Cancer

Cancer

Mary E. Miller
Cancer
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 Abstract
The complexity of cancer symptoms, diagnosis, and treatment can
be ­ overwhelming to an individual diagnosed with the disease. This
­complexity is due in part to the fact that cancer is not one disease, but
a set of diseases in which cells of the human body acquire the ability to
­divide and m ­ ultiply in an uncontrolled way. For this reason, a c­ancer
can be thought of as a cellular disease, driven by mutations in genes
that regulate the function of those cells. In many cancers, these cells will
form tumors, or masses of cancer cells that can increase in size over time,
­potentially impeding the functions of organs and tissues in the body.
For this reason, cancer can also be considered a disease of organs, and
usually cancers are named according to the organ where the cancer cells
were originally located. When cancer cells are able to move through the
body to new t­issues, they become more dangerous to the patient. The
­cancer disease that results will differ depending on the type of cell that is
­dividing and the tissue that is invaded by the cancer. If left untreated, the
growth of cancer cells that have invaded tissues of the body will impair
organ function and cause death. Taken together, cancers represent a huge
­societal impact, taking lives and changing the lifestyles of countless indi-
viduals. Understanding cancer means both understanding the common
underlying features common to most cancers and focusing on the details
of specific types of cancers. This book focuses on four cancers that form
solid tumors: skin, lung, breast, and prostate. In each case, the symptoms,
diagnosis, treatment, and prospects of each cancer are addressed in order
to come to a better understanding of these devastating diseases.

Keywords
breast cancer, cancer, lung cancer, melanoma, non-small cell lung cancer,
prostate cancer, skin cancer, small cell lung cancer
 Contents
List of Figures and Tables........................................................................ix
Acknowledgments....................................................................................xi
Introduction.........................................................................................xiii
Chapter 1 Symptoms and Diagnosis...................................................1
Chapter 2 Causes and Contributing Factors.....................................23
Chapter 3 Treatment and Therapy....................................................33
Chapter 4 Future Prospects...............................................................47
Conclusion............................................................................................49
Bibliography..........................................................................................51
Glossary................................................................................................57
About the Author...................................................................................61
Index....................................................................................................63
 List of Figures and Tables
Figure I.1 Mutations cause cancer................................................... xvi
Figure I.2 Stages of metastasis........................................................... xx
Figure 1.1 Epidermis and dermis of the skin ......................................4
Figure 1.2 Normal male reproductive and urinary anatomy..............18
Figure 2.1 Normal anatomy of the breast .........................................28

TABLES
Table I.1 Phases of the cell division cycle....................................... xiv
Table 1.1 Staging non-small cell lung cancers....................................9
 Acknowledgments
I would like to thank Malcolm Campbell for the opportunity to make
contributions to this book series. His forward approach to science and
scientific pedagogy is inspiring. I thank my husband David and daughter
Mallory for their patience and support of these efforts. I am fortunate to
work at Rhodes College, which has supported my professional and intel-
lectual development. I take pride that I have worked with outstanding
students, and thank them for inspiring my passion for science education.
My outstanding mentors, colleagues, and collaborators have made it pos-
sible to carry out rigorous research and forward high-impact educational
practices. Specifically, I thank Mitch Smith, Dan Engel, Jeff Becker, Fred
Cross, and Pam Hanson, whose advice and influence have shaped my
professional success. The editorial staff at Momentum Press has been sup-
portive and kind, and I appreciate their work in the production of this
book. I hope that some aspect of this work is helpful for individuals work-
ing to better understand or manage these devastating diseases.
 Introduction
Cancer is any disease where cells of the human body acquire the ability
to divide and multiply in an uncontrolled way. In many cancers, these
cells will form tumors, or masses of cancer cells that can increase in size
over time, potentially impeding the functions of organs and tissues in
the body. When cancer cells are able to move through the body to new
tissues, they become more dangerous to the patient. The disease state that
results from cancer will differ depending on the type of the cell that is
dividing and the tissue that is invaded by the cancer. Cancer can begin
in many tissues, which is why there are many different types of cancer.
All cancers carry common features that make them recognizable and in
some cases treatable. If left untreated, the growth of cancer cells that have
invaded tissues of the body will impair organ function and cause death.
Great advances have been made in treating cancer over the past 30 years,
so that survival rates for some cancers have improved dramatically.
This book will be limited to solid tumors, those tumors that are able
to form a mass of cells within the body including skin, lung, breast, and
prostate cancer, as representative of the many types of solid tumor cancers
that impact human health. Non-solid tumors such as cancers of the blood
system (lymphomas) exist, but move around the body and cause disease
in distinct ways from solid tumors. The complexity of diagnosis and treat-
ment requires that each cancer be considered a distinct disease, with some
underlying common features. To begin our discussion of specific types
of cancers, it is important that we understand some of these underlying
common features of cancers.

Cancer Is a Genetic Disease That Disrupts

Cellular Function
No matter the type of cancer, one major common feature is the existence
of populations of cells that have lost control of their normal cell division
and therefore multiply uncontrollably. Cellular division is that process
xiv INTRODUCTION

where a cell replicates all of its components and subsequently segregates

these components so that two genetically equivalent cells are produced.
Healthy cells are the fundamental living units in our bodies and they have
the ability to grow, multiply, and communicate. During cellular division,
the genome or genetic material of the cell must be replicated before it is
segregated, or the cell will be severely impaired. To coordinate DNA du-
plication and subsequent segregation of the human genome, these events
are controlled by key regulators of the cell cycle. Some regulators pro-
mote cell division, for example, the enzymatic complex called the cyclin/
CDK. Other regulators restrict cell division, generally described as cell
cycle checkpoints. The balance between promoting and restricting cell
division is a complicated one, where cyclin/CDK complexes can directly
interact with cell cycle checkpoints. This balanced relationship is further
complicated by the fact that different cyclin/CDK complexes and differ-
ent checkpoints regulate specific phases of the normal cell division cycle
(Table I.1). The commitment to cell division occurs prior to DNA repli-
cation, during the G1 (first growth) phase of the normal cell cycle. During
G1 the cell coordinates intracellular and extracellular signals to ensure that
the cell is in the right environment and physiological state to successfully
complete a round of cell division. The replication of the genome happens
during the part of the cell division cycle called S phase (synthesis), which
follows immediately after the G1 phase. Only after the genome has been
fully replicated will the cell proceed through the cell ­division cycle to the
next step called G2 (second growth) phase. During G2, the cell confirms
genome integrity and prepares for the segregation of the genome, which
happens during mitosis, or M phase. Once M phase is complete, the cell
will undergo ­cytokinesis, where the two ­genetically equivalent cells are

Table I.1  Phases of the cell division cycle

Cell cycle phase Key events
G1 Coordination of extracellular and intracellular signals
S Replication of key cellular components, including the genome
G2 Preparation for mitosis, including confirmation of genome integrity
M Segregation of key cellular components, including the genome
Cytokinesis Separation of cells
 INTRODUCTION
xv

physically separated from each other. The c­ oordination of S phase and M

phase is critical to maintaining a healthy genome, so key regulators of the
cell division cycle provide a quality ­control system during all four phases,
G1, S, G2, and M. Cells that are not actively dividing can be held in a
nondividing state that remains ­responsive to cell cycle regulators. Cancer
cells have gained the ability to divide when they should not, meaning that
key cell cycle ­regulation mechanisms have been disrupted. More impor-
tantly, cancer cells have gained their unregulated ability through muta-
tions in the genome, meaning that as the cancer cell divides, the new cells
will inherit this same growth capacity and increase the number of cancer
cells in the body. Some individuals are born with mutations that can con-
tribute to cancer, but it is very rare to be born with cancer; nearly all cases
begin after a cell accumulates at least one new DNA mutation.
Cancer cells gain the ability to divide and move around the body
because of heritable changes called mutations. The genome is comprised
of deoxyribonucleic acid (DNA), which is composed of paired chains
of nucleotides that physically interact to form the iconic double helix
structure. This DNA double helix can physically interact with proteins
in the cell to create higher order structures called chromatin. Chroma-
tin compacts, protects, and regulates the behavior of DNA. Chromatin
plays a critical role in gene expression, the process by which information
encoded in the sequence of DNA nucleotides is converted to functional
products such as proteins. DNA is used to encode for a protein via an in-
termediary step called transcription where the DNA is used as a template
to produce the similar, complementary, but distinct RNA. The process of
transcription produces RNA that is complementary to the sequence of
nucleotides in DNA, so the information coded in the DNA is retained
in the information encoded in the nucleotide sequence of the RNA. The
RNA code is used to produce proteins through a process called transla-
tion. Proteins are composed of specific sequences of amino acid chains
dictated by the sequence of nucleotides in RNA. In the case of proteins,
each amino acid has chemical and structural properties that collectively
determine the protein’s overall shape and thus its function. Every protein
has distinct chemical and physical properties so that it binds (physically
interacts) with other proteins or molecules. The nucleotide code ­present
xvi INTRODUCTION

in DNA dictates the code present in RNA, which in turn dictates the
amino acid sequence of the protein. The relationship between DNA
and RNA and protein synthesis is common to all life, and together the
processes of transcription and translation are referred to as the central
dogma of life (Figure I.1).
Cancer is triggered when mutations occur in certain types of genes. A
gene that exists in our DNA is considered a functional unit of coded infor-
mation because it contains instructions to produce a functional product, such

Mutation inactivates
tumor suppressor gene

CELLS PROLIFERATE

Mutation inactivates
DNA repair gene

Mutation of proto-oncogene
creates an oncogene

Mutation inactivates
several more
tumor suppressor genes

CANCER
Figure I.1  Mutations in multiple genes are required for cancer to
form. From the National Cancer Institute. https://upload.wikimedia.
org/wikipedia/commons/7/73/Cancer_requires_multiple_mutations_
from_NIHen.png
 INTRODUCTION
xvii

as RNA or proteins. The mutations that cause changes in the DNA ­sequence
of genes might change the function of gene products that are ­important for
­cellular division or cellular survival. Genes with normal f­unctions that can
stop or postpone cellular division and other aspects of cancer are called tumor
suppressor genes. Mutations that ­inactivate tumor suppressor genes will
contribute to cancer. Genes with normal functions that facilitate cell division
can contribute to cancer and are called proto-oncogenes. Once a healthy
proto-oncogene is mutated in such a way that the gene p ­ roduct ­contributes
to cancer, this version of the gene is called an o ­ ncogene. ­Mutations that
activate or overexpress oncogenes will contribute to cancer. The ability of
cancer cells to divide when they should not comes from combinations of
mutations in both tumor suppressors and oncogenes that disrupt proper cell
cycle control and disrupt the ability of the cell to properly sense information
from its environment. It is the dis-regulation of the cell cycle that allows the
formation of an abnormal mass of cells in the body, but it is the cancer cell’s
abnormal interaction with its environment that allows it to change shape,
move inside the body, and grow in new locations.
Cells interact with their environment via proteins located on their sur-
faces, often called receptors. Receptors physically interact, change shape,
and initiate ­biochemical signals inside the cell, allowing a cell to detect
growth hormones or to recognize another cell. Through its receptors, a
cell can sense signals from its environment and respond to them. Cell sig-
naling results in activation of a signal transduction ­cascade, which will
change the function of additional proteins inside of the cell so that divi-
sion is inhibited or triggered, depending on the s­pecific s­ignal received
by the cell. A growth factor stimulates its receptor and triggers cellular
division. In contrast, a different type of receptor can inhibit cell growth in
response to contact with another cell, for example. Slowed cell growth in
response to physical interaction with another cell is called contact inhibi-
tion and is a natural response of cells that are positioned properly within
a tissue. Contact inhibition is how your skin knows when to stop growing
after repairing cuts and scrapes. A cancer cell will ignore contact inhibi-
tion and divide despite the fact that it is in physical contact with other
cells or materials. Mutations that might contribute to lost contact inhibi-
tion could exist in many different genes that contribute to this type of
signal transduction pathway. For example, the receptor could be mutated
xviii INTRODUCTION

so that it can no longer physically ­interact with the surface of other cells.
With a defective receptor, the signal of contact inhibition would never
be detected. Relay proteins within the cell could be mutated so that cell
contact is detected but the cell is ­unable to relay that information to alter
the function of proteins inside of the detecting cell.
Frequently, a combination of mutations in both tumor suppressor
and proto-oncogenes is required in order for a cell to become ­cancerous
and divide uncontrollably. Additional ­mutations may be involved in the
ability of the cancer cell to interact differently with its environment.
Other features of a cancer cell gained through mutations of tumor
­suppressors or oncogenes can increase the likelihood that the c­ ancer cell
will survive in the human body. The human genome contains about
22,000 genes, each encoding one or more distinct products with s­ pecific
composition and function. We do not know how many of these genes
are tumor suppressor or proto-oncogenes, but we know that a c­ ancer
cell will have inherited and/or acquired inactivating mutations in tumor
suppressors activating mutations to become oncogenes. The more
­mutations a cancer carries, the more dangerous the cancer is.

Dangerous Cancer Cells Move Through the Body

As the solid tumor begins to form, different types of cancer cells will gain
different mutations that allow them to survive longer, divide more, and
evade death. As mutations accumulate in the cancer, the concern increases
that the cancer cell will become more aggressive. An aggressive tumor
will either grow quickly and/or spread through the body quickly. Tumors
­become more life threatening when they gain the ability to move beyond
the tissue in which they originated, move through the body, and form
new solid tumors in new locations. A cancer cell that has gained m ­ obility
is described as metastasized. Metastasis correlates with poorer ­prognosis
for the patient. A cancer cell can spread out of its ­originating t­issues
­simply because it is so large that it physically extends past its original
tissue. If this happens, and the tumor continues to grow, the cancer cells
ignore natural growth inhibition signals that would normally be t­ riggered
if a cell was exposed to this new environment. Cancer cells may also have
gained the ability to evade death, usually triggered through a process
 INTRODUCTION
xix

called apoptosis. Apoptosis is a type of cell death that results from natu-
ral signals in the cells, including signals telling a cell it was in the wrong
tissue. Cancer cells that no longer trigger apoptosis will survive better as
they spread. In a different scenario, a very small tumor that has not grown
large enough to extend outside its originating tissue can also metastasize.
In this case, one cell or a small clump of cancer cells will gain the ability
to migrate through tissue or through the blood stream or lymph system
until it lodges in a new location. In a healthy cell, lack of contacts with
the normal tissue proteins and cells inhibits growth and causes apoptosis.
A metastatic cell disengages from its tissue of origin without responding
to growth inhibition or apoptosis. Cancer cells often gain mutations in
genes that would normally trigger apoptosis, or mutations in genes that
encode for receptors or signaling molecules that allow the cell to detect
the proper environment. The ability of cancer cells to migrate away from
the original tumor site might involve mutations that inappropriately lead
to the secretion of digestive enzymes that liberate the cancer cell from
its original tissue. If cancer cells come in contact with a blood or lymph
vessel, the mutant cell may attach to the surface and enter the circula-
tory vessel. The cancer cell would need to be able to change shape and
physically interact with the cells that line the vessel so that it could move
between them. Depending on the cell type, moving into a vessel may
require additional mutations in the cancer, or moving into vessels could
be a normal ability the original cell had before it became cancerous. Once
inside of a vessel, the cancer cell could move through the blood or lymph
system and exit from the vessel anywhere in the body. If the cancer cell
is able to survive in its new tissue environment, it could move to a site
where cellular division can occur and a new tumor mass would form.
This ability to move is how a cancer that began in one tissue can suddenly
­appear in a new tissue. For example, if non-small-cell lung cancer spreads
to the brain, the cancer cells in the brain are actually lung cancer cells. The
disease is metastatic lung cancer, not brain cancer. The ability of a specific
type of cancer to spread through the body will vary, and the new locations
where specific tumors will grow will also vary. It is common for filter-
ing organs (such as lung and liver) to “capture” cancer cells and support
the growth of newly relocated tumors (Figure I.2). Note that as a cancer
metastasizes, it also remains in the original site of cancer formation.
xx INTRODUCTION

Blood stream
Tumour
Cancer cells

Figure I.2  A diagram of cancer cells moving into a vessel of the blood
stream. By Cancer Research UK uploader (Own work) [CC BY-SA
4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia
Commons. https://upload.wikimedia.org/wikipedia/commons/e/e2/
Diagram_showing_cancer_cells_spreading_into_the_blood_stream_
CRUK_448.svg

When cancer cells are found beyond their tissue of origin, they may
first be found in nearby lymph nodes. Lymph nodes are small c­ ollections
of immune cells that are connected to each other through lymph ­vessels.
In healthy individuals, the lymph system allows rapid dissemination and
aggregation of immune cells for efficient recognition and removal of
­foreign material within the body. A normal lymph system carries clear
fluid (lymph) that allows movement of cellular debris and pathogens away
from tissues so they can be detected and destroyed. If a cancer cell gains
access to the lymph system, it may migrate and stay in nearby lymph
nodes. As the cancer grows and divides inside the lymph node, more
­cancer cells may move through the lymph system farther into the body
and form additional new tumors. Likewise, if a cancer cell gains ­access
to the blood, it can spread through the body. The metastatic ­cancer is
­generally the same type of cancer as the primary tumor, though t­ umors are
genetically unstable, so new genetic mutations are likely to a­ ccumulate,
which can enhance the aggressiveness of the cancer.
 INTRODUCTION
xxi

Cancer as a Cellular Disease That Disrupts

Organ Function
In the human body, cells do not function in isolation. Each cell has the
ability to perform unique functions in coordination with other cells. The
formation of higher ordered structures called tissues, where cells with
­similar structure and function aggregate, is an essential aspect to the
health of the human body. The ability of cells to coordinate ­function
within tissues requires that cells properly express specific genes that may
differ between cell and tissue types. No cell produces every possible
­protein encoded in its genome. Cells activate some genes and silence
other genes to produce proteins at the right time and at an appropriate
abundance to accomplish the cell’s functions. Differential gene expression
gives rise to cells with specialized protein composition so that the cell
has distinct structures that drive specific functions of that cell type. Each
cell has a function ­determined by its differential gene expression pattern,
which is why a liver cell looks and functions differently from a colon cell,
for example. The patterns of differential gene expression begin during
­embryogenesis, those first early days of cellular growth and d ­ ivision after
a sperm has fertilized an egg. During this time, cells divide and begin to
differentiate into different cell types. Certain embryonic cell types retain
the ability to differentiate into all other cell types (embryonic stem cells).
As embryonic stem cells differentiate, they will become tissue-specific
cells. Among these population of tissue-specific cells, some “adult” stem
cells remain in a less-differentiated state so that they can replenish older
cells as they die. Adult stem cells are no longer able to form any cell type
and are restricted to a subset of cell types associated with their tissue of
origin. As the d ­ evelopment of the embryo continues, precursor cells dif-
ferentiate further, changing their gene expression patterns and becom-
ing more specialized in their function. Normal stem cells carry many
­features associated with cancer cells, and when stem cells carry mutations
in tumor s­uppressors or oncogenes, they can produce very dangerous
­tumors. When u ­ nderstanding the causes of cancer, the origin of a cancer
cell through these developmental patterns can help us understand the
original source of a cancer and shape some treatments.
xxii INTRODUCTION

Cancers are named after the organ where the cancer is believed to have
originated. In some cases, the cancer’s origin is difficult to identify, and
the cancer will be described by the organs that are effected until a more
definitive diagnosis can be made. Individual organs are considered groups
of tissues that collectively carry out a specific function in the human body.
Cancer cells usually do not directly attack and kill the tissues or organ
where they grow. Rather, the increasing size of the solid tumor physically
hinders that organ’s ability to function. If left untreated, most individuals
will succumb to cancer because of organ dysfunction or failure. There are
many organ in the human body, any of which could be effected by the
growth of a solid tumor in or near the organ. Organs can be grouped into
organ systems, as they relate to each other in their function. For example,
the digestive system includes the organs of stomach and esophagus (and
others), all of which are required to properly digest and absorb food. This
book focuses on cancer of four organs: skin, lung, breast, and prostate.
The language used to describe different types of cancers is shaped
by the types of cells that comprise the tissues in the organs. Given
that d ­ ifferent tissues have unique structures and cellular composition,
the ­disruption of these tissues by the cancer can be recognized using
­histological ­approaches (tissue samples that have been preserved, stained,
and o­ bserved under a microscopy) to aid in cancer diagnosis. Epithelial
tissues provide ­covering to the body’s exterior (skin) as well as linings
on internal organs and cavities. For a cancer cell to invade a tissue, it
will have to move through or bypass the epithelial cells surrounding that
organ. Endothelial tissues line the inside of organs and usually perform
­specialized functions of that organ. Stroma tissues provide a structure
in which other cells can be embedded and oriented with relation to
each other to support the specialized function of the tissue. Connective
­tissues are a broad category that consists of material surrounding cells and
­provide connections between different types of tissues. Cancer cells can
originate from any one of these four tissues.
 CHAPTER 1

Symptoms and Diagnosis

Methods for Detection and Diagnosis of Cancer

In the case of solid tumors, initial diagnosis can be linked to the d
­ etection
of an unusual mass of cells in the body. These masses of cells might be
detectable by physical examination, but frequently are detected using
imaging techniques that allow visualization of tissues inside of the
­
body, such as X-rays, computed tomography imaging (CTI, CT, or
CAT) scans, magnetic resonance imaging (MRI) scans, and positron
­emission  tomography (PET) scans. X-rays are a type of energy with
very short wavelengths that cannot be seen by humans and can pass
through most tissues of the body. Bones and other dense tissues block
some of the X-rays from passing through and form a shadow (appear
white on a black background) in images. Images produced from X-rays
can show ­information from a single direction, but CAT images consist
of a type of X-ray image that is done in cross sections, or slices, through
the body so that you get more detailed images than X-rays. MRI cap-
tures a ­detailed series of images that show cross sections through tissues,
but does not use X-rays. MRI uses a very strong magnet to align the
polarity (a type of ­directionality) of the hydrogens (protons) present
in our body (largely found in water). A radio wave is passed through
the person, making the protons change polarity. Once the radio wave
is removed, the protons flip back to their original orientations, releas-
ing energy. This released energy is sensed by the machine to generate an
image based on how quickly the energy is released from the protons. The
result is a s­eries of very high-resolution images showing the relative size
and position of t­issues and organs. MRI imaging is usually not used for
diagnostic purposes ­unless a person is at high risk for cancer, since the
detailed images from an MRI can produce many false positives (natural
2 CANCER

variations of cell d ­ ensities that are not cancer). PET scans leverage a meta-
bolic ­feature of most c­ ancer cells because cancer cells consume more sugar
than most ­noncancerous cells. For a PET scan, weakly radioactive sugar
is ­introduced into the p ­ atient. As the cancerous cells consume high levels
of the radioactive sugar, they accumulate the radioactivity, which can be
detected in the PET scan. PET scans can reveal any tissue that contains
cells consuming relatively high amounts of sugar, including cancer cells
and cells that divide quickly as a normal part of their function in the body
(such as hair and intestinal lining).
If a mass of cells is detected through imaging techniques, and the
mass is amenable to surgical sampling, a biopsy is done. Tumor s­ amples
are prepared for histological examination by a pathologist using a
microscope. Microscopic analyses of a biopsy are frequently needed
­
to determine if a mass of cells is benign, meaning it is not metastatic
­cancer, or malignant, meaning it has undergone metastasis. Microscopy
magnifies histological samples to reveal the shape of each individual cell
and the relative ­position of small groups of cells. These features allow
pathologists to distinguish between metastatic cancer masses and masses
of benign cells. The ­benign masses will have maintained more of their
original ­cellular shape and structure, which suggests they have maintained
contact inhibition. A histological analysis can also allow detection of the
mitotic index, the percentage of cells in the sample that were actively
dividing at the time that the sample was collected. A high mitotic index is
­suggestive of cancer, and the higher the mitotic index, the more ­aggressive
the cancer. In some cases, the mitotic index will be taken into consider-
ation when staging a cancer or when considering the prognosis of the
cancer patient. ­Variations of histological analysis can be used to obtain
information about protein composition of the cancer cells. For example,
immunohistochemistry (IHC) uses antibodies that bind to specific pro-
teins to highlight the ­presence and relative abundance of those proteins
in the cells. IHC can help identify what type of cell is present in the
tumor. Additionally, samples can be probed for gene expression through
approaches such as fluorescence in situ hybridization (FISH) and com-
parative genomic hybridization (CGH). These two methods can detect
genetic abnormalities in the cancerous tissues. In addition to imaging
scans and histological analysis capable of physically detecting masses of
 Symptoms and Diagnosis 3

cells in the body, some blood tests exist that allow the detection of cancer
biomarkers. A biomarker is a biological material that can be measured
to indicate the presence or absence of a disease. Much like high glucose
levels in urine is a biomarker for diabetes, certain factors might be present
in the body of a cancer patient that are absent in a healthy patient. These
materials do not necessarily cause cancer, but correlate to the presence of
cancer in a patient. The use of these approaches would vary depending on
the type of cancer in question and is critical in diagnosing the presence of
cancer cells and the staging of the cancer. Methods of staging cancers will
be unique to each type of cancer, but usually is comprised of a numbering
or lettering system to indicate how advanced and/or dangerous the cancer
is. Staging of cancers is part of the diagnosis process that informs both
­treatment and prognosis of the disease.

Symptoms and Diagnosis of Skin Cancer

Skin cancer is the most common type of cancer reported by the ­Centers
for Disease Control and Prevention (CDC) in the United States and
­presents in one of three forms: basal cell, squamous cell, and m ­ elanoma
skin ­cancer. Additional types of skin cancer include Bowen disease (a type
of squamous cell cancer), actinic keratosis (which can develop into
­squamous cell cancer), lymphoma of the skin (a rare cancer of the i­ mmune
system that starts in the skin), Merkel cell sarcoma (cancer of cells in the
­epidermis that associate with nerves), and Kaposi sarcoma (cancer of cells
that line blood vessels or lymph nodes). Basal and ­squamous cell skin
cancers are the most common, grow relatively slowly, and rarely spread
to other parts of the body. Basal cell skin cancer begins in cells that reside
in the basal layer of the skin, while squamous cell skin cancer begins
in cells that reside in the squamous layer of cells. Melanomas begin as
normal cells called melanocytes, cells that produce the pigment mela-
nin. Melanoma is less common, but leads to more deaths than the other
types of skin cancer combined. In all three forms of skin cancer, the cells
that become cancerous are part of the epidermis, or the outermost layer
of cells on the skin (Figure 1.1). Squamous cells are located on the top
surface of the skin, whereas basal cells and melanocytes are located at the
base of the epidermis, near the dermis where glands, blood vessels, and
4 CANCER

Figure 1.1  Layers of the Skin. The dermis and epidermis layers of the
skin are drawn with an inset showing a close-up view of squamous
cells, basal cells, and melanocytes. By Don Bliss (Illustrator) (Public
domain or public domain), via Wikimedia Commons. https://upload
.wikimedia.org/wikipedia/commons/c/c1/Layers_of_the_skin.jpg

nerves can be found. Melanomas begin in the skin, but they can also
originate in other pigmented tissues such as the eye or the intestines. In
2014, 76,665 individuals were reported with skin melanomas and 9,324
(12 percent) of them died. The incidence of melanoma is highest among
white men and women. Melanocytes are naturally mobile before they
become ­cancerous, so they metastasize very frequently, which contributes
to the high ­mortality rate for melanomas.
The primary symptom of a skin cancer is a change in the color or
texture of skin. Skin cancers are distinct from common moles, which are
noncancerous growths on the skin resulting from clusters of melanocytes,
which give color to the skin. Some moles called dysplastic nevi (DN)
have the potential to develop into melanoma. They appear larger than
common moles with more variations in color, and have borders that are
difficult to see. In attempts to detect skin cancers, a mole or previous
 Symptoms and Diagnosis 5

growth could change, a sore can change during healing, or new growth
could occur. When considering the likelihood that a change in skin might
be skin cancer, the CDC suggests that individuals consider A-B-C-D-E:

A stands for asymmetrical, meaning that the new growth has an

­irregular shape.
B would stand for border, where an irregular, jagged, or difficult-to-see
border would be of concern.
C indicates color, where uneven color would be of concern.
Diameter, D, becomes a concern when it is larger than an a­ pproximate
size of a pea.
E stands for evolving, meaning that the skin is continuing to change
in the previous few weeks or months.

Any of these changes would warrant a visit to a physician to d ­ etermine

if the changes are potentially skin cancer. A physician might use a
­dermatoscope, a special magnifying lens and light, to more clearly see
changes in the skin. If the area is considered potentially cancerous, then
a biopsy would be taken from the skin in question. As much of the
­concerning area as possible will be removed, and the healing may leave
a scar. A physician might choose to remove an area of skin by shaving
off the top layer of skin with a blade, or using a cookie cutter–like tool
for a punch biopsy removing a circle of skin, or using a surgical knife if
the physician feels that the sample needs to include cells from deeper
­layers of the skin. The biopsy is used to prepare a histological sample that
can be observed by a pathologist using a microscope. If findings are not
clearly cancerous from the histological observations, additional tests may
be performed on the sample such as IHC, FISH, and CGH, as described
above. When IHC approaches are inconclusive, FISH and CGH can help
distinguish between melanoma and DN by identifying changes in the
overall genomic structure of the patient’s sample cells.
If melanoma is detected, then the cancer thickness and mitotic index of
the tumor will be determined. These features allow the pathologist to a­ ssign
a grade to the melanoma. Although there are multiple s­taging ­systems for
skin cancer, the American Joint Commission on Cancer (AJCC) suggests
the TNM system, where T means that the primary tumor has grown within
6 CANCER

the skin. This category is based on the t­ hickness of the melanoma, using the
Breslow measurement. Essentially, a ­melanoma smaller than 1 mm is less
likely to spread to other parts of the body. The mitotic index and level of
ulceration are used to stage different values for a T tumor as follows:

TX (tumor cannot be assessed)

T0 (no sign of primary tumor)
Tis (carcinoma in situ, or only in the epidermis with no spread)
T1a (less than 1 mm thick and mitotic index less than 1/mm2)
T1b (less than 1 mm thick and mitotic index 1/mm2 or more)
T2a (between 1.01 and 2 mm thick without ulceration)
T2b (between 1.01 and 2 mm thick with ulceration)
T3a (between 2.01 and 3 mm thick without ulceration)
T3b (between 2.01 and 3 mm thick with ulceration)
T4a (more than 4 mm thick without ulceration)
T4b (more than 4 mm thick with ulceration)

The next stage is called N, which stands for lymph nodes, meaning
that the melanoma has spread from the skin to one or more lymph nodes
as follows:

NX (cannot be assessed)
N0 (no spread to nearby lymph nodes)
N1 (spread to nearby lymph nodes)
N2 (spread to two or three nearby lymph nodes or to nearby skin that
is near a lymph node)
N3 (spread to four or more lymph nodes, or lymph nodes that are
clumped together, or to the nearby skin)

The M stage indicates that the skin cancer cells can be found in
a­ dditional organs in the body and may include detection of the cancer
biomarker LDH, indicating that the cancer has metastasized as follows:

M0 (no distant metastasis)

M1a (metastasis to skin, below the skin, lymph, or distant parts of the
body with normal blood LDH levels)
 Symptoms and Diagnosis 7

M1b (metastasis to the lungs, with normal LDH level)

M1c (metastasis to any other location with elevated blood LDH
levels)

Once the T, N, and M status has been determined, then an overall

stage is used to describe the cancer as stages 0, I, II, III, or IV, where higher
numbers associate with more serious cancers. This level of s­ taging can be
complex with many subheadings for each overall stage, and care should be
taken to fully understand the staging employed by the physician.

Symptoms and Diagnosis of Lung Cancer

Lung cancer is the most common cause of cancer-related deaths in the
United States. The CDC reports that in 2014, of the 215,951 ­individuals
diagnosed with lung cancer, 155,526 (72 percent) died. Lung c­ancers
originate in cells of the lungs, but can spread to other parts of the
body. Cancers of other tissues can spread to the lungs, impairing lung
function—but these cancers would not be classified as lung ­
­ cancer.
Healthy lungs allow gas exchange into and out of the blood (CO2 out,
O2 in). The ­bronchi connect the lungs to the windpipe or trachea,
and lead to small tubes called bronchioles, which terminate in air sacs
called alveoli. Symptoms of lung cancer can vary and may not appear
directly related to lung function. Unfortunately, lung cancer symptoms
frequently do not present until the cancer has advanced to the point of
­metastasis. When symptoms do appear, they can be difficult to diagnose,
and may produce generalized symptoms of not feeling well. More specific
­symptoms may also include coughing that gets worse or doesn’t go away,
chest pain, shortness of breath, wheezing, coughing up blood, feeling very
tired all the time, and weight loss with no known cause.
Initial diagnosis of lung cancer can involve a physical exam and
­personal history of the patient (e.g., tobacco use). If lung cancer is
­suspected, then laboratory tests would be used to diagnose the type and
stage of lung cancer. X-rays or CAT scans can detect unusual solid masses
in the lung. Patient samples of lung tissue or sputum (mucus coughed
up from the lungs) may be analyzed to determine if cancer is present.
Sputum cytology looks for the presence of abnormal cancer cells in the
8 CANCER

sputum, and a positive sputum test would be highly indicative of lung

cancer. Fine needle aspiration (suction) can be used to obtain samples
of lung tissue. Lung samples could also be obtained via a bronchoscopy,
where a tube is inserted into the lungs through the trachea and bronchia,
allowing the physician to observe the tissues in the lung with a very small
camera. Surgical observation of the lungs, called thoracoscopy, may be
necessary to observe abnormal growths or tumors within the lungs. In
all cases, tumor biopsies are observed under a microscope to look for the
presence of cancer cells.
Lung cancer is grouped into two main types using a h ­ istological
­analysis: small cell lung cancer (10 to 15 percent of diagnosed lung ­cancers)
and non-small-cell lung cancer (80 to 85 percent). ­Symptoms more
­commonly associated with non-small-lung cancer include ­shortness of
breath and a persistent cough. Small cell and non-small-cell ­classifications
are based on the microscopic shape and structure of the biopsied cancer
cells. Small cell lung cancer cells are smaller compared to a variety of other
larger sized lung cell cancers collectively called non-small-cell lung can-
cer. Different types of non-small-cell cancers include squamous cell lung
­cancer, or epidermoid carcinoma, which will appear like long, flat, fish
scale–shaped cells. Large cell lung cancer will appear as larger cells, but
could be a number of different subtypes. Other types of lung cancer exist,
but are rare, and include the slow-forming lung carcinoid tumors that
originate from neuroendocrine cells. Neuroendocrine cells normally pro-
duce and regulate hormone production throughout the body, and in this
case in the lungs. Less common non-small-cell cancers include ­salivary
gland, pleomorphic, and carcinoid tumors.
Staging differs between small cell and non-small-lung cancers, but in
both cases the staging reflects the extent of cancer cell movement out of
the lungs, if this has occurred. MRI, CAT scan, and PET scan are used
to detect metastatic lung cancers. Radionuclide bone scan, ­pulmonary
function test, endoscopic ultrasound, mediastinoscopy, a­ nterior
­mediastinotomy, lymph node biopsy, and bone marrow aspiration biopsy
allow a careful examination of specific tissues for signs of metastasized
lung cancer. Once the extent of metastasis is determined, the lung cancer
is staged to indicate the size and spread of the cancer (Table 1.1). Staging
of the cancer will inform treatment and prognosis.
 Symptoms and Diagnosis 9

Table 1.1  Staging non-small-cell lung cancers based on position, size,

and metastatic features
One or more of the
following: Metastatic
Stage Position Size spread or lung function
0 Airway of lungs Cells None
present
IA Lung <3 cm None
IB Lung, not in lymph Between 2 Main bronchus at least 2 cm below
nodes and 5 cm where bronchus meets trachea
Membrane surrounding the lung
Collapse of part of the lung

IIA Spread to lymph nodes Smaller Main bronchus at least 2 cm below

on the same side of the than 5 cm where bronchus meets trachea
body as the tumor lung Membrane surrounding the lung
Collapse of part of the lung
IIA Lung, not in lymph Between 5 Main bronchus at least 2 cm below
nodes and 7 cm where bronchus meets trachea
Membrane surrounding the lung
Collapse of part of the lung

IIB Spread to lymph nodes Between 5 Main bronchus at least 2 cm below

on the same side of the and 7 cm where bronchus meets trachea
body as the tumor lung Membrane surrounding the lung
Collapse of part of the lung

IIB Lung, not in lymph Larger than Main bronchus

nodes 7 cm The chest wall
The diaphragm
The nerve that controls the
diaphragm
The membrane around the heart
or lining the chest wall
There are one or more separate
­tumors in the same lobe of the lung
The whole lung has collapsed
Developed pneumonitis (inflam-
mation of the lung)

(Continued)
10 CANCER

Table 1.1  Staging non-small-cell lung cancers based on position, size,

and metastatic features (Continued)
One or more of the
following: Metastatic
Stage Position Size spread or lung function
IIIA Lung, lymph nodes near Any size No additional spread
the sternum or bronchus One or more separate tumors in
the same lobe of the lung
The main bronchus
Chest wall
Diaphragm
Membrane surrounding the lung
Membrane around the heart
Part of the lung has collapsed

IIIA Lung, lymph nodes Any size One or more separate tumors in
within the lung or near the same lobe of the lung
the bronchus Main bronchus
Chest wall
Diaphragm
Membrane surrounding the lung
Membrane around the heart
Heart
Major blood vessels
Trachea
Esophagus
Nerves controlling the voice box
Sternum
Carina
Collapse of the entire lung
Inflammation of the lung

IIIA Not in lymph nodes Any size Heart

Major blood vessels that lead to or
from the heart trachea
Esophagus
Nerve that controls the larynx
Sternum
Backbone
Carina
 Symptoms and Diagnosis 11

Table 1.1  Staging non-small-cell lung cancers based on position, size,

and metastatic features (Continued)
One or more of the
following: Metastatic
Stage Position Size spread or lung function
IIIB Lung, lymph nodes Any size One or more tumors in any of the
above the collarbone or lobes of the lung with cancer
on the opposite side of Main bronchus
the chest as the original
Chest wall
tumor
Diaphragm
Membrane around the heart
Heart
Major heart blood vessels
Trachea
Esophagus
Larynx nerve
Sternum
Carina
Collapse of all or part of the lung

IIIB Lung, lymph nodes near Any size Different lobes of the same lung
sternum or bronchus Heart
Blood vessels of the heart
Trachea
Esophagus
Larynx nerve
Sternum
Carina

IV Lung, lymph nodes Any size Both lungs

Fluid surrounding lungs
Brain
Liver
Adrenal glands
Kidneys
Bone

Recurrent Any size Has returned after treatment and

may show cancer in brain, lung, or
other parts of the body
12 CANCER

In the case of small cell lung cancer, two general categories exist:
­limited stage small cell cancer and extensive stage small cell cancer. In
­limited stage, cancer cells may have spread to lymph nodes between the
lungs or near the collarbone. In extensive stage, the cancer cells have
spread beyond the lungs and to lymph nodes above the collarbone and
other areas of the body. Small cell cancer can also be recurrent, where
the cancer has returned after treatment and can be found in the chest,
central nervous system, or other parts of the body. Staging of small cell
lung c­ ancer makes use of categories as described for non-small-cell lung
cancers, though small cell lung cancers are frequently not treatable by
surgery and samples for analysis can be harder to obtain.
Prognosis of lung cancer is frequently expressed in terms of the
­survival rate, specifically the predicted percentage of individuals alive
5 years after the diagnosis of cancer. It is important to note that many
individuals survive much longer than 5 years after diagnosis, especially
when the cancer is treated. Survival rate estimates are relative survival
compared to the general population. A certain type of lung cancer that
has a specific diagnosis and staging might have a relative survival rate of
30 percent. This prediction means that individuals with this diagnosis
are thought to have a 30 percent chance of surviving at least 5 years com-
pared to the general population. It does not indicate that 30 ­percent of
the patients will survive. It is important to understand that since s­ urvival
rates require an accumulation of 5 years of data, new treatments may
have been developed that lack 5-year survival rates. Relative survival
rates are higher for earlier stage cancers. For small cell lung cancer, the
relative survival rate for stage I is approximately 31 percent, stage II is
19 percent, stage III is 8 percent, and stage IV is 2 percent. It is difficult
to treat lung cancer that has spread to other parts of the body. Never-
theless, treatments exist for stage IV lung cancers, and the outcomes
vary depending on the specifics of the diagnosed cancer. The National
Cancer Institute’s SEER database indicates that the relative survival
rate of non-small-cell lung cancer stage IA is approximately 49 percent,
stage IB is approximately 45 percent, stage IIA is 30 percent, stage IIB
is 31 ­percent, stage IIIA is 14 percent, stage IIIB is 5 percent, and stage
IV is less than 1 percent. These data were based on people who were
diagnosed between 1998 and 2000.
 Symptoms and Diagnosis 13

Symptoms and Diagnosis of Breast Cancer

Breast cancer is the second leading cause of cancer-related death in
women, second to skin cancer, with 1 in every 37 women dying from
breast cancer. While less common, men also develop breast cancer, with
an estimation of 2,470 new cases and 460 deaths (19 percent). This
lower incidence is thought to be due to the fact that breast tissue in men
is ­underdeveloped as compared to women, and female hormones that
would affect breast cells are present at lower levels. The American ­Cancer
Society reports that in 2017 about 40,610 American women will die
from breast cancer and 252,710 new cases of invasive breast cancer will
be diagnosed (16 ­percent). The earliest detectable noninvasive form of
breast cancer, called carcinoma in situ (CIS), is estimated to be present in
63,410 new cases.
Breast cancers usually are painless, with the mass of cells having
­uneven edges and a hard feeling to the touch. A breast cancer lump can
be detected by manual exam performed by the patient or a physician.
Breast cancer lumps can cause pain and appear smooth, so any new lump
should be investigated. In addition to the presence of a lump, patients
might ­experience swelling of part or all of the breast, skin irritation, skin
dimpling (looking like an orange peel), breast pain, nipple pain, nipple
retraction (nipple turning inward), redness of nipple or breast skin,
scales on nipple or breast skin, thickening of nipple or breast skin, or
nipple ­discharge (other than breast milk). If breast cancer has spread to
the lymph system, there may be swelling or pain associated with lymph
nodes. To increase the chance of identifying breast lumps early, women
are ­recommended to start yearly imaging screenings called mammograms
optionally at age 40, and regularly at age 44 if they have no risk factors. By
age 55 m ­ ammograms can be reduced to every other year. M ­ ammograms
can reveal the first signs of breast cancer as a smaller lump or mass of cells
in the breast. Diagnosing breast cancer can be complicated by the fact
that breasts form benign tumors that do not spread outside of the breast
tissue. At times, these benign tumors increase the risk of breast cancer
forming and should be carefully monitored.
Because a breast lump of cells may not be malignant, additional tests
would be performed after the mammogram to determine if the mass
14 CANCER

is cancer. When interpreting a mammogram lump, the radiologist will

apply a standardized numbering system (from 0 to 6) called the breast
imaging reporting and data system (BI-RADS). These categories describe
only mammogram results and are not the same as breast cancer staging
categories.

• Category 0 indicates that the radiologist detected a small

­abnormality so that another mammogram or a comparison to prior
mammograms is needed. Category 0 means that more information
is needed before the presence or absence of a mass is determined.
• Category 1 indicates that no lumps or suspicious irregularities were
found.
• Category 2 indicates that a mass was found, but it is considered
benign (no sign of cancer). This category would describe fibrous
calcifications or lymph nodes that are not cancer, so that they can
be referred to in future exams.
• Category 3 indicates a probable benign mass of cells with the rec-
ommendation that another scan be performed sooner than 1 year,
usually every 6 months for 2 years. Category 3 lumps have the
greatest chance of being benign (98 percent of the time they are
not cancer).
• Category 4 describes a suspicious abnormality in the mammogram.
In this case there would be enough concern to order a biopsy of
the mass of cells. Findings in this category can be described as 4A
(low suspicion), 4B (intermediate suspicion), and 4C (moderately
suspicious), but not as much as category 5.
• Category 5 describes a mass that looks like cancer and has a
high chance of being cancer (95 percent); biopsy is strongly
recommended.
• Category 6 describes a mass where a biopsy confirmed cancer
and the mammograms are being done to track tumor size after
treatment.

Dense breast tissue can be a natural and healthy state of the breast
tissue, but makes interpreting mammograms more difficult. When a
mass of cells is identified in a mammogram, a breast ultrasound can
 Symptoms and Diagnosis 15

provide additional useful information, the same technology used to

­visualize e­mbryos during pregnancy. An ultrasound uses sound waves
to measure the density of breast tissue. A transducer that has been
coated with a gel is placed on the surface of the breast, the sound waves
bounce back off of the breast tissue and are used to construct an elec-
tronic image. U ­ ltrasound is particularly good at distinguishing between
a solid mass of cells and a ­fluid-filled cyst (which are indistinguishable
on a m ­ ammogram). U ­ ltrasounds can also be used to help guide the
­removal of breast tissue during a biopsy. Once a patient is diagnosed
with breast cancer, more detailed imaging, such as an MRI, may be re-
quired to quantify tumor size and metastasis. For a breast MRI, contrast-
ing ­material called g­ adolinium is injected into the patient to highlight
breast tissue details. If a person has a high risk of developing breast can-
cer, breast MRI can be used for r­ egular screening purposes. MRI is not
usually used for standard s­ creenings, ­because the rate of false positives is
high (more small benign lumps will be visualized) and would result in
unnecessary biopsies.
When a mass of cells is detected, the diagnosis of breast cancer
­requires a histological analysis of a breast tissue biopsy (often referred
to as a lumpectomy). Biopsies can be taken by fine needle aspiration,
where a small needle is used to remove the tissue sample. Similarly, a core
needle biopsy can be used, where a wide needle is positioned with the aid
of imaging technique and then a spring-loaded trigger moves the needle
in and out of the tissue repeatedly to collect a cylinder (core) of tissue.
A histological analysis of the core needle biopsy can readily determine if
cancer is present. If results from a needle biopsy are uncertain, a s­ urgical
breast biopsy can be performed. A surgeon removes some (incisional
­biopsy) or all (excisional biopsy) of the lump for histological examination
to determine if it contained cancerous cells. If cancer is found, additional
biopsies may be performed on nearby lymph nodes to determine if the
cancer has moved beyond the original tumor site. Additional scans such
as chest ­X-rays, CAT scans, MRI, and PET scans can also aid in detect-
ing metastatic breast cancer outside the breast. A histological analysis of
the tumor cells can be graded to indicate the seriousness of the cancer.
A numerical grade indicates how much the cancer cells look like normal
cells. A grade of 1 would appear more like normal cells, be less likely to
16 CANCER

spread, and be slower growing. A grade of 3 would suggest a faster grow-

ing cancer that would be more likely to spread with grade 2 between 1
and 3. Occasionally, the terms well differentiated, moderately differentiated,
and poorly differentiated are used instead of 1, 2, and 3, respectively. Some
pathology reports will use other grading systems, but in general the lower
the number, the better the prognosis.
In addition to histological analysis of the cells obtained from a
­biopsy, breast cancer cells can evaluated for gene expression patterns to
gain a breast cancer recurrence score. The Oncotype DX test detects the
presence of hormone receptors in tumors that have not spread beyond
3 lymph nodes. Oncotype DX measures 21 different genes and reports
a score indicating the likelihood that the cancer will come back within
10 years after treatment. The MammaPrint test predicts the likelihood
that r­ecurrence will happen in areas of the body beyond the breasts.
­MammaPrint involves 70 different genes, and also reports recurrence like-
lihood within 10 years. Other tests can determine the proportion of cells
undergoing cell division within the tumor. A tumor that contains more
dividing cells produces a poorer prognosis and tends to be faster growing
and likely to metastasize. The Ki-67 test measures the number of cells
actively replicating their DNA in S phase. Understanding the number of
actively dividing cells in a tumor can help guide treatments that might
target cancer cells more effectively.
The information gathered from a physical exam, imaging approaches,
and biopsy will be taken into consideration to stage the tumor using
guidelines from the AJCC. Staging breast cancers takes into consideration
the primary tumor size (T), the movement of cancer cells to lymph nodes
(N), and metastasis to other parts of the body (M). Tumors are placed
into T, N, and M categories, and this information is used to stage the
tumor from 0 to IV, with the lower numbers indicating the earliest stages
of cancer. Clinical staging might occur prior to surgery, before all of the T,
N, and M information has been gathered. Pathological staging takes into
consideration information after surgery and can be very complicated. The
most common areas of breast cancer metastasis are the bones, liver, brain,
or lungs. Staging of breast cancer is unique to the patient and tumor type,
so care should be taken in understanding the specifics of a breast tumor
staging diagnosis.
 Symptoms and Diagnosis 17

• Stage 0 has no spread to lymph nodes or other parts of the body,

and the breast tumor is not invasive.
• Stage I is split into IA and IB where the tumor is 2 cm or less and
in IA not spread outside of the breast or in IB has spread as masses
less than 2 mm in diameter in one to three nearby lymph nodes.
• Stage IIA tumors are also less than 3 cm in diameter, with either
additional masses more than 2 mm in diameter in two to three
nearby lymph nodes, or as spread to the internal mammary lymph
nodes near the breastbone.
• A tumor can also be described as stage IIA if the mass is larger than
3 cm but smaller than 5 cm in diameter—with no spread to lymph
nodes or other areas of the body.
• Stage IIB masses are larger than 3 cm but smaller than 5 cm in
diameter with cells found in one to three nearby lymph nodes and
some cells identified in the internal mammary lymph nodes.
• A tumor that is larger than 5 cm is staged at IIB if the tumor has
not grown into the chest wall or skin, and has not spread to lymph
nodes.
• Stage IIIA tumors are less than 5 cm, spread in four to nine lymph
nodes or an enlarged internal mammary lymph node.
• A tumor can also be staged at IIIA if the tumor is larger than 5 cm
and has not grown into the chest wall or skin, spread in four to
nine lymph nodes.
• Stage IIIB tumor cells have grown into the chest wall or skin.
Spread to the lymph nodes can range from no spread to appear-
ance in one to three axillary lymph nodes with some cells identified
in the internal mammary lymph nodes, or spread in four to nine
lymph nodes with enlarged internal mammary lymph nodes.
• Inflammatory breast cancer is also considered a stage IIIB breast
cancer.
• Stage IIIC tumors can be of any size, but spread more widely to
lymph nodes including 10 or more axillary lymph nodes, lymph
nodes under the collar bone, lymph nodes above the collar bone,
axillary lymph nodes with an enlarged internal mammary lymph
node, and four or more axillary lymph nodes with some in internal
mammary lymph nodes.
18 CANCER

• Once a breast tumor spreads to areas of the body other than the
breast tissue, it is considered stage IV.

Symptoms and Diagnosis of Prostate Cancer

Prostate cancer is the second most common cancer in men, after skin can-
cer, and the third leading death due to cancer in men following lung and
colorectal cancer. Only males have prostate glands and they are located
just below the bladder and in front of the rectum (Figure 1.2). Imme-
diately behind the prostate are additional glands called seminal vesicles
that make most of the fluid found in semen, but the prostate contributes
some of the fluid in the semen. The urethra moves through the center
of the prostate gland and allows passage of urine and semen out of the
body through the penis. At younger ages, the prostate is approximately
the size of a walnut, but can grow larger as men age, which also increases
the likelihood of prostrate cells becoming cancerous. The American
Cancer ­Society predicts approximately 161,360 new cases in 2017 and

Figure 1.2  Normal male reproductive and urinary anatomy showing

the normal prostate and flow of urine from the bladder through
the urethra. By unknown illustrator (Public domain), via Wikimedia
Commons https://upload.wikimedia.org/wikipedia/commons/5/58/
Benign_prostatic_hyperplasia.jpg
 Symptoms and Diagnosis 19

26,730 deaths (17 percent) from prostate cancer. Prostate cancer develops

primarily in men over the age of 65 and is rarely diagnosed before age
40. Approximately 1 in 7 of all men (14 percent) will be diagnosed with
prostate cancer and 1 in 39 (3 percent) will die from it.
Early stages of prostate cancer produce no symptoms, but as the
­disease progresses, patients might experience problems urinating; blood
in urine or semen; difficulty in getting an erection; weakness or numb-
ness in legs, feet, bladder, or bowel from tumor pressure on spinal cord;
or pain in hips, spine, or ribs if cancer has spread to bones. Other health
issues can produce similar symptoms, which makes prostate cancer
diagnosis difficult. The prostate can develop noncancerous growths,
­
making prostate cancer even more complicated to diagnose. Many pros-
tate cancers are first identified using a rectal exam or a test detecting
the ­biomarker prostate-specific antigen (PSA). Rectal exams, or digital
rectal exam (DRE), involves the physician inserting a gloved and lubri-
cated finger into the rectum to detect any unusual lumps or masses of
cells. During this exam, the physician feels for any lumps on either side
of the prostate, or cells that have spread to nearby tissues. Tumor detec-
tion might also make use of imaging approaches such as the trans-rectal
ultrasound, where a small lubricated probe is inserted into the rectum to
create an image of surrounding tissues. The PSA test uses blood to d ­ etect
the presence of prostate antigen, which is produced by both healthy and
cancerous prostate cells, but is often elevated in men with prostate can-
cer. It is important to note that there are several benign conditions of the
prostate that can give rise to elevated PSA in the blood stream, so this test
alone is not diagnostic for prostate cancer. Likewise, individuals with low
PSA levels have been diagnosed with prostate cancer. PSA levels vary in
an individual over time, so thresholds for increased concern of prostate
cancer vary depending on patient age and the preference of the physi-
cian. Generally, healthy men have a PSA of 4 ng/mL, or lower. A PSA
reading of above 4 warrants further tests. In 2012, the Prostate Health
Index (PHI) test was approved for use in the United States by the FDA.
The PHI takes into consideration pro-PSA (pPSA) that is inactive, but
can be modified by another protein to become active. A specific form of
pPSA called [-2]pPSA is stable so that it can’t be activated and is more as-
sociated with the PSA produced in response to cancer, rather than other
20 CANCER

prostate conditions. The PHI test also considers how much total PSA
(active and inactive) is free floating in the blood relative to how much is
bound by other proteins. The relative amounts of free/bound/[-2]pPSA
in the patient is used as an indicator of prostate cancer and ­prognosis
of the likelihood that the cancer might b­ ecome metastatic. The PHI
test is recommended for patients over 50 with a total PSA between 4.0
and 10 ng/mL and whose physical exam does not find signs of cancer.
­Interpretations of PHI tests will vary for each individual based on clinical
history. The Mayo clinic reports that PHI scores below 27 correlate to
about a 10 percent chance of cancer, while a score over 55 would indicate
about a 50 percent chance of cancer.
If physical exams, imaging tests, or blood tests suggest that a patient
might have prostate cancer, then a biopsy and histological analysis is
performed to determine the Gleason score of the prostate tissue. The
Gleason score indicates if cells in the tumor look like normal cells of
the prostate. Cells that look like normal cells would be given a grade of
1, whereas cells that look very abnormal would be given a grade of 5,
with intermediate cells given grades of 2 to 4. Grade 1 and 2 are usu-
ally not cancer. A tumor that is more like normal tissue (lower Gleason
score) is less dangerous and would be described as more differentiated
(a differentiated tissue has specialized for its normal specific function).
Since tumors can have variation of cells within a single mass, two areas of
the biopsy are given grades, and these grades are added to give the final
­Gleason score ranging between 2 and 10. If the higher grade makes up
95 percent or more of the cells, both biopsies are graded as the higher
score. If three grades are detectable in a sample, then the highest two are
added for the Gleason score. Well-differentiated (low grade) cancers are
scored 6 or below, moderately differentiated (intermediate grade) cancers
score a 7, and poorly differentiated (high grade) cancers would score from
8 to 10. If some cancer cells appear, but are too few in number to be cer-
tain, the biopsy would be described as atypical small acinar proliferation
(ASAP), also called atypia. If ASAP is detected, there is a high chance that
cancer exists in the prostate. A histological analysis of a prostate biopsy
that reveals cells that don’t look entirely normal, but have not moved
into nearby tissues, are called prostatic intraepithelial neoplasia (PIN).
 Symptoms and Diagnosis 21

The relation of PIN cells to cancer development is not clear. Another cell
type that might be detected during histological analysis of the prostate
biopsy are proliferative inflammatory atrophy (PIA), which are smaller
cells that might lead directly to prostate cancer.
Staging of prostate cancer plays an important role in treatment and
prognosis. Staging guidelines from the AJCC considers the size of the
tumor, if the cancer has spread to lymph nodes or other parts of the body,
PSA measurements, and Gleason score.

• Stage I indicates the mass of cells is not detectable by physical

exam, is nowhere else in the body, PSA levels are below 10, and
Gleason score is 6 or less. A tumor can also be considered stage
I if it is large enough to be detected by physical examination or
­imaging test, but is restricted to one side of the prostate.
• Both types of stage I tumors advance to stage IIA if the PSA level
is below 20 and the Gleason score is 7, or if the Gleason score
remains at 6 or below and the PSA levels are between 10 and 20.
Regardless of PSA or Gleason scores, tumors advance to stage IIB
if they can be detected by rectal exam or imaging, and are located
on both sides of the prostate, but have not spread to lymph nodes
or other parts of the body. Stage IIB tumors can also be undetect-
able and restricted to the prostate if the PSA level is 20 or more
regardless of the Gleason score, or a Gleason score greater than 7
with any PSA level.
• Stage III prostate cancer has not spread to lymph nodes, but
has spread beyond the prostate and invaded the seminal vesicles
­regardless of PSA or Gleason scores.
• Stage IV prostate cancer has moved beyond the prostate and semi-
nal vesicles regardless of PSA or Gleason scores. These tumors
may not have moved to lymph nodes, but they have moved to the
urethral sphincter (muscle at the base of the urinary bladder that
controls urination), rectum, bladder, and/or the wall of the pelvis.
Stage IV tumors may not have invaded tissues near the ­prostate,
but are found in nearby lymph nodes or have metastasized to
­distant parts of the body.
22 CANCER

Physicians might also report prostate staging using the D’Amico

­system, where tumor size and position, PSA levels, and Gleason scores
are used to put tumors into low-, intermediate-, and high-risk groups.
The relative survival rate of prostate cancer is 90 percent, meaning that
­compared to men without the disease, a prostate cancer patient who
­receives treatment has a 90 percent chance of surviving for 5 years after
diagnosis. Individual survival rates change with different diagnoses
of prostate cancer. Stages I, II, III, and IV cancer that have not spread
­beyond nearby lymph nodes would have a 100 percent relative survival
rate, but prostate cancer that has metastasized to distant lymph nodes or
other parts of the body has a relative survival rate of 29 percent.
 Index
Abemaciclib (Verzenio), 42
Abiraterone (Zytiga), 45
Actinic keratosis, 3
Adriamycin, 40
Afatinib (Gilotrif ), 37
AJCC. See American Joint
Commission on Cancer
(AJCC)
Alectinib (Alecensa), 37
Alleles, 23
Alveoli, 7
American Cancer Society, 18, 30
American Joint Commission on
Cancer (AJCC), 5
Anastrozole (Arimidex), 41
ATM gene, 29
Atypical ductal hyperplasia (ADH)
versus atypical lobular
hyperplasia (ALH), 27
Atypical small acinar proliferation
(ASAP), 20
Bacillus Calmette-Guerin (BCG)
vaccine, 36
Basal cell skin cancer, 3
Bevacizumab (Avastin), 37, 42
Bicalutamide (Casodex), 45
Biomarker, 3
Biopsies, 15
Bowen disease, 3
BRCA1 protein, 28–29
BRCA2 protein, 29
Breast cancer
causes and contributing factors of,
26–30
high-risk factors for, 29
staging categories, 14
symptoms and diagnosis of, 13–18
treatment and therapy for, 38–43
Breast imaging reporting and data
system (BI-RADS), 13
Breast ultrasound, 14–15
Breslow measurement, 6
Brigatinib (Alunbrig), 37
Bronchioles, 7
Cabazitaxel (Jevtana), 45
Cancer
causes and contributing factors of
breast cancer, 26–30
lung cancer, 25–26
prostate cancer, 30–31
skin cancer, 23–25
cellular disease disrupts organ
function, xxi–xxii
common treatments of, 33–34
conclusion, 49
dangerous cancer cells move
through body, xviii–xx
future prospects, 47–48
genetic disease disrupts cellular
function, xiii–xviii
methods for detection and
diagnosis, 1–3
symptoms and diagnosis of
breast cancer, 13–18
lung cancer, 7–12
prostate cancer, 18–22
skin cancer, 3–7
treatment and therapy for
breast cancer, 38–43
lung cancer, 36–38
prostate cancer, 43–46
skin cancer, 34–36
Capecitabine, 35
Carboplatin, 33
Carcinogens, 25
Carcinoma, 26
Carcinoma in situ (CIS), 13
CDKN2A alleles, 24
Cell cycle checkpoints, xiv
Cell division, xiii
64 INDEX
Centers for Disease Control and
Prevention (CDC), 3
Central dogma of life, xvi
Ceritinib (Zykadia), 37
CHECK2 gene, 29
Chromatin, xv
Circulating tumor cells (CTCs), 48
Cisplatin, 33, 35
Combined androgen blockade
(CAB), 45
Comparative genomic hybridization
(CGH), 1
Connective tissues, 22
Contact inhibition, xvii
Cowden syndrome, 29
Crizotinib (Xalkori), 37
Cryotherapy, 34–35
Cyclin/CDK enzymatic complex, xiv
CYP17 enzymes, 45
Dabrafenib (Tafinlar), 37
Daunorubicin, 40
DDR2 gene, 26
DecisionDx-Melanoma, 48
Degarelix (Firmagon), 44
Denosumab (Xgeva, Prolia), 46
Deoxyribonucleic acid (DNA)
genome, xiv
Digital rectal exam (DRE), 19
Dihydrotestosterone (DHT), 44
Docetaxel (Taxotere), 45
Doxorubicin, 35
Ductal carcinoma in situ (DCIS), 27
Dysplastic nevi (DN), 4
E-cadherin protein, 29
EGFR gene, 37
Ellence, 40
Endothelial tissues, 22
Enzalutamide (Xtandi), 45
Epigenetic targets, 47
Epithelial tissues, 22
ERBB2 gene, 26
Erlotinib (Tarceva), 37
Estramustine (Emcyt), 45
Estrogen (ER)-positive cancers, 40
Etoposide, 35
Eumelanin, 24
Exemestane (Aromasin), 41
5-fluorouracil (5-FU), 35
Flare, 44
Fluorescence in situ hybridization
(FISH), 1
Flutamide (Eulexin), 45
Gadolinium, 15
Gamma rays, 34
Gefitinib (Iressa), 37
Gene expression, xv
Gleason score, 20, 21
Gonadotropin-releasing hormone
(GnRH), 44
Goserelin (Zoladex), 44
Histrelin (Vantas), 44
Hormone therapies, 43–44
HOXB13 gene, 30–31
Human estrogen receptor 2
(HER2), 41
Hyperplasia, 26
Immunohistochemistry (IHC), 1
In Situ, 26–27
Inflammatory breast cancer (IBC), 27
Interleukin 2, 35
Interleukin alpha, 35
Intraductal carcinoma. See Ductal
carcinoma in situ (DCIS)
Invasive (infiltrating) ductal
carcinoma (IDC), 27
Ipilimumab (Yervoy), 36
Kaposi sarcoma, 3
Ki-67 test, 16
KRAS gene, 25–26
Letrozole (Femara), 41
Leuprolide (Lupron, Eligard), 44
Lung cancer
causes and contributing factors of,
25–26
symptoms and diagnosis of, 7–12
treatment and therapy for, 36–38
Luteinizing hormone-releasing
hormone (LHRH), 44
Lymphoma of the skin, 3
MammaPrint test, 16
Mammograms, 13
 INDEX
65
MC1R encodes, 24
Melanocytes, 3
Melanomas, 3–4
Merkel cell sarcoma, 3
Mitotic index, 1
Mitoxantrone (Novantrone), 40, 45
National Cancer Institute, 39
SEER database, 34
National Weather Service and the
Environmental Protection
Agency, 24
Necitumumab (Portrazza), 37
Neuroendocrine cells, 8
Nilutamide (Nilandron), 45
Nivolumab (Opdivo), 36
Non-small-cell cancers, types of, 8
Non-solid tumors, xiii
Nucleotides, xv
Oncogene, xvii
Oncotype DX test, 16
One gray (Gy), 33
Optical coherence tomography
(OCT), 47
Orchiectomy, 44
PALB2 protein, 29
Palbociclib (Ibrance) blocks, 42
PD-1 inhibitors, 36
PD-L1 inhibitors, 43
Pembrolizumab (Keytruda), 36, 37
Peutz-Jeghers syndrome, 29
Pheomelanin, 24
Photodynamic therapy, 35
Photoradiation therapy. See
Photodynamic therapy
PIL3CA gene, 26
Positron emission tomography
(PET), 1
Progesterone (PR)-positive
cancers, 40
Proliferative inflammatory atrophy
(PIA), 21
Prophylactic cranial irradiation
(PCI), 37
Prostate cancer
causes and contributing factors of,
30–31
symptoms and diagnosis of, 18–22
treatment and therapy for, 43–46
Prostate Health Index (PHI) test, 19
Prostate-specific antigen (PSA), 19
Prostatic acid phosphatase (PAP),
45–46
Prostatic intraepithelial neoplasia
(PIN), 20–21
Proteins, xv
Proto-oncogenes, xvii
PTEN gene, 26
Radiation therapy, 35
Radical prostatectomy, 43
Radio wave, 1
Raloxifene (Evista), 41
Receptors, xvii
Reflectance confocal microscopy
(RCM), 47
RET gene, 26
Ribociclib (Kisqali), 42
RNASEL gene, 31
ROS1 gene, 26
Signal transduction cascade, xvii
Sipuleucel-T (Provenge), 45
Skin cancer
causes and contributing factors of,
23–25
symptoms and diagnosis of, 3–7
treatment and therapy for, 34–36
Small cell lung cancer cells, 8
staging, 9–11
Sputum cytology, 7–8
Stroma tissues, 22
Talimogene laherparepvec
(Imlygic), 36
Tamoxifen (Nolvadex or
Soltamox), 41
Testosterone, 44
Thoracoscopy, 8
Topotecan, 35
Toremifene (Fareston), 41
TP53 protein, 29
Trametinib (Mekinist), 37
Transcription, xv
Translation, xv
Trastuzumab (Herceptin), 41–42
66 INDEX

Triple negative breast cancer, 42 White blood cells, 35

Triptorelin (Trelstar), 44
Tumor suppressor genes, xvii X-rays, 1
[-2]pPSA, 19 Xeroderma pigmentosum
(XP), 24
Ultrasound, 15
Ultraviolet (UV) light, 23 Zoledronic acid (Zometa), 46
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