancer
Removal of the testicle, which is necessary in order to confirm cancer

and determine cancer type, is also an important step in the treatment of
the cancer. If all of the cancer cells are confined to a tumor in a testicle,
then removal of the testicle eliminates the cancer. In cases where the
cancer seems confined to the testis, a physician may choose to avoid
any follow-up treatment and instead carry out surveillance, carefully
and regularly monitoring the patient for any signs of recurrence of the
disease. Evidence has shown, however, that between 15 and 20 percent
of these surveillance-only patients experience a recurrence of their can-
cer (relapse), so the decision to use surveillance instead of treatment
must be carefully weighed.
Most testicular cancer patients are not good candidates for sur-
veillance. Instead, they undergo additional treatment following the
orchiectomy. The cancer treatments that may be performed after the
orchiectomy include (a) radiation therapy (the use of radiation to kill
cancer cells); (b) chemotherapy (the use of chemicals to kill cancer
cells); and (c) additional surgery, often to remove affected lymph nodes
from the back of the abdominal area.
Young Men 19
At the time of the initial diagnosis, as well as during and after treat-
ment, the physician must look for signs of metastasis. This can be done
by looking for enlarged lymph nodes or for tumors in different parts of the
body using imaging tools such as X-rays and computed tomography
(CT) scans, and with removal and laboratory examination (biopsy) of
some lymph nodes. Also, if a patient’s cancer cells are the type that
produce tumor markers, the physician can determine that cancer cells
are still present in the body if the markers are detected in the blood.
Risk Factors
It is not yet known what causes testicular cancer, but studies are being
conducted that consider a variety of possible factors, including genetic,
as in an individual’s DNA, as well as environmental sources. Among the
environmental factors considered are those to which an individual was
exposed while in the womb. Certain circumstances increase the risk
of developing testicular cancer; those circumstances are knows as risk
factors.
It is known that cryptorchidism, or hidden testis, is a risk factor
for testicular cancer. A person who was born with a testicle that did
not descend from the abdomen, where it first developed, to the scro-
tum—a movement that usually happens when a male fetus is still in the
uterus—has a greater risk of developing testicular cancer than someone
who was born with both testicles properly descended into the scrotum.
Evidence suggests that this risk exists even if surgery is performed to
properly position the testis after birth.
There are several other known risk factors: Someone who has had
one cancerous testicle removed has a greater than normal chance of
developing cancer in his other testicle; a man whose brother or father
♦ Spotligh t on Cance r S cientists

L aw r e n c e E i n h o r n , M.D.
L awrence Einhorn, M.D., has played an important role in making testicular

cancer, as he describes it, “a model for a curable neoplasm [tumor].”1
The son of a physician, Einhorn knew by the time he was in high school
that he wanted to become a doctor. At that time, he certainly could not
have known that his clinical research would help to turn testicular cancer
from a disease that killed most patients to one that had a survival rate
greater than 90 percent.
Einhorn did his undergraduate work at Indiana University and went to
medical school at the University of Iowa. Following his residency, he did
more specialized training at Indiana University Medical Center and the
M.D. Anderson Cancer Center in Houston, Texas. In 1973, he joined the
faculty at Indiana University (IU). His work helped to turn the university
into a premier center for testicular cancer research and treatment.
Dr. Einhorn’s success at IU began shortly after he joined the faculty.
Cisplatin, a chemical that had been formed as an unintentional by-product
during an experiment done by Barnett Rosenberg at Michigan State Univer-
sity in the 1960s, had been found to have the ability to kill cancer cells. Dr.
Einhorn decided to investigate the effectiveness of cisplatin for testicular
cancer patients in a type of research study called a clinical trial. For this
trial, he modified an existing chemotherapy treatment by adding cisplatin.
The survival of the trial subjects was compared to that of the patients whose
treatment did not include cisplatin. The results showed cisplatin to be ex-
tremely effective. Cisplatin quickly became a standard drug used in combi-
nation with others to treat testicular cancer. Over the years, Einhorn and his
Young Men 21
colleagues have modified

the chemotherapy regime,
making it even more ef-
fective and less toxic to
patients.
Beginning in 1996,
Dr. Einhorn, along with
Dr. Craig Nichols, led the
challenging treatment of
cyclist Lance Armstrong,
whose testicular cancer
had spread to his lungs and
brain. Given the type and
extent of Armstrong’s can-
cer, his prognosis was poor,
but following extensive and Figure 1.2 Lance Armstrong, above, initially
individualized treatment by had a poor diagnosis for his testicular cancer
the Indiana group, Arm- because it had metastasized into his lungs and
brain. Treatments developed by Dr. Lawrence
strong recovered. His seven Einhorn not only saved Armstrong’s life but
Tour de France titles were avoided diminishing his lung capacity in the
chemotherapy process, which allowed Arm-
won after his treatment for
strong to go on to win seven Tour de France
testicular cancer. races after his treatment. (© AP Images)
Einhorn is now a dis-
tinguished professor of medicine and the Lance Armstrong Foundation
Chair in Oncology at Indiana University. He continues to successfully treat
(continues)
S pot l igh t on Canc er Sc ientists

(continued)
testicular cancer patients and conduct research on the disease. Some of

his recent work involves treating patients, whose testicular cancer has
responded poorly to existing treatments with very high doses of chemo-
therapy agents followed by infusion of their own blood-making stem cells
to replace those killed during chemotherapy.
had testicular cancer is at increased risk for developing testicular cancer;

and testicular cancer affects men of some ethnicities more than others
and men in some parts of the world more than in others.
Of course, many men who have a risk factor for testicular cancer
do not develop the disease, and many of those who develop testicular
cancer do not fall into one of the groups that has a higher than normal
risk. There is much to be learned about the causes of testicular cancer
and the reasons that some individuals are more likely than others to
develop the disease.
Important Questions
Despite the many successes in the treatment of testicular cancer, many

scientific and medical questions remain. Perhaps the most pressing
medical problem is that, despite remarkable advances in the treatment
of testicular cancer, some patients’ cancers still do not respond to
standard chemotherapy. Researchers want to find ways to help all
testicular cancer patients survive.
Young Men 23
Another problem is that some of the treatments used are harmful to

healthy cells of the body and may therefore cause health problems later
in a patient’s life. While this is a problem faced in the treatment of all
cancers, it is of particular concern for testicular cancer patients, because
they are generally quite young at the time of treatment. Scientists want to
find ways to reduce the toxicity of the treatments without compromising
the excellent success rate.
Epidemiologists and other disease researchers want to understand
more fully the causes of testicular cancer. They certainly want to know
why the annual number of testicular cases has doubled since the 1950s.
Once the causes are known, then there is a chance that testicular cancer
can be prevented.
What occurs at the cellular level to cause testicular cancer? Re-
searchers want to know much more about what events happen to the
DNA and other molecules in testis cells to cause them to grow and form
malignant tumors. They also want to increase their understanding of
the unique structure, function, and behavior of the various types of
testicular cancer cells.
SUMMARY
The incidence of testicular cancer has increased in recent decades;

currently, it affects approximately 8,000 males in the United States
each year. Unlike most cancers, it occurs most commonly in young
men, usually those in their late teens, twenties, and thirties. It is the
most common type of cancer in men between the ages of 15 and 34.
Most testicular cancers are germ cell cancers, meaning that they affect
cells from the testes that would divide to produce sperm. The causes of
testicular cancer are not known, but there are risk factors, such as being
born with an undescended testicle. As a result of scientific and medical

advances in recent decades, especially the discovery of the sensitivity of
testicular cancer cells to the chemotherapeutic agent cisplatin, testicular
cancer—which once killed a high percentage of its patients—has one of
the highest survival rates of all cancers.
2
Detection of Testicular Cancer
KEY POINTS
♦ Early detection of testicular cancer is important for increasing sur-

vival and decreasing the treatment needed.
♦ Males are not routinely screened for testicular cancer by their

doctors.
♦ Awareness of the symptoms of testicular cancer and testicular self-

exams can lead to early detection of testicular cancer.
♦ There are many symptoms of testicular cancer. Most commonly,

there is a change in the size, shape, or texture of the testicle. Other
symptoms may be noted in the scrotum or areas of the body far
from the testes. In some cases, breast tissue may become enlarged.
♦ The symptom(s) that are experienced by a particular patient vary

with the type of testicular cancer and the extent and location of its
spread.
25
Jason: Delayed Detection of Testicular Cancer
Jason Struble was an 18-year-old student at Lafayette High School in Mis-

souri. He was enjoying his senior year, looking forward to college, and
playing varsity basketball. During a late-season game, Jason had some
trouble catching his breath; by the next day, his shortness of breath had
worsened. A medical exam that evening had the doctors confused as to
the source of Jason’s symptom until a call to his pediatrician, who sug-
gested they check Jason’s testicles for signs of cancer. It did not take the
medical team long to complete tests that confirmed the pediatrician’s
suspicion. At the time of Jason’s diagnosis, his cancer was advanced; it
had spread from his right testicle to his lungs—the cause of his shortness
of breath—and to his abdomen.
Jason’s doctors were not the first to notice the enlarged testicle. A
few months earlier, Jason had noticed it himself, but he had read that
one testicle could be larger than another. Perhaps because the enlarged
testicle was not painful, perhaps because he was uncomfortable talk-
ing about what he had noticed, or perhaps because he was young and
seemingly healthy, he had not mentioned the abnormality to anyone. His
father tried to understand Jason’s reticence: “I don’t know if it was out of
ignorance or embarrassment or both that he didn’t say anything.”1 Had
Jason recognized his enlarged testicle as a sign of testicular cancer and
appreciated the urgency of rapid diagnosis and treatment, his outcome
most likely would have been different. Twenty-seven months after his
diagnosis, Jason Struble lost his battle with testicular cancer.
Jason’s silence about his changed testicle is not an unusual behavior
in testicular cancer patients. NBC chief legal correspondent Dan Abrams,
a testicular cancer survivor, emphasized this problem in a Today inter-
view, noting that the average time span from when a person notices an
abnormality to diagnosis is six months.2 There are several reasons that
Detection of Testicular Cancer 27
men delay getting a medical opinion. Some hope the problem will go
away with time, some are embarrassed to mention the problem because
it affects a part of the body associated with sexual reproduction, and most
are unaware that they have an early symptom of testicular cancer that
requires fast medical attention. Because it is young men who are at great-
est risk for testicular cancer, it is especially important for them—and also
for those in whom they might confide, such as parents, coaches, friends,
and partners—to be aware of the symptoms of testicular cancer and the
importance of early detection. Jason learned too late, but he urged his
parents to help educate middle school and high school boys about tes-
ticular cancer. They have worked to fulfill his wish through the activities
of the Jason A. Struble Memorial Cancer Fund, Inc.
Detection of Testicular Cancer:

The Roles of the Physician and Patient
It is essential for individuals to check for any testicular abnormality and

to bring it to the attention of a physician. It is not enough to rely on
routine physical exams for initial detection of the problem. Some physi-
cians do not conduct a testicular exam as a regular part of the physical.
Jason’s father addresses this on his organization’s Web site, reporting
that in the six months leading up to the diagnosis, Jason had three physi-
cal exams, none of which included a testicular exam. “During physical
examinations we have all been asked to turn our heads and cough for a
hernia examination, but how many young men have ever been checked
or even told about testicular cancer? At 61 years of age I can say for
myself—never!”3
The American Cancer Society reports that most physicians think that
testicular exams should be a part of a physical. However, they are not
Figure 2.1 Jason Struble, shown here in his varsity basketball

uniform, remained positive throughout his two-year battle with
testicular cancer. His family continues his wish to raise awareness
among young men about the importance of self-screening in the
early detection of testicular cancer. (Courtesy of the Jason A.
Struble Memorial Cancer Fund, Inc.)
considered routine to the same degree as other tests, such as listening to

the heart. Certainly, a physician cannot check for every disease during a
physical. Whether a physician should perform regular testicular exams
is a subject of debate, but there is clear consensus that routine testicular
cancer screening is unnecessary. There is another—and ultimately a
more important—reason not to rely on a physical exam for testicular
cancer detection. Even if all physicians were to routinely conduct tes-
ticular exams, most cases of testicular cancer would be detected earlier
by patient self-examination. Early detection can increase the chance of
survival and may decrease the need for additional treatment, such as
surgery to remove affected lymph nodes from the back of the abdomen,
and the person in the best position to initially suspect a problem is not
the physician but the patient himself.
The patient cannot help himself, however, if he is not knowledge-
able about testicular cancer. Awareness of the typical ages for testicular
cancer, the symptoms of testicular cancer, and the importance of quickly
bringing a symptom to the attention of a physician is crucial. But aware-
ness may not be enough. Monthly testicular self-exams are advocated
by many, including testicular cancer awareness groups and many health
care providers. Even if testicular self-exams are not performed on a regu-
lar basis, occasional exams will familiarize a man with the size, shape,
and feel of his normal testicles, and this increases the chance that an
abnormality will be noticed early.
The Testicular Self-Exam and

the Symptoms It Can Detect
In humans and some other animals, the testicles are suspended outside
of the abdominal cavity in a sac called the scrotum. As a result, early
signs of testicular cancer—such as a lump on a testicle or an abnormal-

ity in its size or texture—can be easily noticed.
The testicular self-exam is best carried out during or following a
warm bath or shower, so that the scrotum is relaxed, which makes
it easier to feel the testicle inside. Each testicle should be examined
individually using both hands. The thumbs should be placed on the
front of the testicle and the index and middle fingers placed behind.
Using slight pressure, the testicle should be gently rolled so all sur-
faces can be felt. If this is done in front of a mirror, any swelling of the
♦ Screenin g for Testicu l a r Cance r
W hy are all males not routinely screened for testicular cancer? The
National Cancer Institute defines screening as checking for a disease
when there are no symptoms present. For testicular cancer, a screen might
involve a physician performing testicular exams, imaging techniques such as
ultrasound, and blood tests to look for proteins the presence or concentration
of which may indicate testicular cancer. At first, this might seem like an
excellent idea, as screening would certainly find cases of testicular cancer.
But there is a downside. For any screening test, a comparison of the positives
(finding disease early) to the negatives (the consequences of thinking there
is disease when there is not) must be made; this is known as an analysis of
the risk-benefit ratio. If the benefits outweigh the risks, screening is used.
If the risks outweigh the benefits, no screening is performed.
In the case of testicular cancer, a large number of people would have
to be screened to catch relatively few cases of cancer. Those few cases
scrotum can also be noted. The exam takes a few minutes to perform
carefully.
What does a normal testicle feel like? The testis is egg-shaped and
firm, and its surface is smooth. The area along the back of each testicle,
however, will not feel smooth. This is where the epididymis, a cord that
carries sperm, can be felt. Testicular size varies among individuals, and
it is normal for one testicle to be larger than the other. A muscle enables
the testicle to be positioned at different locations in the scrotum; at a
warm temperature the testicles will probably be low in the scrotum (far
would be the benefit. But what are the risks of extensive screening? Since
screening tests are not perfectly accurate there would be some false
positive results, meaning that some people would receive a result that
suggests they have cancer when they actually do not. In addition to the
extreme anxiety that a false positive can cause, additional tests would be
required to rule out cancer. The discomfort and possible medical complica-
tions caused by follow-up tests are a negative factor, and these tests also
take a lot of time and money.
The number of people who would experience a false positive and un-
dergo additional testing is considered to be too high compared to the
number of cases of testicular cancer that a physician would detect through
routine screening. Therefore, the risks are thought to outweigh the ben-
efits. The high risk-benefit ratio, coupled with the relative effectiveness
of treatments and the lack of a study showing that screening decreases
mortality, is why the National Cancer Institute and the American Cancer
Society do not recommend testicular cancer screening.
Figure 2.2 The illustration on the left shows a cross section of the male reproductive
system. On the right is an illustration showing the recommended technique for performing a
testicular self-exam.
from the abdomen). It is normal for one testicle to hang slightly lower in
the scrotum than the other.
What testicular cancer symptoms can be detected through a tes-
ticular self-exam? Any lump that can be felt on the testicle, even one as
small as a grain of rice, is suspicious. Such a lump will usually appear
on the side or front of the testicle and will be painless. Any size change
(enlargement or shrinkage) or hardening of the testicle is also suspi-
cious. Changes are generally noticed in relation to a previous exam,
but can also be detected by comparison to the other testicle. The only
exception to this is the rare simultaneous occurrence of cancer in both
testicles.
Other Symptoms of Testicular Cancer
In addition to lumps and size or texture changes that can be noted from
feeling the testicle, other symptoms of testicular cancer include pain or
discomfort in the testicle or the scrotum, a feeling of heaviness in the
scrotum, or sudden collection of blood or other fluid in the scrotum.
Sometimes testicular cancer causes symptoms outside of the tes-
ticle/scrotum. An ache in the groin—the part of the body where the
leg connects to the abdomen—or in the lower part of the abdomen
may also signal testicular cancer. Some forms of testicular cancer cause
breast tissue to become enlarged or tender. In advanced cases, when
the cancer has spread to lymph nodes in the back of the abdomen,
pain—often severe—can be felt in the lower back. If it has spread to the
lungs, the patient can have shortness of breath and chest pain and may
cough up blood.
Symptoms of Testicular Cancer

Vary from Patient to Patient
There are many possible symptoms of testicular cancer, but most cases
of testicular cancer can be noted initially by a change in a testicle or
the area around it. Some testicular cancer patients initially experience
only a single symptom, while others have more than one symptom.
The symptoms experienced vary with the type of testicular cancer
and, if it has spread, with the extent and location(s) of metastasis.
Therefore, any of the symptoms described could indicate testicular
cancer and therefore should quickly be brought to the attention of a
physician.
♦ Testicul ar Probl ems O ther T han Canc er
S ome testicular abnormalities, such as hydroceles, varicoceles, sper-

matoceles, epididymitis, orchitis, and testicular torsion have some
symptoms in common with testicular cancer. Only a medical evaluation can
distinguish testicular cancer from these abnormalities.
A hydrocele is fluid accumulation in a sac that surrounds the testicle.
It causes the scrotum to swell. Common in newborns, it can occur at any
age, and is generally harmless.
A varicocele is an enlargement of the veins that carry blood away
from the testis. This happens because valves in the veins, which help to
prevent blood from backing up as it leaves the testicle, sometimes do not
work perfectly, causing blood to pool and the veins to swell. These swollen
vessels may feel like spaghetti, and can cause discomfort in the testicle or
scrotum. Varicocele develops around puberty in about 15 percent of men.
It is similar to the swollen varicose veins you might notice on an older
person’s leg and is generally harmless.
A spermatocele is a fluid-filled cyst in the epididymis. It is common,
occurring in about 30 percent of men, and generally harmless.
Epididymitis is an inflammation of the epididymis, usually due to
infection. Symptoms can include scrotal pain and swelling, fever, chills,
nausea, painful urination, and a frequent urge to urinate.
Orchitis is an inflammation of the testis due to infection. Symptoms
include testicular pain and swelling, fever, chills, and nausea.
Testicular torsion is a twisting of the testicle in the scrotum, which
crimps the blood supply and other connections in the spermatic cord that
connects the testis to the abdomen. Symptoms include sudden, severe
scrotal pain and scrotal swelling. Urgent medical attention is needed.
SUMM ARY
Early detection of testicular cancer increases the chance of survival and

may decrease the extent to which further treatments, such as surgery to
remove abdominal lymph nodes, are necessary. While testicular cancer
might be found during a routine doctor’s visit, most cases of testicular
cancer are first noticed by the patient. Testicular self-exams and aware-
ness of symptoms can help to detect testicular cancer early. A common
early symptom of testicular cancer is a change in the shape, size, or
texture of a testicle. Other symptoms may include pain or discomfort in
a testicle or the scrotum, fluid accumulation in the scrotum, and pain in
areas such as the groin, the abdomen, the back, and the chest. In some
cases, a patient may experience shortness of breath, cough up blood, or
have enlarged breast tissue. The specific symptoms vary with the type of
testicular cancer and whether, and to where, it has spread.
3
Diagnosis of Testicular Cancer
KEY POINTS
♦ Diagnosis of testicular cancer is a multistep process that involves

ultrasound imaging, blood tests, surgical removal of the testicle, and
analysis of testicular tissue in the laboratory.
♦ Ultrasound is used to determine details of the testicular mass, such

as size, location, and whether it is solid.
♦ Blood tests are performed to look for certain tumor markers that
may be present in some types of testicular cancer.
♦ Testicular tissue removed in surgery is analyzed in the pathology

lab.
Steps to a Diagnosis
Once a physician suspects testicular cancer, the next step is to confirm

the suspicion with a diagnosis. The first step in the diagnosis of testicular
36
Diagnosis of Testicular Cancer 37
cancer is a testicular exam performed by a physician. If the physician

feels a mass in the testicle that could be a tumor, the patient will be asked
to undergo an imaging procedure known as an ultrasound, which can
provide information about the location and composition of the mass. If
the ultrasound shows a tumor inside the testis, the most likely diagnosis
is testicular cancer. Laboratory analysis of the tumor cells, however, is
required for confirmation. While a sample of these cells could theoreti-
cally be pulled into a needle inserted through the scrotum, sampling a
malignant testicular tumor in this way can risk spreading the cancer to
areas where it would not normally spread. The next step, therefore, is
surgical removal of the entire testicle, which is then examined in the lab
to determine the characteristics of the tumor and the cells of which it is
made. (Since most testicular tumors are malignant, there are thankfully
very few cases in which a testicle is removed unnecessarily.) This tumor
analysis is aided by a blood workup, which is performed before surgery
to detect the presence of molecules that are produced in some types of
testicular cancer.
Ultrasound
An ultrasound is a test that uses sound waves to form images of soft

body tissues. The technique is familiar to many people as the method
used to view a fetus in utero, or in the uterus. Ultrasound is relatively
inexpensive and there is no radiation involved.
A small handheld instrument called a transducer produces high
frequency sounds as it passes back and forth over the structures to be
studied, in this case the testis and surrounding tissues in the scrotum. A
gel is applied to the transducer to help make a good connection between
the instrument and the body. When the sound waves hit body structures,
they bounce back, or echo. These echoes are then picked up by the
transducer and sent to a computer, which converts the sounds into im-
ages. Different tissues produce different echoes, and the combination of
these echoes produces a meaningful image. The ultrasound technician
captures the best images, which are then evaluated by a radiologist, a
specialist who analyzes medical images.
A testicular tumor will produce different echoes than the surround-
ing healthy testicular tissue and will therefore stand out against a
background of normal tissue. Many testicular tumors produce weaker
echoes than healthy tissue, and therefore appear lighter than their
surroundings.
In addition to showing the size of the mass, ultrasound allows the as-
sessment of two features that are key to a cancer diagnosis: (1) whether
the mass is within the testis (intratesticular) or outside of it (extratesticu-
lar), and (2) whether it is a mass of cells (solid) or a sac filled with fluid
or semisolid material (cystic). If the mass is extratesticular and cystic,
it is almost always benign (not cancerous). Most extratesticular solid
masses and intratesticular cystic masses are benign, but a testicular
mass that is intratesticular and solid is usually malignant. Therefore, if a
testicular ultrasound shows that a mass is within the testicle and solid,
the next step will almost certainly be removal of the testicle for labora-
tory analysis of the tumor.
Tumor Markers in the Blood
In addition to having an ultrasound to evaluate a testicular mass, the

patient will visit a lab to have blood drawn so it can be analyzed for the
presence of tumor markers. These are molecules produced by certain
cancer cells that can be detected in bodily fluids. Removal of the testicle
Figure 3.1 This colored ultrasound shows a testicular tumor (blue). Ultra-
sound images are made by the varying reflections of high-frequency sound
waves. Cancerous tissue reflects these waves differently than noncancerous
tissue. (© Mehau Kulyk / Photo Researchers, Inc.)
will generally cause the concentration of any tumor marker to decrease,

so this blood work must be done before surgery. Because some testicular
cancers do not produce a tumor marker and tumor marker concentra-
tion may be low in the early stages of testicular cancer, the absence of
a tumor marker does not rule out testicular cancer. Conversely, because
some cells that are not testicular cancer cells can also produce these
molecules, the presence of a testicular cancer tumor marker does not
confirm testicular cancer. Nonetheless, the presence—and concentra-
tion—of one or more of these markers can aid in making a diagnosis
of testicular cancer. The type of tumor marker found, or the absence of
a tumor marker, is also important in determining the type of testicular

cancer (an essential part of the diagnosis). If a tumor marker is found, its
concentration indicates the degree to which the disease has advanced.
Later, tumor marker concentration can also be used to monitor treatment
success. The tumor markers for testicular cancer are alpha-fetoprotein,
human chorionic gonadotropin, and lactate dehydrogenase.
Alpha-Fetoprotein
Alpha-fetoprotein (AFP) is a protein normally produced by an embryo
(the developmental stage that encompasses the first eight weeks of preg-
nancy) and, later, the fetus (the developmental stage after the eighth
week of pregnancy). The protein is first produced by cells of the yolk
sac, a sac attached to the embryo that produces the first blood cells as
well as the cells that will eventually develop into gametes (cells that
unite during sexual reproduction, sperm in males and ova in females).
Later in development, AFP is produced by liver cells of the fetus. Scien-
tists are not sure of the function of AFP in the developing baby. After the
first trimester of pregnancy, the AFP concentration in the fetal blood
begins to decrease, and this decrease continues during the first year of
a child’s life. From the age of about 8 to 12 months through adulthood,
AFP concentrations in the blood are normally low. Like its role in the
developing embryo or fetus, the role of AFP in adults—if there is one—is
unknown.
Many people are familiar with AFP because of its role as a marker
for some birth defects. AFP of developing embryos or fetuses crosses
the placenta and enters the mother’s circulation. An AFP concentration
in the mother’s blood that is too high may indicate a problem with the
development of the spinal cord; a concentration that is too low may
indicate Down syndrome, a chromosome disorder.
Although all individuals have small amounts of AFP in their blood

serum, in some diseases, such as liver disease and some cancers, AFP
concentrations become elevated. Among the few cancers that cause
AFP to rise are some forms of testicular cancer. Testicular cancer can oc-
cur at any age, and so doctors who are working with a testicular cancer
patient who is younger than one year must remember that an elevated
AFP concentration is normal in this age group.
Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) is a protein that is made by
cells of the developing embryo that are known as trophoblasts, and
later by cells that develop from trophoblasts: cytotrophoblasts and
syncytiotrophoblasts. These cells are part of an embryo-associated
membrane known as the chorion, which forms the fetal part of the
placenta. The placenta is the structure made of both fetal and maternal
tissue that allows materials to pass between maternal and fetal blood.
Unlike AFP, the function of hCG is known. hCG interacts with a
mother’s ovaries to prevent a hormone concentration change that would
result in menstruation and loss of the pregnancy. Pregnancy tests are
designed to detect the presence of hCG in a woman’s urine or blood.
hCG is made of two separate chains, or subunits, an alpha subunit
and a beta subunit. The alpha subunit is not unique to hCG, but the
beta subunit only occurs in the molecule hCG. Therefore, to detect hCG,
scientists look for the beta subunit, or ß-hCG.
hCG is not normally found in the blood serum of males. Its concen-
tration can become elevated in certain diseases, including certain types
of testicular cancer. The production of hCG by certain testicular cancers
is one reason why some testicular cancers cause enlargement of breast
tissue, a condition known as gynecomastia.
Figure 3.2 Human chorionic gonadotropin (hCG) is a protein

released by pregnant women and pregnancy tests, such as the
one shown here, use the presence of hCG in the urine or blood
serum to detect pregnancy. The presence of this protein in men
is a sign of disease, often testicular cancer. (© Jim Varney/Photo
Researchers, Inc.)
Lactate Dehydrogenase
Lactate dehydrogenase (LDH) is a protein that is normally made by

most cells of the body. This protein functions as an enzyme, which is a
protein that speeds up a particular chemical reaction. LDH is involved in
the process by which body cells produce energy from foods. Therefore,
the presence of this enzyme in the blood is normal. Its concentration,
however, can be elevated when tissue is damaged (for example follow-
ing a heart attack or in certain diseases, such as liver disease) and in
many types of cancers, including some testicular cancers.
The Orchiectomy and Analysis
Often, one or both testes are surgically removed in order to evaluate

the tissue. The procedure is called a radical inguinal orchiectomy. To
perform an orchiectomy, a small, shallow incision is made in an area
of the lower abdomen known as the inguinal region. This exposes the
spermatic cord, which connects the testicle to important structures in
the abdomen. The testicle is pulled up from the scrotum into the inci-
sion area. The spermatic cord is then tied and cut. The testicle is then
analyzed by a pathologist.
Histology
Testicular tumors are classified by the pathologist largely by gross appear-

ance (what the tumor looks like with the naked eye) and by histology (what
the tumor cells, and the tissue[s] into which those cells are organized, look
like when the tumor is sliced, stained, and viewed under a microscope).
Pieces of a tumor are thinly sliced and placed on a microscope
slide. Because testicular tumors can be made of more than one cell
type, pathologists have to systematically examine tissue from different

areas of the tumor to be sure that it has been thoroughly analyzed. The
slices are stained with a general tissue stain, usually hematoxylin-eosin.
Stains enable the cells—which would not normally stand out from the
clear background of the microscope slide—to pick up color so they
can be seen. In a hematoxylin-eosin stain, the cells are first stained
with a blue dye (hematoxylin) and then with a red dye (eosin). The
two dyes differ chemically, and therefore bind differently to separate
cell parts. For example, the nucleus becomes stained a bluish purple
color by the hematoxylin, while the cytoplasm becomes stained pink
by the eosin. Pathologists are well trained in how normal—and ab-
normal—testicular cells and tissues stained by hematoxylin-eosin look
under a microscope.
As researchers have become aware of specific molecules that are
present in some cell types but absent in others, pathologists have been
able to use a newer histology method—immunohistochemistry—that
uses chemicals that specifically stain, or label, the many copies of a
particular molecule in a cell. Only cells with that particular molecule
are stained, and the stain occurs in the parts of the cell where those
molecules are located. This technique is especially useful for patholo-
gists in evaluating tumors, because cancer cells can often be identified
by the molecules they have (as well as the molecules they lack).
The staining specificity for immunohistochemistry can be achieved
by looking for the molecule in question with a type of molecule known
as an antibody. Antibodies are proteins that normally play a part in the
immune (defense) system by binding to molecules on cells and viruses
that are not normally found in the body, triggering complex reactions
that help to destroy them. The body has many thousands of different
antibodies, and each antibody type is remarkably specific. For example,
an antibody that can bind to a molecule unique to the measles virus will
not be able to bind to a molecule unique to the chicken pox virus. The
immuno in immunohistochemistry refers to antibodies used to probe for
the molecule in question, histo refers to the histology technique, and
chemistry acknowledges the chemical nature of the molecules and their
interactions in the test.
For immunohistochemistry, scientists use lab animals, such as
mice, to produce antibodies that will bind exclusively to the copies of
a specific molecule they want to be able to look for in a cell. Instead of
staining the tissue slices with a stain such as hematoxylin-eosin that will
dye most parts of the cell, the tissue slices will be coated with a solution
containing these antibody molecules. The antibodies will stick to the
tissue only if the tissue contains the appropriate molecule.
The cell molecules may have antibodies attached to them, but
there is no way to know this because the attached antibodies cannot
be seen. Making the antibodies visible can be accomplished in several
ways. In the simplest method, before the antibody is added to the tissue
slices it is modified by attaching (conjugating) an enzyme to it. Once
an antibody-enzyme has been allowed to attach to the cells, the tissue
is treated with a molecule that the enzyme can break down. It is the
breakdown product of this molecule that acts as a dye. As a result, dye
is only deposited on cells near the molecule in question.
SUMMA RY
The diagnosis of testicular cancer is a multistep process. Once a physi-

cian suspects testicular cancer, the next steps involve analyzing the tes-
ticular mass through ultrasound and the blood for tumor markers (AFP,
hCG, and LDH) that are made by some types of testicular cancer cells.
If an ultrasound determines that the mass is solid as well as inside the

testicle, the tumor is mostly likely malignant. Once this is determined,
the next step is removal of the entire testicle and attached spermatic
cord in a surgery known as a radical inguinal orchiectomy. The testicle
is then sent to a pathologist where it is analyzed. These procedures will
not only confirm a testicular cancer diagnosis, but will determine the
type of testicular cancer a patient has.
4
The Testes
KEY POINTS
♦ Testes develop in the fetus, in the abdominal cavity. They later move
into the scrotum.
♦ After movement into the scrotum, the testes retain their connections
to the abdominal cavity through the spermatic cord. Blood, tissue
fluid, and sperm move in tubes through the spermatic cords.
♦ Testes contain many cells, including testosterone-making Leydig

cells, Sertoli cells that assist in sperm production, and cells in the
process of becoming sperm.
♦ Connective tissue covers each testis and divides it into sections that
each contain seminiferous tubules separated by the interstitium.
Leydig cells are found in the interstitium; Sertoli cells and germ cells
are in the seminiferous tubules.
♦ Seminiferous tubules produce sperm in a stepwise process.
47
A Doctor’s Explanation
During a presurgical meeting with a man suspected of having testicular

cancer, the doctor explains that a confirmed diagnosis, as well as deter-
mination of the type of testicular cancer, will require laboratory evalu-
ation of the testicle following orchiectomy. The patient is also advised
about the different types of testicular cancer, either germ cell cancer,
the most common type, or non–germ cell cancer. The latter is formed
when cells that are not germ cells, such as Sertoli and Leydig cells,
develop into cancer cells and form tumors.
The physician also talks with the patient about the possibility that
his cancer has metastasized to parts of his body outside of the testicle.
Most testicular cancers that spread from their site of origin do so by way
of the lymphatic system to lymph nodes, most commonly those that are
located in an area at the back of the abdomen known as the retroperi-
toneum. The physician might also mention that some cases of testicular
cancer spread by way of the circulatory system.
Understanding the anatomy and workings of the testes, as well as the
circulatory and lymphatic systems to which they connect, is essential in
order to grasp the complexities of testicular cancer.
The Testes, the Scrotum, and the Inguinal Canal
The testes are the male reproductive glands, or gonads. They are key
structures in sexual reproduction. These paired, egg-shaped organs
produce spermatozoa, commonly known as sperm. Each of these male
gametes has the ability to fertilize a female gamete (egg cell, ovum) to
create a zygote, the first cell of the offspring. Testes also produce certain
hormones, which are chemicals made by cells that travel through blood
The Testes 49
to affect the function of other cells. The testes are also referred to as male
sex glands. The term gland implies that these organs secrete materials.
Testes are exocrine glands, which means that they secrete materials
(in this case sperm) through a duct to the outside of the body. They are
also endocrine glands, because they secrete materials (hormones)
directly into the bloodstream.
Each testis is suspended by its spermatic cord in the scrotum (scro-
tal sac), a skin-covered sac that lies just below the abdomen and behind
the penis. Each also has a piece of tissue—the gubernaculum—that
connects it to the inside of the scrotum. A male’s scrotum is formed in
utero at the fetal stage from tissues of the lower abdomen. These tissues
expand to form a pocket-like extension of the abdominal cavity, which
becomes the scrotum.
The fetal scrotum is connected to the abdominal cavity by tissues that
are arranged to form two tubelike passageways known as the inguinal
canals. These connections play an essential role in development: The
testes of the fetus develop at the back of the abdominal cavity near the
kidneys, outside of (and behind) a membrane that lines much of the
abdominal cavity, known as the peritoneum. This area is known as the
retroperitoneum. To move from their location in this retroperitoneal
space to the scrotum, the testes must pass through the inguinal canals. The
descent of each testis into the scrotum normally occurs before birth. Each
testis moves from the retroperitoneum, through the abdominal opening
of the inguinal canal (the internal inguinal ring), through the inguinal
canal, and out the scrotal opening of that inguinal canal (the external
inguinal ring) to the scrotum. Connective tissue then closes the inguinal
canal, separating the abdominal cavity from the scrotum.
Although closure of the inguinal canal prevents materials from mov-
ing freely between the abdominal cavity and the scrotum, connections
between the two areas of the body must be maintained. With regard
to the testes, the following connections are necessary: (1) blood must
be able to flow back and forth between the abdominal cavity and the
testes; (2) sperm made in the testes must be able to travel to the ab-
dominal cavity where it enters the urethra, a tube that carries it from
the body during ejaculation; and (3) excess tissue fluid of the testes,
which originates from the fluid part of the blood in the circulatory sys-
tem, must be able to travel to the abdominal cavity on its journey back
to the circulatory system. The connections between the testes and the
abdominal cavity of the body are made by blood vessels, lymph ves-
sels (the tissue fluid-carrying tubes of the lymphatic system), and the
vas deferens, a sperm-carrying duct. These tubes are tethered together
by muscle and connective tissue in a structure known as the spermatic
cord, which carries these tubes through the connective tissue of the
inguinal canal. Nerves also run between the abdomen and the testes
through the spermatic cord. The spermatic cord thus does much more
than suspend the testes in the scrotum: It allows for the testes to connect
to essential structures in the abdominal cavity. The spermatic cord is
also the conduit for testicular cancer cells to move from the testes to the
abdomen and, at times, beyond the abdomen to other body areas.
The Anatomy of the Testis
The surface of the testis (Figure 4.1) is smooth, except for an area known
as the hilus, where the blood vessels, lymph vessels, and sperm-carry-
ing ducts connect. The smooth surface is created largely by the testis’
main covering, the tunica albuginea. This tough, fibrous layer of con-
nective tissue (supportive tissue made primarily of the protein collagen)
contains embedded muscle cells.
The Testes 51
In the area of the hilus, the tunica albuginea penetrates to the

inside of the testis, forming an area rich in connective tissue known as
the mediastinum testis. Strands of connective tissue fan out from the
mediastinum across the testis to the inside of the tunica albuginea.
These provide structural support and divide the inside of the testis
into regions known as lobules. It is estimated that there are about 250
lobules per testis.
To the outside (scrotal side) of the tunica albuginea is another cov-
ering, the tunica vaginalis, a flattened sac with two layers that wrap
around much of the testis. The tunica vaginalis partially covers but does
not penetrate the testis. This closed sac is actually a remnant of a section
of the peritoneum that moves into the scrotum during fetal development.
(Recall that a condition known as hydrocele can cause scrotal swelling.
In hydroceles, it is the tunica vaginalis that fills with fluid.)
Each testis lobule contains one to about four sperm-producing
tubules known as seminiferous tubules. These are separated by the
interstitium, an area of connective tissue with embedded cells: defense
cells, connective-tissue making cells, and hormone-producing Leydig
cells. Testosterone, the predominant hormone made by the Leydig cell,
is required for many aspects of male development (especially during
fetal development and puberty) and function, including sperm produc-
tion by the seminiferous tubules. The seminiferous tubules make up
approximately 70 to 80 percent of the volume of a testis; the interstitium
makes up an estimated 20 to 30 percent of the volume.
The interstitium is an important exchange area of the testis: Here,
fluid and key molecules enter and leave the blood vessels, and excess tis-
sue fluid enters the lymphatic vessels. Exchange is not limited to liquids.
Certain blood cells also have the ability to move from the circulatory
system to the tissue fluid to the lymphatic system in the interstitium.
Figure 4.1
Leydig cells of the interstitium are capable of becoming cancer cells.

Because a Leydig cell is not a germ cell (i.e., it is not a cell that will develop
into a sperm), a Leydig cell cancer is considered a non–germ cell cancer.
Sperm Production in the Testes
Each testis of a male who has gone through puberty has many hun-
dreds (estimates range from 500 to more than 1,000) of U-shaped
seminiferous tubules actively engaged in spermatogenesis, the
The Testes 53
process by which millions of sperm cells are produced each day. The
looped tubules are also coiled; looping and coiling enables more of
these important structures to fit into the confined space of the testis.
If stretched out, each tubule would be about a foot or two in length; if
the many hundreds of seminiferous tubules from a testis were stretched
out and placed end to end, they would cover the length of at least two
football fields! Sperm production occurs along the entire length of a
seminiferous tubule.
Seminiferous tubules have walls that surround the open area in the
center, called the lumen. Sperm made in the wall, along with fluid that
enables these cells to be moved through the tubule, are released into
the lumen of the tubules. The walls of the seminiferous tubules are made
of cells dedicated to sperm production (the germinal epithelium) and
underlying supportive tissue. The cells of the germinal epithelium of the
seminiferous tubule walls are of two types: germ cells (cells in various
stages of sperm development) and Sertoli cells (cells that aid developing
germ cells). The rest of the seminiferous tubule is made of supportive tis-
sues that surround the germinal epithelium. Immediately underlying the
germinal epithelium is the basement membrane. The tissue layer is made
of structural molecules, such as the protein collagen, that physically
support the germinal epithelium and also connect it to the underlying
loose connective tissue, the peritubular tissue (literally, tissue around
the tube). This tissue, which is also composed of molecules such as
collagen, plays a structural role. Cells that can produce connective tis-
sue molecules are present in the peritubular tissue, and researchers are
learning that these cells also communicate with—and influence—cells
of the germinal epithelium.
These testis cells and the many other non–germ cells have a variety
of functions, all of which are directed at assisting in the primary function
Figure 4.2 This color scanning electron micrograph (SEM) image shows the
seminiferous tubules. The center of each seminiferous tubule is filled with
developing sperm, of which the tails can be seen (blue). (© Susumu Nishinaga/
Photo Researchers, Inc.)
of the testes: to enable sexual reproduction through the production and

release of sperm. It is sperm, and the cells from which they are derived,
that are the testes’ germ cells, a broad term that encompasses cells in
four categories:
1. Cells in the developing embryo/fetus that are the precursors of sper-

matogonia (primordial germ cells and the gonocytes derived
from them)
The Testes 55
2. Cells derived from gonocytes that have the ability to divide in order
to copy themselves or to produce cells that will develop into sperm
cells (spermatogonia; sometimes referred to as spermatogenic
stem cells)
3. Cells derived from spermatogonia (primary spermatocytes, sec-

ondary spermatocytes, and spermatids) that are in various stages
along the developmental pathway toward becoming sperm cells
4. Spermatozoa, or sperm cells
Some of these germ cells develop into germ cell tumors. Evidence
gathered by researchers indicates that cells early in the germ cell de-
velopmental pathway are the ones that become cancer cells, but this
remains an active area of investigation. One of the challenges faced
by scientists is that there is still much to be learned about the many
changes that occur as these cells proceed along the normal develop-
ment pathway: from primordial germ cell formation to mature sperm.
The process of spermatogenesis begins in puberty as spermatogonia
divide (by a process known as mitosis) to produce two cell types: (1)
cells that are copies of the original cell (which ensure that the supply
of stem cells will not be depleted) and (2) cells that will develop into
primary spermatocytes.
A primary spermatocyte undergoes two rounds of a special type of
cell division called meiosis. The first division of the primary spermato-
cyte produces two secondary spermatocytes. Each secondary sper-
matocyte undergoes division to produce two cells called spermatids.
Thus, each primary spermatocyte ultimately produces a total of four
spermatids. The arrangement of germ cells in the germinal epithelium
reflects the stages of their development: spermatogonia lie in the outer
region of the germinal epithelium (farthest from the lumen and closest
to the basement membrane), the spermatocytes are closer to the lumen,

and the spermatids are closest to the lumen.
Meiosis is the type of cell division that produces gametes, sperm in
males and eggs in females. The result of division by meiosis (rather than
by mitosis) is that the spermatids have half the number of chromosomes
as the primary spermatocytes, 23 instead of 46. This halving of the number
of chromosomes is essential for successful sexual reproduction; if it did
not occur, the amount of chromosomal DNA would double in each suc-
cessive generation. The process of meiosis is precise, and the number of
chromosomes is not randomly cut in half. Like all of the body, or somatic
cells, each primary spermatocyte is diploid, meaning it has two copies of
each chromosome, one from the mother (maternal) and the other from
the father (paternal). Imagine that there are 23 pairs of chromosomes,
each carrying a sign with a numeral from 1 to 23. The cell would have two
chromosomes marked 1, two chromosomes labeled 2, and so on through
chromosome pair 23. Meiosis ensures that each cell will get one of each
chromosome 1 through 23. Meiosis reduces the chromosome number so
that each spermatid is haploid, having only one copy of each chromo-
some. It is in the zygote stage, after the maternal and paternal DNA have
come together, that the diploid number is restored.
Each spermatid develops into a sperm cell by a process known as
spermiogenesis, a process of cell differentiation (i.e., a cell becom-
ing specialized) and not cell division. A number of things occur during
spermiogenesis: the cell’s DNA and nucleus undergo changes, cytoplasm
is removed, a flagellum that will enable the cell to move in the female
reproductive tract develops, and a cap of enzymes that will be later used in
fertilization is formed.
The entire process—from primary spermatocyte to mature sperm—
takes about 60 days.
The Testes 57
Sertoli Cells
Sertoli cells assist in many ways with the development of sperm cells.
These large cells span the germinal epithelium, from the basement
membrane to the lumen, and lie side by side, forming a continuous layer
of cells around the tubule.
The sides of the Sertoli cells are attached tightly to each other by
specialized connections, preventing fluid, dissolved molecules, and
cells from moving between the Sertoli cells. As a result, molecules
must pass through the cytoplasm of Sertoli cells to move from the
lumen-side of Sertoli cells to the basement membrane-side of Sertoli
cells. This lack of free movement of materials between cells is an im-
portant contributor to the blood-testis barrier, a system that restricts
access to the developing sperm cells by molecules and immune cells
from the blood and prevents sperm cells from gaining access to im-
mune cells. The evolutionary advantage of the barrier is thought to be
protection of the developing sperm from the body’s immune system,
which would recognize these cells as foreign and destroy them.
Germ cells develop in pocketlike projections of the Sertoli cells,
moving closer to the lumen as they mature. This requires breaking
and reforming of the connections between Sertoli cells. Sertoli cells
secrete a variety of molecules, including androgen-binding protein that
concentrates testosterone, and hormones; they also engulf spermatid
cytoplasm and secrete the fluid that helps carry sperm through the
seminiferous tubule.
Sertoli cells are capable of developing into cancer cells. Because
a Sertoli cell is not a germ cell, a Sertoli cell cancer is considered a
non–germ cell cancer.
Figure 4.3 Sperm surround a Sertoli cell, which provides nourishment for
developing sperm. (© LookatSciences/Phototake)
The Passage of Sperm Out of the Body
Sperm produced along the length of a seminiferous tubule can leave

through either end, as both converge on a meshwork of tubules called
the rete testis. This collects sperm and fluid from all of the seminiferous
tubules and is located in the mediastinum testis. Although rare, cells of the
rete testis can become cancer cells, resulting in cancer of the rete testis.
The Testes 59
Sperm leave the rete testis (and the testis itself) at the hilus by way
of 6 to 12 small tubes known as efferent ductules. These carry the
sperm to the epididymis, a collection tube that lies just outside the
testis.
The highly coiled epididymis (which would be about 16 feet if
stretched out) runs along the back of the testis. In the first section,
much of the fluid produced in the seminiferous tubules is reabsorbed,
concentrating the sperm. The rest of the epididymis serves as more than
a simple conduit for sperm: It is where the sperm mature to the point at
which they are able to successfully fertilize an ovum. Sperm are also
stored in the epididymis until they leave the scrotal area to be released
from the penis through ejaculation.
Sperm leave the epididymis by way of the vas deferens, which
carries sperm from the scrotum, through the inguinal canal, and into
the abdominal cavity. (In the male sterilization procedure known as
a vasectomy, the vasa deferentia—one vas deferens on each side of
the body—are cut.) In the abdominal cavity, the vas deferens loops
up and over the bladder, the structure that stores urine. Sperm are
propelled through the vas deferens by contractions of the muscles
that surround the tube. Just near its end, the vas deferens is renamed
the ejaculatory duct.
The short ejaculatory ducts on each side of the body join with the
urethra—the tube that carries urine from the bladder. The urethra
serves two important functions: It delivers sperm and urine (at sepa-
rate times) to the outside of the body through the penis. The urethra
is the first—and only—tube where sperm traveling from the right tes-
ticle and sperm traveling from the left testicle join. All the other tubes
through which sperm travel are present on both sides of the body.
Figure 4.4 These sperm are moving from the seminiferous tubules through
the rete testis. From there the sperm will finish developing and be stored in the
epididymis. (© Innerspace Imaging/Photo Researchers, Inc.)
Fluid, known as seminal fluid, is added to the sperm in the vas

deferens and the urethra by specialized glands. The combination of
sperm and seminal fluid, the material released from the urethra during
ejaculation, is known as semen.
The Testes 61
The Circulatory System and the Testis
The circulatory system carries blood through blood vessels (arteries, ar-
terioles, veins, venules, and capillaries) that are distributed throughout
the body. Blood consists of fluid (plasma), red and white blood cells,
and platelets. Important molecules, such as nutrients and hormones,
are carried in the plasma. Red blood cells carry oxygen to the body’s
tissues, the many types of white blood cells work in complex ways to
help the body defend itself from microbes and cancer cells, and plate-
lets assist in blood clotting. Under pressure from the pumping heart,
blood is pushed through arteries and the smaller arterioles, tubes that
carry blood away from the heart, eventually reaching the capillaries,
the vessels of the body that exchange materials with body tissues. This
exchange is possible because capillaries have thin walls, made only of
a single layer of cells known as endothelial cells. Plasma (and at times
white blood cells) leaves the blood by passing between endothelial cells,
allowing the fluid (now referred to as tissue fluid) to bathe body tissues.
Molecules can then be exchanged between the cells of the body tissues
and the tissue fluid. Much of the tissue fluid is eventually returned to the
circulatory system, moving back into the capillaries. From capillaries,
the fluid travels in venules to larger veins back to the heart.
The blood supply for the testes comes largely from the testicular
arteries. These two arteries branch from the aorta—the body’s main
artery that carries blood from the heart—as it runs through the retro-
peritoneal cavity. They are then routed through the spermatic cord;
the right testicular artery delivers blood to the right testis and the left
testicular artery delivers blood to the left testis. Once at the testis, the
artery branches, supplying all areas of the testis. Many of the branches
travel along connective tissue to the individual lobules. Capillaries in the
interstitium exchange with the local tissue fluid. Although some of these
capillaries are near the seminiferous tubules, the seminiferous tubules

do not have their own capillary supply: Exchange occurs with the capil-
laries of the interstitium.
Fluid and molecules reenter the capillaries and move to venules,
then to larger veins. The veins that leave the testis join other veins to form
a network of veins in the spermatic cord known as the pampiniform
plexus. From the plexus, two testicular veins enter the retroperitoneum
where they return blood to the inferior vena cava—the main vessel
that returns blood to the heart from the lower part of the body—or to a
branch of the inferior vena cava.
The Lymphatic System and the Testis
Although most tissue fluid eventually returns to the circulatory system

through capillaries, about 1 percent does not. This excess fluid enters
another system of the body: the lymphatic system. Like the circulatory
system, the lymphatic system has vessels through which fluid moves.
But unlike the circulatory system, these vessels do not form a continu-
ous loop. Rather, lymph capillaries of this one-way system pick up fluid
(which at this point is referred to as lymph) from tissues. They then join
progressively larger vessels (lymph veins) and ultimately a large vessel—a
duct—through which the fluid is returned to the circulatory system. In the
lymphatic system, there is no heart that pumps, there are no arteries or
arterioles, and capillaries only collect fluid from the tissues.
The lymphatic system does much more, however, than return fluid
to the circulatory system: It is intimately involved with the body’s im-
mune system, which defends the body against infectious microbes and
cancer cells. The lymphatic system contributes to this defense in two
important ways:
The Testes 63
1. Cells (microbes and cancer cells) as well as tissue fluid can be

picked up by lymph capillaries.
2. As this material moves through lymph vessels on its way to the
circulatory system, it encounters lymph nodes, small structures that
filter lymph. Lymph vessels empty lymph into one end of a lymph
node. The lymph moves slowly through the meshlike node, eventu-
ally leaving through a lymph vessel on the opposite side. The lymph
node is more than a mechanical filter. Cells in a lymph node trap,
destroy, and become activated to destroy microbes and cancer cells.
(Some cancer cells trapped by lymph nodes survive and multiply
within the node, but without the lymph nodes, these cancer cells
would enter the bloodstream unchecked.)
In the testis, many lymph capillaries, like the blood capillaries, are
located in the interstitium. They join others, leaving the testis as larger
lymphatic vessels at the hilus. They enter the spermatic cord, then travel
to the retroperitoneal cavity. From there, vessels join a long and much
larger vessel, the thoracic duct, which returns lymph to the left subclavian
vein, located near the heart. Testicular cancer cells that are picked up
by lymphatic capillaries in the testes first encounter lymph nodes in the
retroperitoneal cavity. These retroperitoneal lymph nodes are therefore
usually the first landing sites for testicular cancer metastases.
SUMMARY
The testes are formed during fetal life in the retroperitoneum, a space
at the back of abdominal cavity. As development proceeds, they move
through the inguinal canals into the scrotum. Each remains connected
to the abdomen through its spermatic cord. The spermatic cord contains
blood vessels, lymph vessels, and a tube that carries sperm from the
testes. Sperm are made in the testes in long tubes known as seminifer-
ous tubules. Production of sperm takes many weeks, and is a stepwise
process that involves cell division and cell changes. Sertoli cells, located
in seminiferous tubules, help in the process of sperm development.
Leydig cells, located in tissue between seminiferous tubules, produce
the hormone testosterone.
5
Germ Cell Cancers
KEY POINTS
♦ Most testicular cancers are germ cell cancers.
♦ Germ cell cancers are categorized as either seminomatous or non-

seminomatous.
♦ Seminomatous germ cell cancers include seminoma and spermato-

cytic seminoma, a cancer that occurs in older men.
♦ Nonseminomatous germ cell cancers include embryonal carcinoma,

yolk sac tumor, trophoblastic tumors (primarily choriocarcinoma),
and teratoma.
♦ Germ cell tumors that are mixtures of more than one tumor type
are called mixed germ cell tumors. They are classified with the non-
seminomatous germ cell cancers because of the way they respond
to available treatments.
65
Most Testicular Cancers Are Germ Cell Cancers
Baseball player Mike Lowell, cyclist Lance Armstrong, skater Scott Ham-
ilton, newscaster Sean Kimerling, and high school student Jason Struble
share a diagnosis of testicular cancer: They also have in common the
type of testicular cancer with which they were diagnosed: a germ cell
cancer.
There are many different types of testicular cancer. Of these, several
develop from germ cells—cells in sperm’s developmental pathway—and
are therefore classified as germ cell cancers. Most testicular cancers are
germ cell cancers; in males who have gone through puberty, more than
90 percent of testicular cancers fall into this category.
There are many different types of germ cell cancer. The type of
germ cell tumor (GCT) a patient has is determined in the laboratory.
The pathologist determines the way the tumor looks to the eye as well
as histologically, when stained slices are examined under a microscope.
Immunohistochemistry can add important diagnostic clues by show-
ing whether certain cell-specific molecules are present. Serum tumor
marker information can also assist in tumor identification.
Germ cell tumor classification has changed over time, and there is
variation in how GCTs are classified from one part of the world to an-
other. The United States and many other countries use the classification
scheme of the World Health Organization (WHO). In the WHO system,
GCTs are classified as either pure (composed of one histological—or
tissue—type) or mixed (composed of more than one histological type).
The pure histological types of GCTs are seminoma, spermatocytic
seminoma, embryonal carcinoma, yolk sac tumor, trophoblastic
tumors, and teratoma. Mixed GCTs are made up of varying combina-
tions of these types.
Germ Cell Cancers 67
For testicular cancers other than seminoma and spermatocytic

seminoma, the transformed cell types become very different from germ
cells. They change to take on some properties that are similar to cells of
early embryos (as in embryonal carcinoma); more developed embryos,
fetuses, and adults (as in teratoma); or extraembryonic membranes,
structures that are attached to an embryo and assist in its development
(as in yolk sac tumor and trophoblastic tumors).
♦ Early Hum an D evel opm ent
A fter a few days of cell division, the mammalian zygote develops into a
blastocyst (a hollow structure with an inner cell mass that will be-
come the fetus) and a chorion made of trophoblasts, which will form the
fetal part of the placenta.
As the blastocyst implants into the lining of the uterus, the chorion
develops to form two placenta-producing layers (the cytotrophoblast and
the synctiotrophoblast). The inner cell mass forms two layers: the en-
doderm and the ectoderm. Later, a third layer, the mesoderm, will form.
Trophoblasts, cytotrophoblasts, and synctiotrophoblasts secrete hCG.
Later in embryonic development, a well-developed yolk sac appears.
The yolk sac is the structure that is responsible for production of a fetus’s
first blood cells and primordial germ cells. The placenta, the structure that
connects and exchanges materials between the fetus and the mother, is
also well developed.
The yolk sac and chorion are both extraembryonic membranes, structures
that are attached to a developing embryo and assist in its development.
Figure 5.1 This light micrograph shows a section of a seminoma, a type of

germ cell cancer (lower left). (© CNRI/Photo Researchers, Inc.)
Physicians and researchers group these different tumor types into

two categories: seminomatous GCTs (seminomas) and nonsemino-
matous GCTs (nonseminomas). This categorization, while artificial, is
useful because it reflects not only the differences noted (the presence or
absence of properties shared with developing embryos/fetuses/adults),
but also differences in how tumors can be treated by doctors. Seminomas
respond to radiation and chemotherapy, while nonseminomas respond
only to chemotherapy and often require more aggressive treatment.
Nonseminomatous GCTs include embryonal carcinoma, yolk sac
tumor, trophoblastic tumors, teratoma, and mixed GCTs. Seminomatous
GCTs include seminoma (sometimes referred to as classic seminoma)

and the less common and quite different spermatocytic seminoma.
Because spermatocytic seminoma is so different, often the term semino-
matous GCT is used to refer only to seminoma.
Some mixed GCTs have seminoma as a component. Why, then, are
all mixed GCTs—regardless of the presence of seminoma—classified
as nonseminomas? The reason is related to treatment: If the tumor is
treated as a nonseminoma, both the seminoma and the nonseminoma-
tous component will respond; if the tumor is treated as a seminoma,
only the seminoma component will respond.
Germ Cell Tumors in Boys and Older Men
Most individuals who develop testicular cancer do so between the

onset of puberty and their mid-forties. But testicular cancer can also
occur in boys (males before puberty) and older men. For all age
groups, the most common type of tumor is a GCT, although these
represent a smaller fraction—only about two-thirds—of the testicular
tumors in boys.
The distribution of GCT types differs among age groups. Spermato-
cytic seminoma occurs mostly in men older than 50, and it never oc-
curs in men younger than 30. In adults, the most common GCTs are
seminoma (about 50 percent of the cases), mixed GCT (a little less than
50 percent), and embryonal carcinoma (less than 10 percent). In boys,
yolk sac tumor and teratoma are the most common GCT types, while
seminoma and embryonal carcinoma occur only rarely.
The differences are not just in tumor incidence. Scientists have
discovered that there are genetic differences between GCT cells that
occur in boys, those that occur in men, and spermatocytic seminoma.
♦ Extr a gonada l Germ Cel l T u mo r s
T esticular germ cell tumors can metastasize to parts of the body far
from the testicle, such as the retroperitoneum and the mediastinum,
an area of the chest. But sometimes, a testicular GCT can occur in these
areas in the apparent absence of a testicular GCT. These are known as
extragonadal germ cell tumors (EGGCTs). The term extragonadal implies
that these primary tumors (tumors that have developed in—rather than
metastasized to—a location) occur outside the gonad. Another common
location for EGGCTs is a gland in the brain known as the pineal gland.
At times, a physician may discover that the mass is not a true EGGCT
because a small mass can actually be found in the testicle. But many ap-
pear to be true EGGCTs.
A commonly accepted explanation for the presence of these tumors
is that an error occurred during migration of primordial germ cells in the
fetus; instead of migrating from the yolk sac to the primitive testis devel-
oping in the abdomen, the germ cells traveled to a different area, such as
the mediastinum. But researchers are exploring other hypotheses. One is
that cells in a testis that have started to, but not yet, become cancer cells
migrate from the testes to other areas; only when they reach these other
areas do they become cancer cells.
Brian Piccolo, football player for the Chicago Bears, died in 1969 at
the age of 26 of embryonal carcinoma that originated in the mediasti-
num. Thankfully, advancements in the treatment of this type of cancer
have been made since the 1960s. His story was told in the film Brian’s
Song.
It appears that GCTs in these three categories have different causes and
pathways of development.
There are also interesting differences between teratomas that occur
before and after puberty. Teratoma in children is always benign—it does
not invade neighboring tissues or spread to other parts of the body by
metastasis. In adults, teratoma can be benign but it can also be malignant,
spreading to nearby tissues and capable of spreading to distant sites. An
additional age-related difference is that teratoma in children is almost
always a pure tumor, while in adults it is usually found as a component of
a mixed GCT. The reasons for these differences are not understood.
Seminoma
Seminoma (classic seminoma) is the most common type of GCT found

in adults. About half of the GCTs in adults are seminomas, and seminoma
is a component of many mixed GCTs. Seminoma is rarely found in boys,
and occurs mostly in men in their mid-thirties to mid-forties. This is later
in life than adult nonseminomas tend to occur.
The main symptom for most seminoma patients is an enlarged but
pain-free testicle. A small percentage of seminoma patients may also
have enlarged breast tissue (gynecomastia). If the tumor has metasta-
sized, symptoms may be felt in parts of the body to which the cancer has
spread, most commonly the abdomen. For most patients, however, the
tumor has not metastasized at the time of diagnosis.
Sometimes the tumor will spread locally to nearby structures such
as the epididymis or spermatic cord. Seminoma spreads to distant areas
through the lymphatic system: first to retroperitoneal lymph nodes,
and later to lymph nodes in the middle of the chest (mediastinal) and
above the collarbone. The disease can spread further still by way of
the circulatory system, to sites such as the liver, lung, and bones.
In some cases, seminoma cells secrete hCG, which is detectable in
low concentration in the blood. hCG can cause gynecomastia. Semi-
noma cells never secrete AFP, which is an important factor in certain
diagnoses. For example, if the histology shows pure seminoma but blood
tests show elevated concentrations of AFP, a doctor will know that the
tumor is not seminoma, but actually a mixed GCT (nonseminoma) that
will require different treatment.
When a pathologist cuts into a seminoma tumor, it appears light
in color. There is no significant necrosis (dead tissue) or hemorrhage
(bleeding). The tumor is homogeneous, meaning that different areas of
the tumor are similar in appearance.
After staining the sample with hematoxylin-eosin, microscopic
examination shows that the cells are organized to form sheets of neatly
arranged cells, commonly in clusters that are separated by connective
tissue in which many white blood cells, especially lymphocytes, have
gathered. Neighboring cells do not overlap. The cells are fairly uniform
in appearance, and cell features such as a cell membrane, cytoplasm,
and nucleus with one or more nucleoli are easily seen.
A challenge for pathologists is the existence of forms of seminoma
that vary in cell characteristics and cell arrangement and differ from
the normal microscopic appearance. Some variants may look like other
tumor types. In one variant, syncytiotrophoblasts, large cells with many
nuclei per cell, are found among the typical cells.
Spermatocytic Seminomas
Spermatocytic seminoma is not a variant of seminoma; it is a unique

type of GCT. It accounts for only a small percentage of testicular
cancers. Most commonly, the disease occurs in men older than 50. It
occasionally occurs in younger men, but not in those under 30. Unlike
other histological types, spermatocytic seminoma is never a compo-
nent of GCTs.
The primary symptom is a painless mass in the testis. The tumor may
invade local tissues such as the epididymis, but it rarely metastasizes.
A patient’s prognosis is therefore excellent. The cut surface of the tumor
is light in color, and some tumors may have small areas of necrosis or
hemorrhage.
Microscopically, one characteristic of spermatocytic seminoma is
the presence of three cell types that differ in size: small, intermediate
(the predominant cell type), and large. These cells are not arranged in
well-organized sheets as in seminoma. Groups of cells are often sepa-
rated by areas that have only a small amount of connective tissue and
may be filled with fluid.
Even though prognosis is usually excellent, on occasion, parts of the
tumor change to form a sarcoma, a connective-tissue-like tumor. The
sarcoma may metastasize to the retroperitoneum and organs. Currently,
prognosis for these patients is poor.
Embryonal Carcinoma
Embryonal carcinoma is the most common nonseminomatous, pure
GCT in adults, but it is much less common than seminoma and mixed
GCTs, accounting for less than 10 percent of adult GCTs. It tends to occur
in men between their mid-twenties and mid-thirties, about 10 years ear-
lier than seminoma. It rarely occurs before puberty and is a component
of more than 80 percent of mixed GCTs.
Embryonal carcinoma is usually noticed because of a mass in the
testis. Often, but not always, the mass is painless. Gynecomastia may
occur. Many patients have metastases at the time of diagnosis and may
have symptoms resulting from the spread to lymph nodes or organs.
Sometimes the cancer invades local structures such as the epi-
didymis and spermatic cord. It metastasizes via the lymphatics to the
retroperitoneal and mediastinal lymph nodes. At times, it may spread
through the blood, often to the lungs. Some tumors make hCG, which
can be detected in the blood serum.
When a tumor of this type is examined in the lab, large areas of
necrosis and hemorrhage are typically seen. Microscopically, the cells
are large and have different shapes and they tend to overlap. Many cells
appear to be in the process of division, and abnormalities in the division
process can be seen. Syncytiotrophoblasts may be present.
Embryonal carcinoma cells are undifferentiated—they are not ma-
ture cells with a set function. Many of the cells look like epithelial cells,
which cover surfaces of the body; in some areas, they are even arranged
like epithelial cells around cavities, forming structures that look roughly
like glands. Embryonal carcinoma cells can be arranged in many differ-
ent patterns, and a pathologist must be able to recognize them all.
Yolk Sac Tumor
Yolk sac tumor is the most common testicular cancer in children. The
name comes from the fact that the tumor has characteristics—such
as AFP production—that are similar to the embryonic yolk sac. It
occurs in boys from infancy to age 11; the median age is about 16
months. Yolk sac tumor also appears in adults, but almost always as a
component of mixed GCTs. About 40 percent of mixed GCTs contain
yolk sac tumor.
♦ Immunohistoc he m istry and

Testicula r Can c er Types
I mmunohistochemistry can be used to distinguish one testicular

cancer type from another. For example, what if the pathologist wants
to determine if a tumor is seminoma or embryonal carcinoma? Cells of
these two cancers have many molecules in common, including a surface
protein known as placental alkaline phosphatase (PLAP). Detection of
such molecules cannot help tell the two cancer types apart. However,
the cells of the two cancers differ in the presence of other surface
molecules, such as c-Kit, Ki-1, and podopladin. The difference in the
presence of these proteins can help tell the two cancers apart: Seminoma
cells, but not those of embryonal carcinoma, have c-Kit and podopladin
on the surface; embryonal carcinoma cells, but not those of seminoma,
have Ki-1.
Scientists continue to look for cellular molecules that can identify
particular cancer cells. They are also interested in gaining a better under-
standing of the normal roles of these proteins, as well as their relationship
to the development of particular cancers.
PLAP is an enzyme that is normally made by trophoblasts of the cho-
rion. The normal function of podopladin is unclear, but it has been found
in fetal germ cells, and has been suggested to play a role in fetal germ cell
development. Ki-1 and c-Kit are receptor molecules; each allows the cell
to detect and respond to a particular outside chemical signal. These are
normally made by certain blood cells.
Yolk sac tumors are usually discovered by parents who notice

that a child’s testicle has rapidly enlarged. In about 10 to 20 percent of
children, the tumor has metastasized at time of diagnosis. Metastasis
may occur via the lymphatics to the retroperitoneal lymph nodes. Often,
however, spread is through the blood only; for these patients, the first
site of metastasis is often the lungs.
Almost all yolk sac tumors, including mixed GCTs that contain yolk
sac tumor cells, make AFP, and detection of elevated serum AFP can
help to identify yolk sac tumor as a component of a mixed GCT. When
the tumors are large, necrosis and hemorrhage are often present.
Two tumor features that can be seen microscopically are crucial to
diagnosis: the presence of multiple histological patterns (characteristic
cell arrangements) in a single tumor, and the presence of structures
known as Schiller-Duval bodies, collections of cancer cells that surround
fingerlike, blood-vessel containing projections of connective tissue.
Commonly, hyaline globules, collections of AFP (or another protein)
normally produced by the yolk sac, are also present.
Choriocarcinoma
Almost all trophoblastic tumors fall into the category of choriocarci-
noma. The name comes from its similarity to the chorion, which forms
the fetal part of the placenta.
Choriocarcinoma occurs only very rarely (less than 1 percent of
cases) in pure form. Most men diagnosed with this form of cancer are in
their teens and twenties. Choriocarcinoma occurs in about 8 percent of
mixed GCTs. Choriocarcinoma spreads rapidly and widely, and has the
worst prognosis of all the germ cell cancers.
Choriocarcinoma differs from other germ cell cancers in presenta-

tion: Most patients seek medical help from the symptoms of metastasis
and not the tumor itself. Often, by the time of diagnosis, the tumor has
regressed (shrunk).
Choriocarcinoma spreads through the blood to the lungs and
often to the liver, gastrointestinal tract, brain, and other organs. It
also spreads through the lymphatic system to the retroperitoneal
lymph nodes. Symptoms include shortness of breath, coughing up or
vomiting blood, and dark stools (due to gastrointestinal bleeding).
Bleeding can occur in many areas of the body, causing anemia (too
few red blood cells). Neurological problems that result from spread
to the brain can also occur. The high concentrations of hCG may
cause gynecomastia and an underactive thyroid (a gland that controls
metabolism).
Microscopically, choriocarcinoma has two main cell types:
syncytiotrophoblasts and cytotrophoblasts. These cells are arranged in
varying patterns. The two cell types normally compose the placenta-
forming extraembryonic membrane known as the chorion. Like
trophoblast cells of the chorion, these cells produce large quantities of
hCG. While hCG is sometimes produced in other types of testicular cancer,
it is always secreted in large concentrations in choriocarcinoma.
Teratoma
The word teratoma comes from the Greek word for monster (teraton) and
reflects the fact that the tumor is an odd conglomeration of recognizable
tissues. Although not in testicular cancer, other types of teratomas can
actually have hair and teeth.
Pure teratoma rarely occurs in adults; only about 2 to 3 percent of

adult GCTs are teratomas. Teratoma occurs frequently as part of mixed
GCTs in adults; about half of these tumors contain teratoma. Pure tera-
toma occurs more commonly in children. Some feel that the pediatric
percentage is underreported because teratoma is benign in this popula-
tion. Most teratomas in children occur in those younger than four years
of age, and most often in one- and two-year-olds.
There are two types of teratoma: mature and immature. A mature
teratoma has adultlike, differentiated cells only. Usually several types of
tissue are present in one tumor. For example, tumors might have neural
tissue, bone, and cartilage. An immature teratoma may also have adult-
like differentiated cells, but less differentiated cells (more embryonic,
or fetal-like) are also present. These less-differentiated cells, however,
are more differentiated than those seen in embryonal carcinoma. Some
teratomas have tissues from only a single germ layer (monodermal tera-
toma), while others have tissues from two, or all three, germ layers. What
is a germ layer? As normal embryonic development proceeds, cells of
the inner cell mass begin to differentiate, taking on specific structures
and roles. As part of this process, three layers of tissue (germ layers)
form in the embryo: the ectoderm, the endoderm, and the mesoderm.
The ectoderm is on the outside and will eventually develop into adult
structures such as the epidermis (outer skin layer) and nervous system.
The endoderm is on the inside and will develop into adult tissues that
line body cavities such as the lungs and digestive tract. The mesoderm,
in the middle, will develop into tissues such as muscle and bone.
The difference between pre- and postpuberty teratomas is that most
teratomas that occur before puberty are mature, while most that occur
after puberty are immature. Both immature and mature adult teratomas
can metastasize.
Figure 5.2 A color transmission electron micrograph (TEM) shows three malig-
nant teratoma cells. Each teratoma cell shown here has a large, irregular-shaped
nucleus (brown). (© Steve Gschmeissner/Photo Researchers, Inc.)
In children, because there is never metastasis, the only symptom

is a testicular mass. Adults may present with a mass or symptoms of
metastasis.
The pathologist will note that the cut tumor surface is not homog-
enous—different tissue types can be seen in different areas of the tumor.
Cysts filled with fluid of different consistencies are commonly found.
Microscopically, cells, some of which appear abnormal compared to

their normal counterparts, are arranged to form tissues. At times, these
different tissues can be seen arranged to form primitive organlike struc-
tures, such as skin. Synctiotrophoblasts may be present.
Mixed Germ Cell Tumors
Mixed GCTs normally occur only in males who have gone through pu-
berty. Any of the different GCT types, with the exception of spermatocytic
seminoma, may be present in a single tumor. After seminoma, mixed
GCTs are the most common type of adult GCT.
More than 80 percent of mixed GCTs have embryonal carcinoma as
one of the components, and about half contain teratoma. Yolk sac tumor
and seminoma occur less frequently, but are still commonly found. Cho-
riocarcinoma is found in less than 10 percent of the mixed GCTs.
The different tumor types vary in aggressiveness, metastasis loca-
tions, and treatment sensitivity, and so it is important for the pathologist
to list the different tumor types and to estimate the percentage of each.
This information will affect treatment decisions.
S UMMA RY
GCTs arise from germ cells and are the most common type of testicular
cancer. The type of GCT a patient has is determined by analysis of the
tumor in the pathology lab and by the presence or absence of certain
tumor markers in the blood. It is important to diagnose the type of GCT
accurately because they may require different treatment. GCTs are
grouped into two large categories: seminomatous GCTs and nonsemino-
matous GCTs. Seminomatous GCTs are of two types: seminoma (classic
seminoma) and spermatocytic seminoma, which occurs in older men.

Nonseminomatous GCTs include embryonal carcinoma, yolk sac tumor,
trophoblastic tumors (primarily choriocarcinoma), and teratoma. Some
GCTs are made of more than one tumor type and are known as mixed
GCTs. These tumors (some of which may contain seminoma) are classi-
fied as nonseminomatous for treatment purposes. The most commonly
diagnosed GCTs in young men are seminoma and mixed GCT. In boys,
yolk sac tumor and teratoma are prevalent.
6
Non-Germ Cell Testicular Tumors
KEY POINTS
♦ Non-germ cell testicular tumors are much less common than germ
cell tumors.
♦ Non-germ cell tumors make up a greater percentage of the testicular

tumors that occur in boys than those that occur in adults.
♦ Leydig cell tumors, Sertoli cell tumors, rete testis carcinoma, and
primary testicular lymphoma are non-germ cell tumors of the testis.
♦ Some non-germ cell tumors are benign. Many of the malignant

forms carry a poor prognosis.
Testicular tumors that arise from cells that support germ cells or play
other roles in testicular function—non-germ cell testicular tumors—oc-
cur much less frequently than their germ cell tumor counterparts.
Testicular tumors that do not arise from germ cells represent a greater
82
Non-Germ Cell Testicular Cancers 83
proportion of testicular tumors in children than in adults. Some of these

tumors are benign, but others are malignant. Unfortunately, the great
success in the treatment of germ cell tumors has not been replicated for
non-germ cell tumors, and many still carry a poor prognosis. There are
many different types of non-germ cell tumors; in this chapter, Leydig cell
tumors, Sertoli cell tumors, carcinoma of the rete testis, and testicular
lymphoma are described.
Leydig Cell Tumors
Leydig cell tumors (LCTs) account for about 1 to 3 percent of testicular

tumors. About 25 percent of LCTs occur in children, generally between
the ages of 5 and 10, and are benign. About 10 percent of adult LCTs are
malignant. Malignant LCTs respond poorly to existing treatments, so prog-
nosis is poor. LCTs produce sex hormones (predominately testosterone,
and at times estrogen), which in many cases cause body changes. These
changes may appear when the tumor is small, before it can be felt in the
testis. If a testosterone-producing tumor occurs in someone who has not
yet gone through puberty, it will most likely cause precocious, or early,
puberty. The hormonal effects of such a tumor are usually not noticed
postpuberty because of background testosterone. If an estrogen-produc-
ing tumor occurs before puberty, symptoms such as gynecomastia and
poor development of the gonads and genitals may occur. Postpuberty,
symptoms include gynecomastia, decreased libido, and erectile dysfunc-
tion. Even after tumor removal, these effects from estrogen may persist.
Sertoli Cell Tumors
Sertoli cell tumors (SCTs) occur less frequently than LCTs: They account
for less than 1 percent of testicular tumors. The most common type is
Figure 6.1 Gynecomastia, or enlargement of male breast tissue (left), is caused

by an elevated level of the hormone estrogen. Some testicular tumors produce
excess amounts of this hormone. (© Dr P. Marazzi/Photo Researchers, Inc.)
SCT NOS (not otherwise specified); variants include the very rare large
cell calcifying SCT (LCCSCT). As the name suggests, LCCSCTs are large
and contain calcium deposits. SCT NOS typically occurs in adults, while
LCCSCT is often found in younger patients. In some cases, LCCSCT occurs
as part of a syndrome, such as Peutz-Jeghers, a rare genetic disorder in
which patients develop intestinal polyps and have a greatly increased risk
of developing various cancers. SCT NOS is rarely malignant, but some
LCCSCTs are malignant. The prognosis for maligant LCCSCTs is poor.
Non-Germ Cell Testicular Cancers 85
Rete Testis Carcinoma
Rete testis carcinoma is a rare tumor that arises in the sperm-collecting

ducts of the testis. These tumors most commonly occur in elderly men,
but are not restricted to this age group. Prognosis is poor.
Lymphoma
Lymphoma, a solid cancer of lymphocytes (a category of white blood

cells that play key roles in the body’s defense) can occur at many body
sites. When the initial site is the testis, the lymphoma is referred to as
primary testicular lymphoma. In adults, the most common form that
occurs in the testis involves a type of lymphocyte known as a B cell—a
cell that normally matures to secrete defensive proteins known as anti-
bodies. Most primary testicular lymphomas are unilateral, meaning that
one testicle is affected, but some are bilateral, meaning that both testes
are affected. Primary testicular lymphoma accounts for 3 to 5 percent of
testicular tumors; as with GCTs, however, the incidence of this disease
appears to be increasing and it is not known why. Testicular lymphoma
is the most common type of testicular cancer in older men. Prognosis is
usually poor.
SUMMA RY
Cells of the testis that are not germ cells, but rather support germ cells
or have other functions in the testis, can also form tumors. These are
referred to as non-germ cell tumors. They are much less common than
GCTs, but they make up a greater proportion of testicular tumors in
children than in adults. Some of these tumors are benign, but others are
malignant. Non-germ cell cancers have not shared the treatment success
Figure 6.2 This color scanning electron micrograph (SEM) shows a normal
B-lymphocyte, or B-cell. Lymphomas, or cancers of the lymphocytes, can occur
in the testes and are known as primary testicular lymphomas. (© Eye of Science/
Photo Researchers, Inc.)
of germ cell cancers, and prognosis is often poor. Non-germ cell tumors
include Leydig tumors, Sertoli cell tumors, carcinoma of the rete testis,
and primary testicular lymphoma.
7
Treatment of Testicular Cancer
KEY POINTS
♦ Treatment of testicular cancer begins with an orchiectomy.
♦ Additional treatments, if any, depend on the type of cancer and the

cancer stage.
♦ Testicular cancer may be in stage I (least advanced, localized), II

(cancer has spread to regional lymph nodes), or III (most advanced,
cancer has spread beyond regional lymph nodes).
♦ Additional treatments may include removal of retroperitoneal lymph

nodes, chemotherapy, and radiation therapy.
♦ Sometimes there are no additional treatments and the patient is

instead carefully monitored for signs of relapse.
Doctors performed two types of surgery to treat Scott Hamilton’s testicu-

lar cancer, an orchiectomy to remove the testicle and surgery to remove
87
retroperitoneal lymph nodes. He also underwent chemotherapy. Lance

Armstrong’s treatment involved an orchiectomy, chemotherapy, and
surgery to remove cancer tissue from his brain. Mike Lowell’s treatment
involved an orchiectomy and radiation therapy. The treatments of all
of these individuals began with an orchiectomy. Why was there such
variation in the treatments that followed?
The initial step in the treatment (and diagnosis) of testicular cancer
is the orchiectomy. Once this has been done, the decision about which
additional procedures to use for a given patient is based on the type of
cancer the patient has and the cancer stage—the extent to which the
cancer has advanced and the locations to which it has spread. There is
some variation among physicians in treatment preferences; variation also
arises as a result of patient decisions about their treatment options.
Mike Lowell’s follow-up treatment was radiation therapy alone
because his cancer was a seminoma, which is sensitive to radiation.
Because his disease was not advanced at the time of diagnosis, he did
not need additional surgery or chemotherapy. Follow-up treatment for
Scott Hamilton and Lance Armstrong did not involve radiation because
they were diagnosed with nonseminoma, which is not sensitive to
radiation. Because of the extent to which their cancers had spread,
both chemotherapy and surgery were needed. Variation in the body
locations to which their cancers had spread (the result of differences
in the composition of their tumors) meant different follow-up surgeries.
Hamilton’s spread was typical of most nonseminomas in that it went to
his retroperitoneal lymph nodes. Because Armstrong’s nonseminoma
was primarily choriocarcinoma, its course was different than most
testicular cancers. Hence, he did not need retroperitoneal lymph node
removal, but he did require surgery to remove cancer that had spread
to his brain.
Treatment of Testicular Cancer 89
Testicular Cancer Stages
For testicular cancer, the cancer stages range from stage I (least ad-
vanced) to stage III (most advanced). Each of the three stages is broken
down further into subcategories (i.e., IIIA, IIIB, IIIC) that further describe
the details of the cancer’s spread. The process of determining the cancer
stage is referred to as cancer staging. In cancer staging, information
about serum (blood fluid) tumor marker concentration is gathered, as
well as information about whether the tumor has spread to tissues near
the testis, to the regional lymph nodes, or to more distant sites. The stag-
ing system used to determine the extent of cancer spread is known as
the TNM (tumor-node-metastasis) system. In this system, T stands for
the spread of the tumor to nearby structures, such as the tunica vaginalis
and the spermatic cord; N stands for metastasis to regional (usually ret-
roperitoneal) lymph nodes; and M stands for metastasis of the cancer
to nonregional (distant) lymph nodes or organs, such as the lungs and
brain. Information about the serum (S) tumor markers AFP, hCG, and
lactate dehydrogenase supplements data from the TNM system.
Cancer staging requires blood work to determine tumor marker con-
centration; analysis in the pathology lab of the testicle and structures
near it (e.g. spermatic cord) to determine the extent of local spread; and
imaging studies—such as a CT scan of the abdomen and pelvis and a
chest X-ray—to look for metastasis. In addition to using the CT scan to
determine whether there is metastasis to retroperitoneal lymph nodes,
the determination is at times based on analysis in the pathology lab of
surgically removed lymph nodes.
Table 7.1 shows the categories into which a patient’s testicular cancer
can be placed based on evaluation of serum tumor marker concentra-
tion (S) and information about the local spread of the primary tumor
(T), its metastasis to regional lymph nodes as determined by imaging
studies (N) or analysis in the pathology of excised lymph nodes (pN),

and its metastasis to nonregional lymph nodes and organs (M) in the
TNM system.
Table 7.2 shows testicular cancer stages based on grouping of S
and TNM information. In stage I, the cancer is restricted to the testis or
surrounding tissues. In stage II, the cancer has spread to the regional
(usually retroperitoneal) lymph nodes, but no further. In stage III, the
cancer has spread beyond the regional lymph nodes or tumor marker
information suggests that it might have. When the cancer stage is deter-
mined by information gained by tissue analysis in the pathology lab, the
term pathologic stage is used. Otherwise, the term clinical stage is
used. The pathologic stage is more accurate.
Retroperitoneal Lymph Node Dissection
Testicular cancers spread in a predictable manner. In most cases, the

first site of metastasis is the lymph nodes in the retroperitoneum. This
predictability is good news for testicular cancer treatment, because it
means that if the cancer has spread only as far as the retroperitoneum,
orchiectomy followed by surgery to remove the retroperitoneal lymph
nodes—a retroperitoneal lymph node dissection (RPLND)—can
often cure the disease.
Lymph nodes in the retroperitoneum are grouped according to loca-
tion within the retroperitoneum. The surgeon decides which groups of
retroperitoneal lymph nodes to remove and all of the lymph nodes in
those groups are removed, even if some of the individual lymph nodes
do not appear to be affected.
RPLND is a treatment option for patients in clinical stage I (imag-
ing studies show no spread to the retroperitoneum) or clinical stage II
(imaging studies show spread to the retroperitoneum) who have non-

seminomatous germ cell tumors (NSGCTs). In some cases, RPLND is the
only treatment used. In other cases, RPLND is used in combination with
chemotherapy. For advanced stages of testicular cancer, RPLND may
be used to remove tissue that remains in the retroperitoneum following
chemotherapy and/or radiation therapy.
Why perform a RPLND on clinical stage I patients when there is no
evidence of spread to the retroperitoneum? The answer lies in the limita-
tions of the CT scan used to determine spread to the retroperitoneal
lymph nodes. Clinical stage I does not mean that the cancer has not
spread to the retroperitoneum; rather, it means that imaging studies
do not show that it has spread to the retroperitoneum. Physicians have
found that it is not uncommon for the pathology lab to find metastasis
to one or more nodes of clinical stage I patients. These patients were
understaged by the CT scan; they were actually in pathologic stage II
and not clinical stage I. For these patients, RPLND provides treatment as
well as more accurate staging. Staging errors can occur in the opposite
direction as well. Some patients who are placed in clinical stage II based
on the CT scan are found to have no metastasis to the retroperitoneal
lymph nodes on laboratory examination of the nodes.
The Development of RPLND Surgical Procedures
RPLND to treat testicular cancer was first performed in the early 1900s.
As more physicians began to use the technique and scientists learned
more about which lymph nodes could become involved by metastasis,
the procedure evolved to increase the number of lymph nodes removed.
By the late 1970s, the procedure involved removing lymph nodes from
both sides of the retroperitoneum (bilateral RPLND), including those
Table 7.1 Serum Tumor Marker (S) and TNM Staging for

Testicular Cancer.1,2,3
Primary Tumor (T)*
pTx Primary tumor cannot be assessed (orchiectomy not performed)

pT0 No evidence of primary tumor (e.g., only scar tissue is found in testis)
Tumor has not spread beyond the testicle and the epididymis. The tumor
pT1
may have invaded the tunica albuginea.
Tumor has not spread beyond the testis and epididymis but has invaded
pT2 blood vessels or lymphatic vessels, or the tumor has grown through the
tunica albuginea and invaded the tunica vaginalis.
Tumor has invaded the spermatic cord. Blood vessels/lymphatic vessels
pT3
may or may not be invaded
Tumor has invaded the scrotum. Blood vessels/lymphatic vessels may or
pT4
may not be invaded
Regional Lymph Nodes Evaluated by Imaging Studies (N)
Nx Regional lymph nodes cannot be assessed.
N0 No metastasis to regional lymph nodes
Metastasis to a lymph node that is ≤ 2 cm in greatest dimension, or me-
N1
tastasis to multiple lymph nodes ≤ 2 cm in greatest dimension
Metastasis to one lymph node that is >2 cm ≤ 5 cm in greatest dimen-
N2 sion, or metastasis to more than one lymph node, any one of them >2
cm but ≤ 5 cm in greatest dimension
Metastasis to at least one lymph node that is > 5 cm in greatest
N3
dimension
Regional Lymph Nodes Evaluated After Removal and Analysis (pN)**
pNx Regional lymph nodes cannot be assessed.
pN0 No metastasis to regional lymph nodes
Metastasis with a lymph node ≤ 2 cm in greatest dimension and/or me-
pN1
tastasis to ≤ 5 lymph nodes with none > 2 cm in greatest dimension
Metastasis with a lymph node > 2 cm but ≤ 5 cm in greatest dimension,

pN2 or metastasis to > 5 lymph nodes, none > 5 cm or tumor growth outside
the lymph node
pN3 Metastasis to at least one lymph node that is > 5 cm in greatest dimension
Metastases to Nonregional Lymph Nodes and/or Organs (M)
Mx Distant metastasis cannot be assessed.
No distant metastasis (no spread to lymph nodes outside the area of the
M0
tumor or to organs)
M1 Distant metastasis
M1a Metastasis to nonregional lymph nodes or to the lung
M1b Metastasis to organs such as liver, brain, and bone
Serum Tumor Markers (S)***
Sx Marker studies not available or not performed
S0 Markers within normal limits
S1 LDH > 1.5 × N and hCG > 5,000 and AFP > 1,000
S2 LDH 1.5–10 × N or hCG 5,000–50,000 or AFP 1,000–10,000
S3 LDH > 10 × N or hCG > 50,000 or AFP > 10,000
* The designation pT implies that the tumor (T) has been analyzed in the pathol-
ogy laboratory.
** The designation pN implies that the lymph node (N) has been analyzed in the
pathology laboratory.
*** LDH units: N, the upper limit of normal for the assay used; hCG units: milli inter-
national units (mIU)/mL; AFP units: ng/mL.
Source: Adapted from American Cancer Society, “Detailed Guide, Testicular Cancer: How is
Testicular Cancer Staged?” http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_
testicular_cancer_staged_41.asp?sitearea= (accessed August 21, 2008). National Cancer Institute,
“Testicular Cancer Treatment,” http://www.cancer.gov/cancertopics/pdq/treatment/testicular/
HealthProfessional/page4 (accessed August 21, 2008); and A. Bahrami, J. Y. Ro, and A. G. Ayala, “An
Overview of Testicular Germ Cell Tumors,” Archives of Pathology and Laboratory Medicine, 131, 8
(2007): 1267–1280.
Table 7.2. S
tages of Testicular Cancer Based on Grouping of
Serum Tumor Marker (S) and TNM Classification System.
N
M S
pT (N or pN)
Stage (distant (serum tumor
(tumor) (regional
metastasis) markers)
lymph nodes)
I pT1-4 N0 M0 Sx
IA pT1 N0 M0 S0
IB pT2-4 N0 M0 S0
IS Any pT/Tx N0 M0 S1-3
II Any pT/Tx N1-3 M0 Sx
IIA Any pT/Tx N1 M0 S0-1
IIB Any pT/Tx N2 M0 S0-1
IIC Any pT/Tx N3 M0 S0-1
III Any pT/Tx Any N M1 Sx
IIIA Any pT/Tx Any N M1a S0-1
IIIB Any pT/Tx N1-3 M0 S2
Any pT/Tx Any N M1a S2
IIIC Any pT/Tx N1-3 M0 S3
Any pT/Tx Any N M1a S3
Any pT/Tx Any N M1b Any S
Adapted from American Cancer Society, “Detailed Guide, Testicular Cancer: How is Testicular
Cancer Staged?” http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_testicular_can-
cer_staged_41.asp?sitearea= (accessed August 21, 2008); National Cancer Institute,“Testicular Can-
cer Treatment,” http://www.cancer.gov/cancertopics/pdq/treatment/testicular/HealthProfessional/
page4 (accessed August 21, 2008); and A. Bahrami, J.Y. Ro, and A. G. Ayala,“An Overview of Testicular
Germ Cell Tumors,” Archives of Pathology and Laboratory Medicine, 131, 8 (2007): 1267–1280.
Figure 7.1 An orchiectomy followed by retroperitoneal lymph

node dissection (RPLND)—surgical removal of the testicle and the
retroperitoneal lymph nodes—can often cure testicular cancer if
there has not been metastasis to the lungs or brain. In other cases
this surgery can be used in combination with chemotherapy and/or
radiation therapy. (© Dr. Barry Slaven/Visuals Unlimited, Inc.)
above (suprahilar) and below (infrahilar) where the ureters and blood
vessels connect to the kidneys. In addition, a surgical technique used to
reach lymph tissue from behind the aorta and the vena cava was intro-
duced. One problem with the RPLND surgeries being done at that time
was that removal of the suprahilar nodes led to some added surgical
complications. Another problem was that, in the process of removing
retroperitoneal lymph nodes, nerves that controlled ejaculation were
often damaged. This resulted in sperm being ejaculated into the blad-
der rather than through the urethra (retrograde ejaculation), which
rendered the patient infertile.
In the 1980s, physician John Donohue and his colleagues at Indiana
University began to investigate whether they could safely reduce the
number of lymph nodes removed in a RPLND in order to minimize surgi-
cal complications, including the nerve damage that caused retrograde
ejaculation. To do this, they evaluated lymph nodes of many patients so
they could map the common pathways of spread to the retroperitoneal
nodes. As part of this study, they compared the metastasis patterns of
right-sided and left-sided tumors. They found that for early stage tes-
ticular cancer, right-sided tumors metastasized to different sets of lymph
nodes than left-sided tumors.
Based on this and other information, RPLND surgery began to
change. The surgically complex removal of suprahilar lymph nodes
could often be eliminated without increased risk of death from cancer.
And, rather than performing a full bilateral dissection, surgeons began
to perform modified—more unilateral—surgeries, with certain lymph
nodes (mostly those on the left side of the retroperitoneum) removed for
left-side tumors and others (mostly those on the right side) removed for
right-side tumors. With fewer nodes removed, damage to nerves that are
important to normal ejaculation was minimized. Did the change from
bilateral RPLNDs to the more one-sided approach affect the success of

the surgery? Initial studies suggested that there was no important effect.
But Joel Sheinfeld of Memorial Sloan-Kettering Cancer Center in New
York argues that without bilateral RPLND there is increased cancer risk
to the patient. He supports his argument in part with a study that looked
for metastasis to lymph nodes that were outside the normal areas used
in many modified surgeries. They evaluated 500 patients who under-
went RPLND for stage I and IIA nonseminomatous testicular cancer in
the years 1989 to 2004. They found that up to 23 percent of those who
had laboratory-verified metastasis to retroperitoneal lymph nodes had
metastasis to retroperitoneal lymph nodes that that would not have been
removed during modified RPLND.4
As more was learned about nerve control of ejaculation, surgical
procedures were modified so that important nerve tissue could be
pulled out of the way to prevent damage during lymph node removal.
This further decreased the chances of retrograde ejaculation. This modi-
fied surgical procedure is known as nerve-sparing RPLND. The nerve-
sparing surgical procedures for RPLND have evolved to the point where,
even for stage II disease (when a bilateral RPLND is often performed),
surgeons are still frequently able to preserve a man’s ability to ejaculate
normally. There are still some complex surgical situations, however, in
which nerve function cannot be spared.
Traditional RPLND is an open surgery, meaning that the lymph nodes
are accessed by opening the abdominal cavity with a long incision that
runs down most of the abdomen. In 1992, surgeons from the University
of Chicago reported on their use of a minimally invasive procedure to
perform a RPLND. Only tiny holes had to be made to allow the insertion of
surgical instruments. Because one of these instruments is an imaging tool
known as a laparoscope, the procedure is referred to as laparoscopic
RPLND. An important benefit of the minimally invasive procedure, used

by a growing number of physicians, is a reduction in surgical complications
and a more rapid recovery time. Controversy remains, however, about
whether it is as effective as open surgery in prevention of recurrence.
Chemotherapy
Testicular cancer, even after it has metastasized, typically responds

well to chemotherapy—the use of chemicals to treat disease. Testicular
cancer is more sensitive to chemotherapy than most cancers, although
the reason for this is not understood.
Chemotherapy may be the sole postorchiectomy treatment, or it
may be used in combination with other treatments such as RPLND.
For seminoma patients, chemotherapy is most often used if there is a
retroperitoneal lymph node mass greater than 5 centimeters (bulky
retroperitoneal disease/stage IIC) or if the cancer has metastasized
beyond the retroperitoneum (stage III). For nonseminoma patients,
chemotherapy is used to treat bulky retroperitoneal disease and disease
that has metastasized beyond the retroperitoneum; it is also a treatment
option for nonbulky retroperitoneal disease (stages IIA and IIB).
Successful chemotherapy to treat testicular cancer began with the
work of Min Chiu Li at Sloan-Kettering in the late 1950s, a time when
chemotherapy as a treatment for cancer was in its infancy. Li had
received his medical degree in China and was further trained in medicine
and research after coming to the United States in 1947. Fresh from his
success in using chemotherapy to cure gestational carcinoma in women,
Li hoped that chemotherapy would also be effective against testicular
cancer. He treated patients who had metastatic testicular cancer using
a combination of three chemicals: dactinomycin (a chemical made by
a bacterium); chlorambucil (a chemical related to the chemical warfare

agent mustard gas); and methotrexate (a chemical that had been
successfully used against leukemia in children and the one that Li had
used against gestational choriocarcinoma).
In 1960, Li reported the results of his study: 50 percent of the patients
responded to the chemotherapy and 10 to 20 percent of the patients
responded with complete remission (CR), meaning that no signs of
cancer could be found.5 CR is not the same as a cure, and some patients
in remission eventually relapsed (their cancer returned). However, half
of the CR patients did not relapse, meaning that 5 to 10 percent of those
treated were cured. Given today’s testicular cancer chemotherapy suc-
cess rate, these numbers may appear grim, but as a first step the results
were remarkable. As a result of Li’s work, dactinomycin as single-agent
chemotherapy or used with the other chemicals in combination che-
motherapy became the treatment standard for disseminated testicular
cancer until the mid-1970s.
Two new chemotherapy agents—vinblastine (a chemical derived
from a plant) and bleomycin (a chemical derived from a bacterium)—
were introduced several years later. These two drugs were tested in
combination in testicular cancer patients by Melvin L. Samuels at The
University of Texas M.D. Anderson Cancer Center in Houston in the early
1970s. Samuels found these two drugs acted synergistically—the effect
of the two together was greater than would be expected by simply add-
ing the success rates of each when used in single-agent chemotherapy.
Most importantly, these patients did much better than patients receiving
dactinomycin-based therapy: The CR rate was 57 percent, and most of
these CR patients were cured.6
The discovery of the chemotherapy agent cisplatin by Barnett Rosen-
berg in 1965 set the stage for another leap forward. Following studies
that showed cisplatin’s success as single-agent chemotherapy and the

vinblastine/bleomycin work of Samuels, Larry Einhorn at Indiana Uni-
versity treated patients using combination chemotherapy with vinblas-
tine (V), bleomycin (B), and cisplatin (P)—(PVB)—in the mid-1970s.
He achieved a CR rate of 70 percent with chemotherapy alone, and 11
♦ The Dis cove ry of Cisp latin
T he value of cisplatin—an inorganic compound containing the heavy

metal platinum—to chemotherapy was discovered accidentally by
Barnett Rosenberg at Michigan State University in 1965. During an ex-
periment to examine the effect of an electrical field on bacteria, Rosen-
berg found that the reproductive process of the bacterium was affected.
Instead of growing a bit longer and then dividing in two, the bacteria
would grow to extremely long lengths (300 times normal) but not di-
vide. He became intrigued, sought the assistance of colleagues in other
disciplines, and soon discovered that the elongation was due not to the
electric field but to a chemical that had been formed through interac-
tion of the platinum electrodes used to create the electric field and the
liquid medium in which the bacteria were suspended. That chemical was
cisplatin, a previously known compound, cis-diamminedichloroplatinum
or Peyrone’s salt.
Rosenberg recognized that if cisplatin could affect bacterial division,
it might also affect the division of cancer cells. Preclinical studies (labora-
tory studies done before patients are treated) showed it to be an effective
antitumor agent, and clinical studies by Einhorn and others showed its
effectiveness in testicular cancer patients.
percent more became disease-free following RPLND. Thus, a total of 81

percent became disease-free following treatment. Most importantly, 53
percent of the patients were cured.7
In the early 1980s, a large study was conducted by a group known
as the Southeastern Cancer Study Group that compared PVB therapy to
Figure 7.2 Dr. Barnett Rosenberg discovered the chemotherapeutic properties

of cisplatin. (© James L. Amos/Photo Researchers, Inc.)
therapy in which etoposide (E)—a chemical made from a plant prod-

uct—was substituted for vinblastine; postchemotherapy RPLND was
performed if possible when disease was found in the retroperitoneum
following chemotherapy, and additional chemotherapy (PV only) was
given if needed. Etoposide was selected because its effectiveness in
combination with cisplatin had been shown in an earlier trial and to
eliminate a side effect of vinblastine. The BEP group was shown to do
better than the PVB group, with 83 percent and 74 percent becoming
disease-free, respectively.8
Researchers continue to develop and evaluate new chemotherapy
drugs and regimens, especially for patients whose prognosis is poor and
those who cannot be cured by initial chemotherapy (induction ther-
apy) and therefore need additional chemotherapy (salvage therapy).
Today, most patients with metastatic testicular cancer whose prognosis
is good and who are treated with induction chemotherapy receive three
cycles of BEP therapy; because of bleomycin toxicity, some receive four
cycles of EP instead. Intermediate- and poor-prognosis patients com-
monly receive four cycles of BEP as induction chemotherapy.
Patients who do not achieve CR—or who achieve CR and then re-
lapse—are subsequently treated with a variety of regimens. Approaches
include treatment with combination chemotherapy using ifosfamide—a
drug related to chlorambucil, cisplatin, and either vinblastine, etopo-
side, or paclitaxel at standard dosages or treatment with high-dose
chemotherapy. High-dose chemotherapy has most commonly involved
treatment with etoposide and carboplatin. Since use of high doses of
chemotherapy drugs destroys hematopoietic, or blood cell-producing,
stem cells of the bone marrow, high-dose chemotherapy would normally
be fatal. Doctors solve this problem by stem cell rescue—transfusion
of hematopoietic stem cells that were harvested from the patient’s own
blood before the chemotherapy. These stem cells repopulate the bone
marrow, where they divide repeatedly to maintain their own population
and produce various blood cell types. Einhorn reviewed the cases of
184 patients whose salvage therapy involved high-dose chemotherapy
and stem cell rescue. With post-treatment follow-up times ranging from
14 to 188 months (median 48 months), 116 of 184 patients (63 percent)
were found to be in complete remission, an excellent success rate in this
population.9
Testicular Cancer Chemotherapy from Plants

Three drugs used to treat testicular cancer—etoposide, vinblastine, and
paclitaxel—are organic compounds that come from plants. Since plants
have been used for medicinal purposes throughout history, it was a
logical leap for scientists to evaluate plant extracts for their chemothera-
peutic value.
Etoposide is made in the laboratory by modification of a chemical
(podophyllotoxin) produced by plants in the genus Podophyllum: P.
emodi Wall. (common name, Bankakri), which grows in the Himalayas
of India and Nepal, and P. peltatum L. (American mayapple) which
grows in eastern North America. For years, rhizome (underground stem)
extracts from these toxic plants were used by indigenous peoples for
medicinal purposes, such as remedying constipation. Extensive work
on the purification and modification of active substances in extracts
from these plants led to etoposide synthesis from podophyllotoxin by
Hartmann Stähelin, a Swiss physician scientist, in the 1960s.
Vinblastine was isolated from the Madagascar periwinkle, Catharan-
thus roseus. For years, this plant was used by people in different parts of
the world to treat a range of ailments. Canadian physician and researcher
Robert Noble at the University of Western Ontario became curious about
the medical properties of this plant after his brother sent him leaves from
the plant and explained that they were used to make a Jamaican tea used
in diabetes treatment. Noble tested extracts from the plant, but could find
no effect on diabetes. He did find that it decreased the white blood cell
count and thus reasoned that it might work against blood cell cancers.
Biochemist Charles Thomas Beer joined Noble’s lab and isolated the ac-
tive compound, vinblastine, which proved in clinical trials to be an effec-
tive chemotherapeutic agent. Both Noble and Beer were inducted into the
Canadian Medical Hall of Fame in recognition of their important work.
Testicular Cancer Therapy from Bacteria

Dactinomycin, an early testicular cancer chemotherapy agent, and
bleomycin, used since the 1970s to treat testicular cancer, are organic
compounds derived from fungus-like bacteria belonging to the actino-
mycetes group, genus Streptomyces.
Dactinomycin (Actinomycin D) was discovered in the 1940s by
Selman Waxman, a soil microbiologist at Rutgers University. Waxman
was especially interested in chemicals produced by soil bacteria. These
microbe-produced chemicals intrigued him because some—which he
termed antibiotics—would hinder other microbes and so could pos-
sibly be used to treat infectious diseases. Waxman discovered several of
these compounds, including streptomycin, which successfully treated
tuberculosis. Waxman was awarded the Nobel Prize in Physiology or
Medicine for this work.
Some of the antibiotics Waxman discovered, such as dactinomycin,
were effective against other microbes, but were too toxic for use in
humans. Although disappointing from an infectious-disease viewpoint,
it was recognized that some of these drugs might be able to kill cancer
cells. This was found to be the case for dactinomycin, which was subse-
quently shown by Min Chiu Li to act against testicular cancer.
Figure 7.3 Bacteria of the genus Streptomyces are used to make antibiotics
and chemotherapy drugs. Shown here is Streptomyces griseus, which is used to
produce the antibiotic streptomycin. (© Dr. Christine Case/Visuals Unlimited,
Another microbiologist, Japanese physician Hamao Umezawa,

was also interested in the chemicals produced by these soil bacteria.
Umezawa grew many strains of the bacteria, filtered the medium in
which each had grown, and evaluated the filtered media for ability to kill
other microbes and cancer cells. Through this process, he discovered
the chemotherapy agent bleomycin.
Why would soil bacteria produce chemicals that affect other
microbes and cells in general? A commonly accepted explanation is
that these chemicals help the bacteria compete with microbes in the
environment, but scientists are exploring many other possibilities.
Mode of Action of Chemotherapeutic Agents

Chemotherapy chemicals work in a variety of ways to kill cells or
prevent them from dividing. In some cases, the chemical does not
directly kill the cell, but rather leads to changes that cause the cell to
kill itself through a process known as apoptosis, a programmed series
of events that lead to cell death. Vinblastine and paclitaxel prevent
cell division by affecting microtubules, structures made of the protein
tubulin that assemble and then disassemble to separate gene-bearing
chromosomes during cell division. Vinblastine does this by preventing
microtubule assembly, while paclitaxel hinders microtubule disassem-
bly. Etoposide works by interfering with an enzyme (topoisomerase
II) that helps to keep DNA, the cell’s genetic material, from becoming
knotted as it winds or unwinds to control cellular processes. The en-
zyme normally does this by making breaks in the DNA, which are then
rapidly repaired. In the presence of etoposide, however, these DNA
breaks are not rapidly repaired, resulting in permanent DNA damage.
Cisplatin and bleomycin also cause DNA damage. There is still much
to be learned about how bleomycin works to inhibit cancer cells,
but it has been shown to bind—along with a metal such as iron—to
DNA, causing breaks. Oxygen plays a role in the process, and it has
been suggested that the bleomycin-metal complex causes oxygen to
convert to toxic compounds, such as superoxide, which actually cause
the DNA damage. Recently, researchers at Indiana University School
of Medicine and Purdue University have produced three-dimensional
images of bleomycin (with an attached metal) bound to DNA. Their
hope is that a better understanding of how bleomycin interacts with
DNA will help to find ways to improve bleomycin function.
Chemotherapy Side Effects
Chemotherapy agents are by definition cytotoxic: They are toxic to cells.

The benefit for cancer treatment is that these agents hinder the cancer
cells. But there is a downside: The chemicals can also harm other cells in
the body, causing unwanted effects. Some of these side effects, such as
vomiting, can be reduced by other drugs. Problems can also be reduced
by ensuring that the chemicals chosen for combination chemotherapy
do not have the same toxicities, which would compound the problem. For
example, bleomycin can cause lung inflammation (pneumonitis), and
some individuals develop scar tissue in the lungs (pulmonary fibrosis),
which can be fatal. Yet because it is does not cause myelosupression,
the depression of blood cell production by the bone marrow, bleomycin
can be combined with a drug such as etoposide that does.
Radiation Therapy
The use of radiation to treat cancer is a commonly used postorchiec-

tomy treatment for stage I and IIA-B seminoma patients. It is not used as
a treatment for nonseminoma patients because, for reasons that are not
known, nonseminoma is less sensitive to radiation than is seminoma.
Radiation therapy, unlike chemotherapy, has the advantage of tar-
geting the treatment to a particular area of the body. Because seminoma
metastasizes in a predictable fashion, radiation targets the regional
lymph nodes.
For testicular cancer, the patient lies on a table and areas of the
body to be protected from radiation, especially the remaining testicle,
are protected by a shield. Radiation is an external-beam process, which
means that a machine outside the body sends a high-power energy

beam (e.g. X-rays) into the body. The machine can rotate so that the
patient is irradiated from different angles.
Care is managed by a radiation oncologist who determines the fields
(areas) to be irradiated, the total dosage (rads), and the number of days
over which treatments are given. The radiation dosage needed for success-
ful treatment of testicular cancer is low compared to some other cancers.
Radiation works by damaging cellular DNA. The cancer cells are
generally more sensitive to radiation than healthy cells. This is because
healthy cells can often repair the radiation-induced damage done to
them in between treatments. There are negative side effects to radiation
therapy, however, such as diarrhea, nausea, vomiting, and fatigue. The
skin in the irradiated area may become red and sensitive, similar to sun-
burn. Infertility is usually temporary, but may last for one to two years.
Surveillance
For some patients in the earliest stage of testicular cancer, no treatment

beyond the orchiectomy is planned. Instead, these patients may undergo
surveillance. Surveillance involves the monitoring of the patient’s blood
work and the use of imaging techniques to look for signs of a relapse and
providing additional treatment only if surveillance shows a recurrence.
For those patients who elect surveillence and do not have a recurrence,
the benefit is clear: They will avoid the risks associated with additional
treatments.
S UMMA RY
The treatment for testicular cancer depends largely on the type of tes-
ticular cancer a patient has and the cancer stage. For testicular cancer,
if the cancer is localized to the testis or nearby structures, the patient is

considered to be in stage I. Stage II means that the cancer has spread to
regional lymph nodes (mostly commonly retroperitoneal lymph nodes).
Stage III means that the cancer has spread to distant locations beyond
the regional nodes. The first treatment step for all is the orchiectomy. In
some stage I patients, the orchiectomy is the only treatment and patients
are carefully monitored for relapse and given additional treatment only
in the event of a relapse. In most cases, additional treatment is used.
Treatment options include retroperitoneal lymph node dissection,
chemotherapy, and radiation therapy. Radiation therapy is only used
for seminoma patients, as nonseminoma does not respond well to this
treatment.
8
What Causes Testicular Cancer?
KEY POINTS
♦ Testicular cancer most likely occurs as the result of a combination of

genetic and environmental factors, but the causes are not yet known.
♦ Environmental factors suspected of playing a role in testicular can-

cer development include those of the intrauterine environment to
which a male is exposed during fetal life.
♦ Some occupations, such as firefighting, appear to increase the risk

of testicular cancer development.
♦ Established risk factors for testicular cancer are cryptorchidism and

having a family member with testicular cancer. Also, men who have
had cancer in one testicle are at increased risk of developing cancer
in the other testicle.
♦ Testicular cancer rates are higher in some parts of the world than
others. In the United States, white men are at greater risk of testicular
cancer than African American men.
110
What Causes Testicular Cancer? 111
The Leather Tanners
Gloversville is one of the “Glove Cities” of Fulton County, New York,

so named for their prominent role in leather glove manufacturing and
leather tanning in the nineteenth and twentieth centuries. In a three-
year period in the 1980s, three “Glove City” tanners were diagnosed
with testicular cancer. Their cases are summarized in the Morbidity and
Mortality Weekly Report, a Centers for Disease Control and Prevention
publication: “The first case occurred in 1982, when embryonal carci-
noma was diagnosed in a 31-year-old worker who had begun work in
leather tanning 13 years earlier. A second case of combined seminoma
and embryonal carcinoma was diagnosed in 1984 in a 36-year-old
worker who had begun work in this industry 19 years earlier. The third
case of embryonal carcinoma was also diagnosed in 1984 in a 25-year-
old worker who had worked in tanning for 8 years.”1
These three men had more in common than the type of testicular
cancer and their employment history with Fulton County tanneries: They
had all been employed by Gloversville’s Pan American Tannery during
the same time period, on the same shift, and in the same area of the same
department—the spray line of the leather-finishing department. The spray
line involved conveyor belts that moved tanned hides past dye-depositing
spray guns and then to swabbers who spread the dye onto the leather.
Two of the men were swabbers and the other was a foreman whose job
included cleaning spray guns and working as swabber. This cancer cluster
was first reported in the journal Lancet. Stephen Levin and colleagues
described the spray line: “The men had to lean over the hide, with their
faces close to the leather. They wore no gloves and contamination of the
skin and clothing by liquid dye was virtually continuous. During spray-line
operations, a fine mist was present in the air, accompanied by a strong,
solvent-like odor, which was said to be detectable up to 200 meters from
the tannery. General ventilation was provided only by windows; these

were usually kept open, except in winter.”2
Why did these men develop testicular cancer? Was it related to their
job, or were the similarities in their work histories simply a coincidence?
After all, tannery work was a common occupation in Fulton County, so
even if testicular cancer were to occur at a “normal” rate, it is not a surprise
that tanners in the county would be affected. It is usually not possible
to determine with certainty the cause of a given person’s cancer, but
a partial answer to the cause question comes from statistical analyses
that showed the testicular cancer rate among Pan American finishing
department workers to be significantly greater than the expected rate,
which was derived from actual testicular cancer rates in males from up-
state New York. If their cancers were related to their jobs at the tannery,
did these men have other risk factors that increased their chances of
getting cancer? After all, there were many men employed in their depart-
ment who did not develop testicular cancer. If it was job related, what
chemicals or other work conditions were responsible? This question is
nearly impossible to answer on a case-by-case basis. The men had been
exposed to many chemicals, and as a further complication, two of the
men had worked previously on spray lines at other tanneries.
In the Levin report, speculation surrounded the solvent dimethylfor-
mamide (DMF). One of the reasons for singling out DMF was because it
had been suspected in other testicular cancer clusters, including two at
aircraft maintenance facilities. Suspicion is not proof, however, and the
cause of testicular cancer in these men remains uncertain.
Environment, Genetics, and Testicular Cancer
The incidence of testicular cancer has increased in recent decades:

In the past five decades, the incidence has more than doubled. This
Figure 8.1 Tannery workers, such as those shown here, are at a higher risk for
testicular cancer. Exposure to dimethylformamide (DMF), a chemical solvent
used in tanneries, is suspected to be to blame for this increased risk, although
it has not been proven conclusively. (© Stephanie Maze/CORBIS)
increase in occurrence suggests that the environment plays an important

role in testicular cancer development; while a person’s genetic makeup
undoubtedly plays a role, genetics alone would not account for these
recent increases.
The study on the leather tanners suggests a role for environmental
factors such as chemical pollutants, but many questions persist. If envi-
ronmental factors play a role in testicular cancer, what other environmen-
tal factors might be involved? Can radiation play a role? Can particular
microorganisms infect a person and contribute, directly or indirectly, to
development of this cancer? Since testicular cancer typically develops

early in life, can the intrauterine environment to which the developing
fetus is exposed (e.g., toxicants, normal maternal chemicals such as
hormones) play a role? Can a person’s own hormonal environment
influence testicular cancer development? To what extent is a person’s
hormonal environment influenced by factors in the external environ-
ment? Researchers continue to examine testicular cancer data in an
attempt to identify relevant environmental factors for testicular cancer
development. The task is challenging for many reasons, which include
the small size of the pool of affected individuals, the fact that testicular
cancer is not a single disease, and that analysis typically begins only
after a diagnosis of testicular cancer has been made.
Studies have attempted to uncover links between testicular cancer
and other factors, such as maternal age, but without success. An intrigu-
ing question arose about diethylstilbestrol (DES), a synthetic estrogen
prescribed to many pregnant women between the late 1930s and
early 1970s to prevent miscarriage. Sons of women who took DES during
pregnancy could be at greater risk for testicular cancer. Many different
investigations looked into this question. While it has been shown that
DES daughters are at increased risk of a type of vaginal/cervical cancer
and reproductive abnormalities, the only clearly demonstrated effect on
DES sons is an increased risk for epididymal cysts, which are benign. It
has not been established that DES sons are at increased risk of testicular
cancer; some studies have shown that DES sons are at increased risk,
while others have not shown a DES-testicular cancer relationship.
Katherine McGlynn and colleagues at the NCI have recently found
evidence of a link between DDT, a pesticide now banned in the United
States, and testicular GCTs. Their study took advantage of the fact that
hundreds of U.S. servicemen had given blood samples well before any of
them developed testicular cancer. These blood samples were still avail-
able and could be evaluated to see if any chemicals in them might be
linked to later development of testicular cancer. The researchers found
that those who had high concentrations of a DDT breakdown product
in their blood were significantly more likely to eventually develop
testicular cancer than those with low concentrations. DDT and other or-
ganochlorine (organic compounds with chlorine) pesticides have long
been suspected in testicular cancer because they can affect hormones
in the body, which themselves have been suspected to influence the risk
of this cancer.
Another way to assess environmental factors is to examine occu-
pational risk—whether certain occupations (such as leather tanning)
carry increased testicular cancer risk. For example, many studies show
that firefighters are at increased risk for testicular cancers due to their
occupational exposure to soot and chemicals such as benzene. (Brit-
ish Columbia now defines testicular cancer as an occupational risk for
firefighters.) Another study suggested that the use of handheld radar
guns by police (often positioned near testicles) might increase testicular
cancer risk. Many other occupations have also been evaluated.
What is the role of genetics? A known, established risk factor for
testicular cancer is a family history of testicular cancer. The greatest
risk is having a brother with testicular cancer, which increases the
risk up to tenfold, more than is normally seen with other cancers. This
suggests an important role for genetics in the development of testicular
cancer. (It is important to remember, however, that brothers often have
numerous environmental factors in common.) If a gene or genes play
a role, on what chromosomes are these susceptibility genes located?
Studies to find regions of chromosomes that may affect testicular cancer
risk rely on analysis of affected families, defined as families with two
Figure 8.2 The pesticide DDT was widely used in the first half of the twentieth
century. In this photograph an army field hospital is being sprayed with DDT. It
was later discovered that exposure to DDT led to an elevated risk of testicular
cancer. (© National Library of Medicine/U.S. Institutes of Health)
or more individuals with testicular cancer. For testicular cancer, such

studies are limited by the small number of affected families. To date,
no studies have conclusively pointed to a specific chromosome region
as associated with testicular cancer development. More likely, testicular
cancer risk is influenced by many genes scattered throughout a person’s
chromosomes.
If scientists do eventually find genes associated with testicular can-

cer, this will not rule out a role for the environment. Most likely, testicular
cancer will be found to be caused by a combination of environmental
and genetic factors.
Established Risk Factors for Testicular Cancer
In addition to a family history of testicular cancer, there are two other

known risk factors: cryptorchidism (undescended testicle) and a per-
sonal history of testicular cancer.
Up to 5 percent of boys are born with cryptorchidism. Men who have
a history of cryptorchidism have a testicular cancer risk that is 2 to 8 times
the normal rate. For most of those born with cryptorchidism, the testicle
descends spontaneously into the scrotum within a few months of birth.
However, for the remainder the testicle does not descend on its own, and
treatment (commonly with orchiopexy, a surgery that places the testicle
in the scrotum) is warranted. The age at which this surgery is performed
varies, but many urologists now recommend surgery before the age of
one year. Orchiopexy is important for eventual sperm production; rela-
tive to testicular cancer, it allows for a testicular abnormality—such as a
lump—to be felt, increasing the likelihood of early detection.
Since cryptorchidism increases the chance of testicular cancer, can
the risk of developing testicular cancer risk be reduced by orchiopexy?
If so, does the age at which orchiopexy occurs affect this risk? A study
of close to 17,000 men in Sweden compared the testicular cancer risk in
those who underwent orchiopexy before the age of 13 to those who had
surgery at 13 years or older (approximately pre- vs. postpuberty) and found
that early surgery halved the risk.3 However, a similar study in Denmark
showed that orchiopexy age had no effect on testicular cancer risk.4
Why is cryptorchidism a risk factor for testicular cancer? Could it be

because it can somehow cause testicular cancer? Alternatively, could
cryptorchidism and testicular cancer have the same cause or causes?
The answers to these questions are not yet known. The path to the
answer will likely be influenced by an interesting fact: The increased
testicular cancer risk extends to the normally descended testicle as well
as to the cryptorchid testis.
A personal history of testicular cancer is a risk factor for testicular
cancer. In other words, a person who develops testicular cancer is at in-
creased risk for developing testicular cancer in the other (contralateral)
testicle. Sometimes the two cancers occur simultaneously, but often the
second cancer occurs later. These second cancers are primary cancers
and are not due to metastasis. Men who have been treated for testicular
cancer are informed of the risk to the other testicle so they can be alert
to symptoms, and the other testicle is carefully evaluated during follow-
up exams.
Testicular Cancer Rates Vary

Among Different Groups
In the United States, testicular cancer occurs more frequently in white
men than in African American men—some reports say the rate is up to 5
times higher. It is also more frequent in white men than in Asian, Pacific
Islander, or Alaska Native men. The incidence is lower for Hispanic white
men than non-Hispanic white men
In addition, testicular cancer rates are not uniform across the globe.
There is a high incidence of testicular cancer in Scandinavian countries,
Germany, and New Zealand. The lowest rates are in Asia and Africa. It
is not known why this is the case, but, interestingly, this increased risk
does not appear to disappear when people from these parts of the world
migrate to different places.
SUMMA RY
The causes of testicular cancer are not known, but it most likely occurs
as a result of a combination of environmental and genetic factors. Since
testicular cancer tends to occur at a young age, scientists are particularly
interested in determining the role of the intrauterine environment in
testicular cancer development. The intrauterine environment includes
truly external factors such as toxicants as well as more internal factors,
such as hormones produced by the mother. Certain occupations may
put a person at greater risk of developing testicular cancer. A man is
more likely to develop testicular cancer if he has a family member, par-
ticularly a brother, who developed testicular cancer and if he was born
with an undescended testicle. Another risk factor for testicular cancer
is testicular cancer itself: A man who develops testicular cancer has an
increased chance of developing a new testicular cancer in the other
testicle. Testicular cancer rates are greater in some parts of the world
than other. In the United States, testicular cancer occurs at a greater rate
in white men than in African American men.
9
Challenges
and
Questions for the Future
KEY POINTS
♦ Despite the remarkable progress that has been made in the field of
testicular cancer, many questions and challenges remain.
♦ Most men survive testicular cancer, but better success is needed

to help those whose initial prognosis is poor or those who do not
respond successfully to initial treatment.
♦ Physicians want to be able to minimize the treatment needed for

testicular cancer while maintaining the current success rate.
♦ Researchers want to learn more about the many steps that occur as
a normal cell of the testicle is transformed into a cancer cell, and
they want to understand why, and when, these changes occur.
♦ Physicians and researchers from a variety of training backgrounds

can contribute to the field of testicular cancer research.
120
Challenges and Questions for the Future 121
There have been remarkable successes in the diagnosis and treatment

of testicular cancer, but important and exciting challenges remain.
Some of these challenges are at the clinical level where they most affect
patient survival. Some are at the environmental level where solutions
may eventually prevent some testicular cancers from developing. Other
challenges are at the molecular level, where solutions may explain the
many changes that occur in a cell as it is transformed to a cancer cell.
Answers to molecular questions are interesting from a broad range of
scientific perspectives, and they will ultimately help in the battle against
testicular cancer.
Diagnosis of Testicular Cancer
One of the challenges for the pathologist is the determination of testicu-

lar cancer type, as some can resemble others. In addition, for mixed
GCTs, it is important that all tumor subtypes be identified. Immunohis-
tochemistry, which can detect molecules specific to certain tumor cell
types, has provided an important tool to pathologists. As scientists learn
more about which molecules are specific to certain tumor cell types, the
ability of immunohistochemistry to fine-tune diagnosis will increase.
Treatment Options
Advances in testicular cancer treatment make testicular cancer one of
the most curable cancers. In some situations, such as stage I seminoma,
the cure rate is close to 100 percent. Yet each year in the United States,
hundreds of men die of testicular cancer; much of the effort to develop
new treatment methods is therefore directed at this group. Some non-
GCTs still carry a poor prognosis, and successful efforts are needed to
address these rare cancers. Even for GCTs, with an overall cure rate of
greater than 90 percent, the cure rate is lower (approximately 80 percent)

once the disease has metastasized. For GCTs, more progress needs to
be made in certain poor-risk categories: patients who relapse later than
normal (two years post-therapy), patients with primary mediastinal non-
seminomatous GCTs, teratoma patients whose tumors have undergone
malignant transformation to form aggressive neural ectodermal tumors,
and patients in need of salvage therapy.
The remarkable successes with chemotherapy and radiation in tes-
ticular cancer treatment bring another problem: long-term side effects,
such as second cancers. While radiation and chemotherapy always bring
such risks, the concern is greater for the typical testicular cancer patient
because his young age at treatment increases the post-treatment years
during which a new cancer can develop. These problems are being ad-
dressed in several ways. New chemotherapy and radiation protocols are
being evaluated. In addition, for certain low-risk patients, surveillance
rather than therapy is the preferred choice.
Surveillance carries obvious benefits, as those whose orchiectomy
is followed only by monitoring will not experience the side effects of
chemotherapy or radiation therapy. Surveillance addresses the problem
that many low-risk patients can be cured by orchiectomy alone and so
for these individuals, chemotherapy or radiation is over-treatment. The
obvious dilemma that follows from this is that it is not currently pos-
sible on a case-by-case basis to predict which patients will not develop
metastases. There is some information in this area; for example, it has
been shown for stage I seminoma, larger primary tumors are more likely
to metastasize than smaller ones. If metastasis potential based on tumor
characteristics at the cellular or molecular level can be determined, in-
dividual treatment decisions will be easier. Whatever treatment changes
are made, it is important that they do not compromise the existing
successes. This is also true for RPLND, where debate is ongoing over
minimally invasive versus open surgery, and on the surgical templates
themselves.
Growing Understanding of Testicular Cancer
Researchers want to understand completely the steps by which a normal

cell becomes a testicular cancer cell. For GCTs, progress has been made
in this area, but many questions remain. Scientists have found that for
postpuberty GCTs other than spermatocytic seminoma, GCTs are pre-
ceded by carcinoma in situ, which appears to always develop into a
GCT. Interestingly, carcinoma in situ and GCTs share another common
feature: They have extra DNA from a particular region of chromosome
number 12. Sometimes this genetic material exists as an abnormal in-
dependent chromosome piece known as an isochromosome, at other
times it is attached to an existing chromosome, but it is always present,
suggesting that certain genes in this region are important in cancer de-
velopment. Additional GCT characteristics that scientists want to learn
more about are the presence of extra chromosomes (postpuberty GCTs
often have three or four sets of chromosomes rather than two) and the
loss of certain chromosome regions.
An interesting question surrounds the relationship among GCT types.
The differences between pre- and postpuberty GCTs (for example, extra
chromosome 12 material is not characteristic of prepuberty GCTs) are
a curiosity, as is the difference in age profile between seminoma and
nonseminoma patients. Scientists want to understand the relationship
between carcinoma in situ and the various GCT types and whether each
GCT type arises directly from carcinoma in situ or whether some GCT
types develop from other GCT types.
Chemotherapy questions at the cellular level remain. Testicular

cancer cells are generally more sensitive that other cancer cells to
cisplatin, but scientists want to understand the underlying reason for
this. They are also particularly interested in understanding the reasons
that, for some men, testicular cancers do not respond to cisplatin. If the
reasons for the lack of cisplatin sensitivity can be found, then hopefully
those whose cancer will not respond can be identified before cisplatin
therapy failure.
Opportunities in Testicular Cancer Research
Testicular cancer research, which can take place in a clinical setting

with patients, in the laboratory setting with animals or cells or molecules,
and through computer analysis of cancer data, is an exciting field. Re-
searchers come from a variety of backgrounds: Some are physicians
(M.D., D.O.), some hold higher degrees (e.g., Ph.D.) in various scientific
fields, some hold dual degrees (M.D./Ph.D.; Ph.D./MPH). They may dif-
fer in the academic areas in which they have trained. Some have studied
molecular biology; others have focused in areas such as immunology,
genetics, molecular biology, developmental biology, or epidemiology;
and most have training that encompasses several disciplines. Physicians
may differ in the areas in which they specialize. Some have trained in
urology; others have trained in areas such as radiation oncology. All
of these individuals are important to improved understanding of the
causes of testicular cancer and improving treatment success.
S UMMA RY
Many interesting questions and challenges remain regarding testicular

cancer. The most important of these include improving treatment for
Figure 9.1 Doctors and researchers across many medical and science disci-
plines are working to improve our understanding of testicular cancer. (© Radu
Razvan/Shutterstock images)
the testicular cancer types and cases that still carry a poor prognosis,
and learning about the many cellular and molecular changes that occur
as a normal cell of the testicle is transformed into a cancer cell. These
challenges can be overcome by the work of individuals from a variety of
academic and clinical backgrounds.
notes
♦
Chapter 1
1. Lawrence H. Einhorn, “Testicular Cancer: An Oncological Success Story,”
Clinical Cancer Research 3, 12 (1997): 2630–2632.
Chapter 2
1. Mike Eisenbath, “Jason’s Story,” http://www.testicularcancer.org/
abouttcstoryone.htm (accessed August 21, 2008).
2. Sean Kimerling Testicular Cancer Foundation, “Survivor Stories,” http://
www.seankimerling.org/pages/programs/programs_videos_survivor.
html (accessed August 21, 2008).
3. Tom Struble, “A Father’s Challenge to Educators and the Medical Community,”
Jason A. Struble Memorial Cancer Fund, http://www.testicularcancer.
org/ourchallenge-educators.htm (accessed August 21, 2008).
Chapter 7
1. American Cancer Society, “Detailed Guide, Testicular Cancer: How is
Testicular Cancer Staged?” http://www.cancer.org/docroot/CRI/con-
tent/CRI_2_4_3X_How_is_testicular_cancer_staged_41.asp?sitearea=
(accessed August 21, 2008).
2. National Cancer Institute, “Testicular Cancer Treatment,” http://www.
cancer.gov/cancertopics/pdq/treatment/testicular/HealthProfessional/
page4 (accessed August 21, 2008).
3. A. Bahrami, Jae Y. Ro, and Alberto G. Ayala, “An Overview of Testicular
Germ Cell Tumors,” Archives of Pathology and Laboratory Medicine 131, 8
(2007): 1267–1280.
4 S. E. Eggener, B. S. Carver, D. S. Sharp, R. J. Motzer, G. J. Bosl, and J. Shein-
feld, “Incidence of Disease Outside Modified Retroperitoneal Lymph Node
Dissection Templates in Clinical Stage I or IIA Nonseminomatous Germ
Cell Testicular Cancer,” Journal of Urology 177, 3 (2007): 937–943.
5. M. C. Li, W. F. Whitmore Jr., R. Golbey, and H. Grabstald, “Effects of Com-
bined Drug Therapy on Metastatic Cancer of the Testis,” Journal of the
American Medical Association 174 (1960): 1291–1299.
126
notes 127
6. . L. Samuels, V. J. Lanzotti, P. Y. Holoye, L. E. Boyle, T. L. Smith, and D.

M
E. Johnson, “An Update of the Velban-Bleomycin Program in Testicular
Neoplasia with a Note on Cis-dichlorodiammineplatinum,” Cancer of the
Genitourinary Tract. New York: Raven Press, 1979, 159–172.
7. L. H. Einhorn, “Testicular Cancer: An Oncological Success Story,” Clinical
Cancer Research 3, 12 (1997): 2630–2632.
8. S. D. Williams, R. Birch, L. Irwin, A. Greco, P. J. Loehrer, and L. E. Einhorn,
“Disseminated Germ Cell Tumors: Chemotherapy with Cisplatin Plus
Bleomycin Plus either Vinblastine or Etoposide,” New England Journal of
Medicine 316 (1987): 1435–1440.
9. Lawrence H. Einhorn, Stephen D. Williams, Amy Chamness, Mary Brames,
Susan Perkins, and Rafat Abonour, “High-Dose Chemotherapy and Stem-
Cell Rescue for Metastatic Germ-Cell Tumors,” The New England Journal of
Medicine 357, 4 (2007): 340–348.
Chapter 8
1. Centers for Disease Control and Prevention, “Epidemiologic and Reports
Testicular Cancer in Leather Workers—Fulton County, New York,” Morbid-
ity and Mortality Weekly Report 38, 7 (1989): 111–114.
2. S. M. Levin, D. B. Baker, P. J. Landrigan, S. V. Monaghan, E. Frumin, M.
Braithwaite, and W. Towne, “Testicular Cancer in Leather Tanners Exposed
to Dimethylformamide (letter),” Lancet 2, 8568 (1987): 1153.
3. A. Petterson, L. Richiardi, A. Nordenskjold, M. Kaijser, and O. Akre, “Age
of Surgery for Undescended Testis and Risk of Testicular Cancer,” The New
England Journal of Medicine 356, 18 (2007): 1835–1841.
4. C. Myrup, et al., “Correction of Cryptorchidism and Testicular Cancer
(correspondence),” The New England Journal of Medicine 357 (2007):
825–827.
glossary
♦
alpha-fetoprotein A protein normally made in fetal life that can be
found at high concentrations in the blood of those with some types
of testicular cancer.
antibiotic An antimicrobial compound produced by a microbe.
antibody A defensive protein that can bind specifically to other
molecules.
apoptosis Programmed cell death.
blood-testis barrier A physical barrier formed by Sertoli cell
junctions that prevents materials from passing between the blood
and the cells of the testis.
cancer stage The degree to which a cancer has advanced.
carcinoma in situ An early cancer that has not invaded surrounding
tissues.
chemotherapy The use of chemicals to treat cancer.
choriocarcinoma A type of nonseminomatous germ cell testicular
cancer.
chorion A membrane associated with the embryo that forms the fetal
part of the placenta.
clinical stage The cancer stage determined before tissue is removed
and analyzed in a pathology laboratory.
complete remission The disappearance of all signs of a cancer.
computed tomography (CT) scan An imaging technique that uses
X-rays to produce a three-dimensional image.
cryptorchidism A condition in which a testicle does not descend
into the scrotum before birth.
cytotoxic Toxic to cells.
128
glossary 129
cytotrophoblasts Cells derived from trophoblasts that are part of the

chorion.
diploid Having two copies of each chromosome.
efferent ductules Tubes that carry sperm from the testis to the
epididymis.
ejaculatory duct A sperm-carrying tube (the end of each vas deferens)
that joins the urethra.
embryonal carcinoma A type of nonseminomatous germ cell
testicular cancer.
endocrine gland A group of cells that secrete materials directly into
the bloodstream.
enzyme A protein that speeds up a chemical reaction but is not itself
changed by the reaction.
epidemiologist A scientist who studies epidemiology, a science that
examines the distribution and causes of disease.
epididymis A long, coiled tube that carries sperm from the efferent
ductules that leave the testis to the vas deferens.
exocrine gland A group of cells that secrete materials through a
duct.
external inguinal ring The end of the inguinal canal closest to the
scrotum.
extraembryonic membranes Structures, such as the yolk sac, that
are attached to an embryo and assist in its development.
extragonadal germ cell tumors Germ cell tumors that arise outside
of the gonads.
gametes Reproductive cells (in males, sperm).
germ cell Gametes, or cells that develop into gametes.
130 glossary
germ cell cancer A cancer of a cell that would normally develop into
a germ cell.
germinal epithelium The part of the seminiferous tubule dedicated
to sperm production, i.e., the germ cells and the Sertoli cells.
gonads Organs that form gametes (in males, the testes).
gonocytes Cells in the embryo/fetus that are precursors of
spermatogonia.
gubernaculum The tissue that connects the testis to the inside of the
scrotum.
gynecomastia Enlargement of breast tissue in males.
haploid Having one copy of each chromosome.
hematopoietic Blood cell forming.
hilus The region of a testis where blood, lymphatic, and sperm-
carrying vessels connect.
histology The microscopic study of tissues.
hormone A substance made by one part of the body that travels
through the blood to another and affects its activity.
human chorionic gonadotropin A small protein hormone normally
produced by the placenta to maintain pregnancy, which can be
found at high concentration in the blood of those with some types
of testicular cancer.
hydrocele Fluid accumulation in a sac that surrounds the testicle.
immunohistochemistry The use of antibodies to specifically label
certain cellular molecules.
induction therapy Initial chemotherapy.
inguinal canals Tubelike passageways that connect the abdomen to
the scrotum.
glossary 131
internal inguinal ring The end of an inguinal canal that is furthest

from the scrotum.
interstitium An area of connective tissue that separates the
seminiferous tubules of the testes.
isochromosome An abnormal chromosome, formed by abnormal
chromosome division, with two identical arms (ends).
laparoscopic RPLND A type of retroperitoneal lymph node
dissection performed using minimally invasive surgery in which
the retroperitoneal lymph nodes are accessed by tiny incisions,
one of which is used to insert a visualization instrument known as
a laparoscope.
Leydig cells Cells of the interstitium of the testes that produce
testosterone.
lobules Sections of the testes separated by connective tissue.
lymph Tissue fluid contained in lymph vessels.
lymph nodes Small organs located along lymphatic vessels that filter
lymph and destroy, or become activated to destroy, microbes and
cancer cells.
lymph vessels The tubes that collect excess tissue fluid and return it
to the circulatory system.
malignant tumor A tumor that spreads to nearby tissues and may
spread to more distant sites by metastasis (cancer).
mediastinum An area of the chest between the lungs.
mediastinum testis An area of the testis that is rich in connective
tissue and contains the rete testis.
meiosis A type of cell division process that in animals produces
haploid cells, or cells with only one copy of each chromosome
(sperm in males).
132 glossary
metastasize To spread from the site of the original tumor to other

parts of the body.
mitosis A type of cell division that produces cells identical to the
parent cell.
mixed germ cell tumor A type of germ cell tumor that contains more
than one type of germ cell tumor.
neoplasm A tumor, either benign or malignant.
non–germ cell cancer A cancer of a cell of the gonad (testis in the
male) that is not in the gamete (sperm in the male) developmental
pathway.
nonseminoma A type of germ cell tumor that includes embryonal
carcinoma, yolk sac tumor, trophoblastic tumors such as
choriocarcinoma, teratoma, and mixed germ cell tumors.
orchiectomy A surgical procedure to remove a testicle.
orchiopexy A surgical procedure to move an undescended testicle
into the scrotum.
orchitis Inflammation of the testis.
pampiniform plexus Network of veins in the spermatic cord.
pathologic stage The cancer stage as determined by tissue analyzed
in a pathology laboratory.
pathologist A physician who studies tissues to determine the presence
and extent of disease.
peritoneum The lining of the abdominal cavity.
placenta The structure that connects and exchanges materials
between the fetus and the mother.
primary spermatocytes Cells in the sperm developmental pathway
produced from spermatogonia that divide to produce secondary
spermatocytes.
glossary 133
primordial germ cells Cells in the developing embryo/fetus that are

the precursors of gonocytes.
radiation therapy The use of radiation to kill cancer cells.
radiologist A physician who specializes in the use of radiation
therapy.
rete testis A network of tubules that collect sperm made by
seminiferous tubules in the testis.
retrograde ejaculation Movement of sperm into the bladder rather
than the urethra.
retroperitoneal lymph node dissection (RPLND) Removal of
lymph nodes from the retroperitoneum.
retroperitoneum An area at the back of the abdomen behind the
peritoneum.
risk factor Something that increases the chance of developing a
disease.
salvage therapy Treatment used after a cancer has failed to respond
to initial treatments.
secondary spermatocytes Cells in the sperm developmental
pathway produced from primary spermatocytes that in turn produce
spermatids.
semen The sperm and seminal fluid released from the urethra during
ejaculation.
seminal fluid Fluid added to sperm in the vas deferens and urethra.
seminiferous tubules Small tubes in the testes that produce sperm.
seminoma A type of germ cell cancer.
Sertoli cells Cells of the testis that assist in sperm development.
serum The fluid portion of the blood that remains after blood
coagulates.
134 glossary
single agent chemotherapy Treatment of cancer with a single

chemical agent.
somatic cells Body cells that are not germ cells.
spermatic cord The cord that suspends the testis in the scrotum and
provides connections to the abdomen.
spermatids Cells derived from secondary spermatocytes that in turn
develop into sperm cells.
spermatocele A fluid-filled cyst in the epididymis.
spermatocytic seminoma A type of germ cell cancer that develops
in older men.
spermatogenesis The stepwise process of sperm formation.
spermatogonia Spermatogenic stem cells that can divide to make
copies of themselves and to primary spermatocytes that will develop
into sperm.
spermiogenesis Maturation of a spermatid into a sperm.
stem cell rescue Infusion of bone marrow stem cells to replace those
killed through chemotherapy.
syncytiotrophoblasts Cells derived from trophoblasts that are part
of the chorion.
teratoma A type of nonseminomatous germ cell testicular cancer.
testicular torsion Twisting of the spermatic cord resulting in loss of
blood supply to the testicle.
testosterone A steroid sex hormone produced largely by the testes that
functions in the development and maintenance of male secondary
sexual characteristics.
tissue fluid Fluid that surrounds and bathes tissues of the body.
TNM system A system used for cancer staging that evaluates the local
spread of the primary tumor (T), its metastasis to regional lymph
glossary 135
nodes (N), and its metastasis to nonregional lymph nodes and

organs (M).
trophoblastic tumor A type of nonseminomatous germ cell testicular

cancer.
trophoblasts Cells of the chorion.
tumor An abnormal mass of cells produced by cell division (neoplasm),

which can be benign or malignant.
tumor markers Molecules whose presence or increased concentration

in the blood or other tissues can indicate particular cancer types.
tunica albuginea A smooth layer of connective tissue that forms the

outside layer of a testicle.
tunica vaginalis A flattened sac that wraps around much of a testis.
ultrasound A diagnostic procedure that uses sound waves to analyze

tissue.
urethra A tube that carries sperm and urine to the outside of the
body.
varicocele An enlargement of the veins that carry blood from the

testis.
vas deferens A tube that carries sperm from the epididymis to the
urethra.
X-ray A type of radiation used for disease diagnosis.
yolk sac An extraembryonic membrane that is responsible for

production of a fetus’s first blood cells and primordial germ cells.
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index
♦
A stage. See stages of cancer

treatment. See treatment for cancer
abdomen, pain in, 33, 35
cancer staging, 89
Abrams, Dan, 26
carcinoma in situ, 123
Actinomycin D. See dactinomycin
Catharanthus roseus, 103
AFP. See alpha-fetoprotein
age and cancer. See cancer, age and; cells. See also germ cells; non-germ cells
testicular cancer, age of onset division, 7
alpha-fetoprotein (AFP), 17, 40–41, 45, 72 Centers for Disease Control and Preven-
American Cancer Society, 27, 31 tion, 111
American Urological Association, 16 chemotherapy
antibiotics, 104 from bacteria, 104–105
antibody, 44–45 described, 18, 87–88, 98–103, 109
apoptosis, 106 mode of action, 106
Armstrong, Lance, 21, 66, 88 nonresponse to, 22
Australopithecus, 6 from plants, 103–104
side effects, 107
B success of, 122
bacteria, chemotherapy from, 104–105 children, conceiving after treatment, 15
B cell, 85 chorion, 41
Beer, Charles Thomas, 104 choriocarcinoma, 65, 76–77, 81
benign tumor, 38, 82 chromosomes, 56
biopsy, 17, 19 circulatory system and testis, 48, 61–62
bleomycin, 99, 100, 106 cis-diamminedichloroplatinum. See
blood-testis barrier, 57 cisplatin
blood tests, 36 cisplatin, 20, 24, 100–101
blood vessels, 61 c-Kit (receptor molecule), 75
bone marrow, 107 classic seminoma. See seminoma
breast tissue, enlargement of. See clinical stage, 90
gynecomastia clinical trials, 20
Brian’s Song, 70 complete remission (CR), 99
Burkitt’s lymphoma, 6 computed tomography (CT) scans, 19
CR. See complete remission
C cryptorchidism, 19, 24, 110, 117–118
cancer CT scans. See computed tomography
age and, 7 scans
history of, 6–7 cytotoxic, 107
research, 8, 124 cytotrophoblasts, 41, 77
149
150 INDEX
D etoposide, 102, 103, 106

exocrine gland, 49
dactinomycin, 104
external inguinal ring, 49
DDT, 114–115, 116
extraembryonic membranes, 67
deoxyribonucleic acid. See DNA
extragonadal germ cell tumors (EGG-
DES. See diethylstilbestrol
CTs), 70
detection of testicular cancer
extratesticular mass, 38
described, 15–18, 26–27
early —, 25, 35
roles of physician and patient, 27, 29
G
screening for, 30–3 gametes, 40, 56
self-examination, 29–32 genetic causes of testicular cancer, 19,
symptoms of testicular cancer, 33 22, 69, 110, 119
diagnosis of testicular cancer germ cells
challenges of, 121 defined, 11, 12
histology, 43–45 described, 54–56, 80
lactate dehydrogenase, 43 germ cell cancer
orchiectomy and analysis, 43 defined, 12
steps to, 36–37, 45 described, 14, 23, 65, 66–69
tumor markers in blood, 38–42 tumors in boys and older men, 69, 71
ultrasound, 37–38 types of, 66–69, 71–80. See also
diethylstilbestrol (DES), 114 specific types of testicular cancer
dimethylformamide (DMF), 112, 113 germ cell tumor (GCT), 66, 123
DMF. See dimethylformamide germinal epithelium, 53
DNA, 7, 56 gland, 49
Donohue, John, 96 Gloversville, New York, 111
gonads, 48
E gonocytes, 54
groin pain, 33, 35
efferent ductules, 59
gubernaculums, 49
EGGCTs. See extragonadal germ cell
gynecomastia, 25, 33, 35, 41, 71, 73–74,
tumors
83, 84
Egypt, cancer in, 6
Einhorn, Lawrence, 20–22, 100, 103
ejaculatory duct, 59 H
embryo, 78 Hamilton, Scott, 16, 66, 87–88
embryonal carcinoma, 65–69, 73–74, 81 haploid, 56
endocrine gland, 49 hCG. See human chorionic gonadotropin
environmental causes of testicular hematopoietic stem cells, 102
cancer, 19, 110, 115, 119 hematoxylin-eosin stain, 44–45
enzyme, 43 hemorrhage, 72
epidemiologists, 23 Herceptin, 8
epididymis, 31, 59 hidden testis. See cryptorchidism
epididymitis, 34 hilus, 50
ethnicity and cancer rates, 118–119 histology, 43–45, 76
INDEX 151
Homo erectus, 6 Li, Min Chiu, 98–99, 104

hormones, 48–49 lobules, 51
human chorionic gonadotropin (hCG), Lowell, Bertica, 14
41–42, 45, 72 Lowell, Mike, 12, 13, 66, 88
human development, early, 67 lung problems, 107
hyaline globules, 76 lymph, 62
hydroceles, 34 lymphatic system and testis, 48, 62–63,
71–72
I lymph nodes, 14, 48
lymphoma, 85, 86
immunohistochemistry, 44–45, 75
lymph vessels, 50
Indiana University, 20–21, 96, 100, 106
induction therapy, 102
inguinal canal M
defined, 49 malignant tumor, 12, 46. See also cancer;
described, 48–50 testicular cancer
internal inguinal ring, 49 McGlynn, Katherine, 114
interstitium, 47, 51 M.D. Anderson Cancer Center, 20, 99
intratesticular mass, 38 mediastinum testis, 51
isochromosome, 123 meiosis, 55–56
Memorial Sloan-Kettering Cancer Center,
J 97, 98
metastasized, 14
Jason A. Struble Memorial Cancer Fund,
MGCTs. See mixed germ cell tumors
Inc., 27
Michigan State University, 20, 100
mitosis, 55
K mixed germ cell tumors (MGCTs), 18, 66,
Kimerling, Sean, 16–17, 66 68, 72, 80, 81
Ki-1 (receptor molecule), 75 Morbidity and Mortality Weekly Report,
111
L mummies, bone tumors in, 6
myelosupression, 107
lactate dehydrogenase (LDH), 43, 45
Lafayette High School (Missouri), 26
Lancet, 111 N
laparoscopic RPLDN, 97–98 National Cancer Act, 7
LCCSCT. See Sertoli cells, large cell National Cancer Institute (NCI), 7, 14–15,
calcifying 30–31, 114
LDH. See lactate dehydrogenase NCI. See National Cancer Institute
Leakey, Louis, 6 necrosis, 72
leather tanners, 111–116 neoplasm, 20
Levin, Stephen, 111–112 Nichols, Craig, 21
Leydig cells Nixon, Richard, 7
non-germ cell tumor, 48, 52, 82, 83, 86 Noble, Robert, 103–104
testosterone-making cell, 47, 64 non-germ cells, 12, 53–54, 57
152 INDEX
non-germ cell cancer/tumor placenta, 41

described, 82–83, 85 placental alkaline phosphatase (PLAP),
formation of, 48 75
Leydig cell tumors, 83 plants, chemotherapy from, 103–104
lymphoma, 85 PLAP. See placental alkaline
rete testis carcinoma, 85 phosphatase
Sertoli cell tumors, 83–84 pneumonitis, 107
nonseminoma, 16, 17, 68, 88 Podophyllum
nonseminomatous germ cell cancers, emodi Wall, 103
65, 68, 80, 81, 91. See also chorio- peltatum L., 103
carcinoma; embryonal carcinoma; primary spermatocytes, 55
teratoma; trophoblastic tumor; yolk primordial germ cells, 54
sac tumor pulmonary fibrosis, 107
Purdue University, 106
O PVB therapy, 100–102
occupational causes of testicular cancer,
110, 111–117, 119 R
orchiectomy race and cancer rates, 118–119
analysis following, 17, 43, 48 radical inguinal orchiectomy, 43, 46
defined, 12 radiation therapy
described, 87–88, 109 described, 14, 18, 87–88, 107–108,
treatment following, 18 109
orchiopexy, 117 success of, 122
orchitis, 34 radiologist, 38
ova, 40 receptor molecule, 75
research. See cancer, research
P rete testis, 58–59, 60, 86
rete testis carcinoma, 82, 85, 86
paclitaxel 103, 106
retrograde ejaculation, 96
pampiniform plexus, 62
retroperitoneal lymph node dissection
Pan American Tannery, 111
(RPLND), 87, 90–91, 95–98, 109, 123
pathologic stage, 90
retroperitoneum, 48, 49, 63
pathologist, 12, 46
risk factors. See testicular cancer, risk
patient’s role and detection of testicular
factors
cancer, 27, 29
Rosenberg, Barnett, 20, 99, 100–101
peritoneum, 49
RPLND. See retroperitoneal lymph node
personal history of testicular cancer, 117,
dissection
118, 119
Rutgers University, 104
Peyrone’s salt. See cisplatin
physical examination, 15, 27, 35
physician’s role and detection of S
testicular cancer, 27, 29 sac. See scrotum
Piccolo, Brian, 70 salvage therapy, 102
INDEX 153
Samuels, Melvin L., 99, 100 spermatoceles, 34

Schiller-Duval bodies, 76 spermatocytic seminoma, 65–66, 69,
screening for testicular cancer, 29, 72–73, 81
30–31 spermatogenesis, 52–53, 56
scrotum spermatogonia, 55
changes in, 25, 33, 35 spermatozoa. See sperm, cells
described, 48–50 stages of cancer. See also testicular
location, 29–32 cancer, stages of
testes move into, 47 described, 88–94
SCTs. See Sertoli cells I, 87, 89, 91, 94, 97, 109
SCT NOS. See Sertoli cells, not otherwise subcategories, 89
specified III, 87, 89, 94, 97, 98, 109
secondary spermatocytes, 55 II, 87, 94, 98, 109
self-examination for testicular cancer, 28, Stähelin, Hartmann, 103
29–32, 35 stem cell rescue, 102
semen, 60 Streptomyces, 104, 105
seminal fluid, 60 Struble, Jason, 26–28, 66
seminiferous tubules, 47, 51, 60, 64 surgery, 18, 35
seminoma, 12, 14, 17, 65, 68–69, 71–72, surveillance, 18, 108, 122
80, 109 symptoms of testicular cancer, 33
seminomatous germ cell cancers, syncytiotrophoblasts, 41, 74, 77
65, 68–69, 80. See also seminoma;
spermatocytic seminoma T
Sertoli cells (SCTs) tanners. See leather tanners
described, 57–58 teratoma, 65–69, 77–80, 81
large cell calcifying — (LCCSCT), 84 testicle. See testis
non-germ cell tumor, 82, 83–84, 86 testicular arteries, 61
not otherwise specified (NOS), 84 testicular cancer. See also germ cell
sperm production, 47–48, 64 cancer; non-germ cell cancer/tumor
Sheinfeld, Joel, 97 age of onset, 11–24
single-agent chemotherapy, 99 causes of, 19, 22, 69, 110–119
Sloan-Kettering. See Memorial Sloan-Ket- cells, 63
tering Cancer Center challenges/questions, 120–125
somatic cells, 56 detection of. See detection of
Southeastern Cancer Study Group, 101 testicular cancer
sperm diagnosis of. See diagnosis of
carried by epididymis, 31 testicular cancer
cells, 55 immunohistochemistry and —, 75
passage out of body, 58–60 questions about, 22–23
production, 12, 23, 47, 52–56, 64 rates of, 110, 118–119
unites with ova, 40 research, 124
spermatic cord, 34, 63 risk factors, 19, 22, 23, 117–118
spermatids, 55–56 stages of. See stages of cancer
154 INDEX
treatment. See treatment for cancer serum tumor marker and TNM
types of, 12, 15, 75 staging, 92–93, 94
typical patient, 12–15 stages of cancer. See testicular
testicular torsion, 34 cancer, stages of
testis toxicity, 23
anatomy of, 50–52 trophoblastic tumor, 65–68, 81
change in size, shape, texture, 25, trophoblasts, 41
32, 35 tumor, 12
circulatory system and, 48, 61–62 tumor markers, 17, 38–42, 45
described, 48–50 tumor-node-metastasis system (TNM),
examination, 30–32, 37 89–94
hidden, 19 tunica albuginea, 50
lump/enlarged, 15–16, 32 tunica vaginalis, 51
lymphatic system and, 48, 62–63
male sex gland, 49 U
noncancerous problems, 34
ultrasound, 17, 36, 37–38, 45–46
pain, 33, 35
Umezawa, Hamao, 105
removal of, 12, 36, 37, 46
University of Chicago, 97
self-examination, 32
University of Iowa, 20
sperm production in, 52–56
University of Texas, 99
tissue, analysis of, 36, 46
University of Western Ontario, 103
undescended. See cryptorchidism
urethra, 50
testosterone, 51, 64
tissue fluid, 50
TNM. See tumor-node-metastasis system V
Today, 26 varicoceles, 34
transducer, 37 vas deferens, 50, 59
treatment for cancer, 8, 18–19 vasectomy, 59
chemotherapy. See chemotherapy vinblastine, 99, 100, 103, 106
described, 87–88
future of, 121–123 W
nonresponsive, 22
Waxman, Selman, 104
radiation therapy. See radiation
World Health Organization, 66
therapy
retroperitoneal lymph node dissec-
tion. See retroperitoneal lymph X
node dissection X-rays, 19
about the author
♦
Kathleen M. Verville earned her B.S. in biology from the College

of Mount Saint Vincent in 1977 and her Ph.D. in biological sciences from
the University of Delaware in 1984. In 1985, she became a faculty mem-
ber in the biology department at Washington College in Chestertown,
Maryland, where she is an associate professor of biology. She teaches
a general biology course as well as classes in microbiology, immunol-
ogy, microbial ecology, and emerging pathogens. Her training, research
interests, presentations, and publications are largely in the fields of
environmental microbiology and science education. Dr. Verville enjoys
teaching and mentoring students. In her capacity as chair of the Wash-
ington College Premedical Committee, she has worked closely for over
20 years with students interested in careers in medicine. Dr. Verville is
a recipient of Washington College’s Alumni Award for Distinguished
Teaching. She and her husband, Frank Vella, Ph.D., also a scientist, live
in Delaware. They have three grown children: Laura, Christopher, and
Michael.
155
about the consulting editor
♦
Donna M. Bozzone earned her B.S. in biology from Manhattan

College in 1978 and her M.A. and Ph.D. in biology, from Princeton
University in 1980 and 1983, respectively. She continued her education
as a postdoctoral research associate at the Worcester Foundation for
Experimental Biology. She joined the faculty of Saint Michael’s College
in 1987 where she is now professor of biology.
Dr. Bozzone’s areas of specialization are in developmental and
cellular biology. She teaches or has taught courses in introductory
biology, science writing, cell biology, developmental biology, genetics,
plant developmental physiology, and a senior seminar on the history
of biology. She is the recipient of the Joanne Rathgeb Teaching Award
from Saint Michael’s College. An author of more than 25 publications,
Dr. Bozzone is also a member of the Publication Review Panel for the
Journal of College Science Teaching and an ad hoc reviewer for Ameri-
can Biology Teacher. An enthusiast for science education at all levels,
Dr. Bozzone designs laboratory teaching materials for students in high
school and college, and also works with students who are training to
become biology teachers. She and her husband, Douglas Green, who is
also a biology professor at Saint Michael’s, live in Vermont with their two
teenage daughters.
156

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Testicular

Diagnosis and Treatment of Cancer

Stages of Cancer Development

Kathleen M. Verville, Ph.D.

Copyright © 2009 by Infobase Publishing, Inc.

Library of Congress Cataloging-in-Publication Data

Text design by James Scotto-Lavino

Printed in the United States of America

This book is printed on acid-free paper.

2 Detection of Testicular Cancer 25

3 Diagnosis of Testicular Cancer 36

5 Germ Cell Cancers 65

6 Non-Germ Cell Testicular Cancers 82

7 Treatment of Testicular Cancer? 87

8 What Causes Testicular Cancer? 110

9 Challenges and Questions for the Future 120

A pproximately 1,500 people die each day of cancer in the United

consequence, normal tissue and organ functions may be seriously

Donna M. Bozzone, Ph.D.

♦ Although testicular cancer is a relatively rare cancer, the number of

♦ Advances in the treatment of testicular cancer have helped make

A Typical Testicular Cancer Patient

Figure 1.1 Mike Lowell, shown here playing for the

Detection of Testicular Cancer

Sometimes, as in Lowell’s case, testicular cancer is detected during a

In other cases, the patient may discover a problem. He might notice

(nonseminomatous germ cell tumors), these two categories actually en-

Treatment of Testicular Cancer

Removal of the testicle, which is necessary in order to confirm cancer

♦ Spotligh t on Cance r S cientists

L awrence Einhorn, M.D., has played an important role in making testicular

colleagues have modified

S pot l igh t on Canc er Sc ientists

testicular cancer patients and conduct research on the disease. Some of

had testicular cancer is at increased risk for developing testicular cancer;

Despite the many successes in the treatment of testicular cancer, many

Another problem is that some of the treatments used are harmful to

The incidence of testicular cancer has increased in recent decades;

born with an undescended testicle. As a result of scientific and medical

♦ Early detection of testicular cancer is important for increasing sur-

♦ Males are not routinely screened for testicular cancer by their

♦ Awareness of the symptoms of testicular cancer and testicular self-

♦ There are many symptoms of testicular cancer. Most commonly,

♦ The symptom(s) that are experienced by a particular patient vary

Jason: Delayed Detection of Testicular Cancer

Jason Struble was an 18-year-old student at Lafayette High School in Mis-

Detection of Testicular Cancer:

It is essential for individuals to check for any testicular abnormality and

Figure 2.1 Jason Struble, shown here in his varsity basketball

considered routine to the same degree as other tests, such as listening to

The Testicular Self-Exam and

signs of testicular cancer—such as a lump on a testicle or an abnormal-

♦ Screenin g for Testicu l a r Cance r

Other Symptoms of Testicular Cancer

Symptoms of Testicular Cancer

♦ Testicul ar Probl ems O ther T han Canc er

S ome testicular abnormalities, such as hydroceles, varicoceles, sper-

Early detection of testicular cancer increases the chance of survival and

2 Detection of Testicular Cancer 25

3 Diagnosis of Testicular Cancer 36

5 Germ Cell Cancers 65

6 Non-Germ Cell Testicular Cancers 82

7 Treatment of Testicular Cancer? 87

8 What Causes Testicular Cancer? 110

9 Challenges and Questions for the Future 120

♦ Although testicular cancer is a relatively rare cancer, the number of

♦ Advances in the treatment of testicular cancer have helped make

♦ Spotligh t on Cance r S cientists

♦ Early detection of testicular cancer is important for increasing sur-

♦ Males are not routinely screened for testicular cancer by their

♦ Awareness of the symptoms of testicular cancer and testicular self-

♦ There are many symptoms of testicular cancer. Most commonly,

♦ The symptom(s) that are experienced by a particular patient vary

♦ Diagnosis of testicular cancer is a multistep process that involves

♦ Ultrasound is used to determine details of the testicular mass, such

♦ Testicular tissue removed in surgery is analyzed in the pathology

♦ Testes contain many cells, including testosterone-making Leydig

1. Cells in the developing embryo/fetus that are the precursors of sper-

3. Cells derived from spermatogonia (primary spermatocytes, sec-

1. Cells (microbes and cancer cells) as well as tissue fluid can be

♦ Germ cell cancers are categorized as either seminomatous or non-

♦ Seminomatous germ cell cancers include seminoma and spermato-

♦ Nonseminomatous germ cell cancers include embryonal carcinoma,

♦ Immunohistoc he m istry and

♦ Non-germ cell tumors make up a greater percentage of the testicular

♦ Some non-germ cell tumors are benign. Many of the malignant