Cancer is a group of diseases characterized by uncontrolled growth and
spread of abnormal cells. Tumor metastases to distant sites generally
have a greater effect than the primary tumor on the frequency of
complications and the patient’s quality of life and mortality.
Avoiding known risk factors may prevent cancer. Cancer may also be
prevented by appropriate use of vaccines and chemoprevention in
selected groups of high-risk patients.
The histologic diagnosis of a tumor is the most important determinant of
how a malignancy will be treated. The stage of cancer and the diagnosis
influence the treatment and prognosis. As part of staging, diagnostic
imaging facilitates identification of disease metastases.
The initialsigns and symptoms of malignant disease are variable and
depend on histology, location, and tumor size. This may influence
treatment options if they affect performance status, which is a measure
of a patient’s functional capacity.
Cancer is predominately treated with three modalities:surgery, radiation,
and systemic therapy. The goal of therapy should always be to cure the
Biochemical resistance to chemotherapy is the major impediment to
successful treatment with most cancers. Resistance can occur de novo
in cancer cells or develop during cell division as a result of mutation.
There are different types of systemic therapy: chemotherapy, targeted
agents, endocrine therapy, and biologic response modifiers. Systemic
therapy may be used in varying combinations and different settings. Use
depends on histology, cancer stage, and the patient’s predicted tolerance
Response to treatment is assessed by evaluating therapy’s antitumor
and toxic effects, including impact on the patient’s overall quality of life.
Evaluation should occur at scheduled intervals and include physical
examination, laboratory tests, and repeat diagnostic imaging.
Systemic therapies used to treat cancer are potentially carcinogenic, Case 93-11 (Questions 1–4)
teratogenic, or mutagenic. Handling and administering these agents
poses a risk to healthcare workers. Appropriate policies and procedures
must be in place to maximize safety and minimize risk while following
national guidelines and standards.
INTRODUCTION TO NEOPLASTIC DISORDERS
Cancer (neoplasm, tumor, or malignancy) is not a single disease. It is a group of
diseases characterized by uncontrolled growth and spread of abnormal cells. Cancer
cells do not respond to the normal processes that regulate cell growth, proliferation,
and survival, and they cannot carry out the physiologic functions of their normal
counterparts. Other characteristics of cancer cells include their ability to invade
adjacent normal tissues and break away from the primary tumor (metastasize) and
travel through the blood or lymph to establish new tumors (metastases) at a distant
site. Their ability to stimulate the formation of new blood
vessels (angiogenesis) and their endless replication potential further contribute to
their continued growth and survival.
1 Cancers can arise in any tissue in the body. If
cancer cells are allowed to grow uncontrollably, they can eventually result in the
Each year, the American Cancer Society publishes an estimate for the number of new
cases and number of cancer-related deaths. The National Cancer Institute publishes
cancer statistics that include cancer risk, prevalence, and survival information.
American Cancer Society estimates that 1 of 2 American men and 1 of 3 American
women will eventually develop cancer and that approximately 1,658,370 new cases
of cancer will be diagnosed in 2015.
3 The most common cancers and causes of
cancer-related deaths in adult Americans are listed in Table 93-1. The incidence of
cancer and cancer-related deaths can be affected by both age and ethnic background,
with the incidence greater in the elderly and African-American populations.
factors that are associated with an individual’s increased risk for cancer include
environmental and lifestyle factors, genetic predisposition, immunosuppression, and
exposure to one or more potential carcinogens.
Cancers arise from the transformation of a single normal cell. Damage or mutation to
the cell’s DNA is caused by an initial “event.” These events may include lifestyle,
environmental, or occupational factors, as well as some medical therapies (e.g.,
cytotoxic chemotherapy, immunosuppressive or radiation therapy) and hereditary
factors. Cigarette smoking is probably the single largest factor that contributes to
cancer development, responsible for approximately 30% of cancer deaths per year.
Other preventable causes, including physical inactivity, obesity, and nutrition, are
estimated to cause an additional 30% of cancer deaths per year.
million skin cancers diagnosed yearly are also potentially preventable with adequate
Cancer is a genetic disease. Two gene classes, oncogenes and tumor suppressor
genes, are important in the pathogenesis of cancer. Damage to cellular DNA can
result in mutations that lead to the development of oncogenes and loss or inactivation
of tumor suppressor genes. Oncogenes are genes whose overactivity or presence in
certain forms can lead to the development of cancer. Oncogenes arise from normal
genes called proto-oncogenes through genetic alterations such as chromosomal
translocations, deletions, insertions, and point mutations.
Estimated Sites of New Cancer Cases and Deaths in the United States, 2015
Prostate 220,800 (26%) Breast 231,840 (29%)
Lung and bronchus 115,610 (14%) Lung and bronchus 105,590 (13%)
Colon and rectum 69,090 (8%) Colon and rectum 63,610 (8%)
Urinary bladder 56,320 (7%) Uterine corpus 54,870 (7%)
Melanoma of the skin 42,670 (5%) Thyroid 47,230 (6%)
Non-Hodgkin lymphoma 39,850 (5%) Non-Hodgkin lymphoma 32,000 (4%)
Kidney and renal pelvis 38,270 (5%) Melanoma of the skin 31,200 (4%)
Oral cavity and pharynx 32,670 (4%) Pancreas 24,120 (3%)
Leukemia 30,900 (4%) Leukemia 23,370 (3%)
Liver and intrahepatic bile duct 25,510 (3%) Kidney and renal pelvis 23,290 (3%)
Allsites 848,200(100%) All sites 810,170 (100%)
Lung and bronchus 86,380 (28%) Lung and bronchus 71,660 (26%)
Prostate 27,540 (9%) Breast 40,290 (15%)
Colon and rectum 26,100 (8%) Colon and rectum 23,600 (9%)
Pancreas 20,710 (7%) Pancreas 19,850 (7%)
Liver and intrahepatic bile duct 17,030 (5%) Ovary 14,180 (5%)
Leukemia 14,210 (5%) Leukemia 10,240 (4%)
Esophagus 12,600 (4%) Uterine corpus 10,170 (4%)
Urinary bladder 11,510 (4%) Non-Hodgkin lymphoma 8,310 (3%)
Non-Hodgkin lymphoma 11,480 (4%) Liver and intrahepatic bile duct 7,520 (3%)
Kidney and renal pelvis 9,070 (3%) Brain and other nervous system 6,380 (2%)
Allsites 312,150 (100%) All sites 277,280 (100%)
Source: Siegel RL et al. Cancer statistics, 2015. CA Cancer J Clin. 2015:65(1):5–29.
Growth and proliferation of normal cells are influenced by proteins, known as
growth factors. When growth factors bind to receptors on the cell surface, they
activate a series of enzymes within the cell that stimulate cell signaling pathways and
gene transcription. These genes encode for proteins that regulate cell growth and
proliferation. The coordination and integration of cellular signaling processes are
referred to as signal transduction. Proto-oncogenes are responsible for encoding
several components of signal transduction pathways, including growth factors,
growth factor receptors, signaling enzymes, and DNA transcription factors.
Abnormal forms or excessive quantities of these stimulatory proteins disrupt normal
cell growth signaling pathways, leading to excessive growth and proliferation and,
ultimately, a malignant transformation.
Tumor suppressor genes are normal genes that encode for proteins that suppress
inappropriate cell division or growth. Gene deletions or mutations can cause these
proteins to become inactivated, eliminating the normal inhibition of cell division.
Alterations in a third class of genes, DNA repair genes, are also implicated in
cancer. DNA repair genes encode for proteins that correct errors that may arise
during DNA duplication. Mutations in these genes further contribute to the
accumulation of genetic changes that promote cancer progression.
Cancer development is a multistep process. Therefore, multiple genetic mutations,
including activation of oncogenes and loss or inactivation of tumor suppressor genes
within a cell, are necessary for malignant transformation.
are required for tumor invasion of normal tissues and metastases.
Cancer cells, like normal cells, proceed through a specific and orderly set of events
during cellular replication referred to as the cell cycle (Fig. 93-1). The cell cycle
), each responsible for a different task
necessary for cell division. During the first activity phase, the M phase, the cell
undergoes mitosis, the process of cell division. After mitosis, the cell enters the first
resting (or gap) phase, the cell makes the
enzymes necessary for DNA synthesis. The synthesis of DNA occurs during the S
phase. After S phase, the cell enters a second resting phase (G2
proteins are synthesized to prepare for cell division during M phase. Cells that
complete mitosis may either continue to proceed through the cell cycle to divide
again, differentiate or mature into specialized cells and eventually die, or enter a
Proliferation of normal cells is carefully controlled to balance the loss of mature
functional cells with the production of new cells. As mentioned, proto-oncogenes and
tumor suppressor genes provide the stimulatory and inhibitory signals, respectively,
that regulate the cell cycle. The transition of cells through the cell cycle is an
ordered, tightly regulated process, which involves a series of checkpoints that assess
these signals and the number and integrity of the cells.
8 Cyclins, a group of interacting
proteins found in the nucleus, and cyclin-dependent kinases (CDKs) make up the
molecular machinery that regulates passage of cells through various phases of the cell
cycle. The cyclins combine with CDKs to form complexes that act as molecular
switches. One of these molecular switches regulates whether a cell moves through a
critical restriction point that occurs late in G1 phase to S phase. If insufficient
amounts of cyclins or CDK are present during G1 phase, the cell will not enter S
phase to start cell division. Cells that pass through this restriction point are
irreversibly committed to the next phase of the cell cycle.
the CDK complex signals the end of the phase. The balance of regulation of cyclins
and CDKs is influenced by several factors, including cyclin gene transcription, cyclin
degradation, CDK inhibitors, and the transfer of phosphate groups to various proteins
and enzymes. Activating signals from the cell’s external environment are transmitted
to the nucleus via growth factor receptor signaling pathways, which influence
formation of cyclins and cyclin–CDK complexes. The complexes generate phosphate
groups from molecules of adenosine triphosphate (ATP) and transfer them to a
protein called a retinoblastoma protein (pRb). If pRb acquires enough phosphate
groups, it will release the transcription factors the cell needs to make proteins
essential for a cell division. In other words, phosphorylated pRb promotes cell cycle
to S and, subsequently, cell division. Other signaling pathways
inhibit cell proliferation through endogenous CDK inhibitors, which result in
Figure 93-1 Cell cycle and effects of representative cytotoxic drugs on phases of the cell cycle.
In cancer cells, the regulation and function of cyclins, CDK, and inhibitory
proteins may be disrupted by malignant transformation, or these proteins can undergo
changes that cause malignant transformation. Examples of defects in these processes
include deletion of the Rb gene, a tumor suppressor gene that encodes for pRb, and
dysregulation of the CDK through overactivation or loss of CDK inhibitors.
mentioned above, pRb regulates cell cycle transition from the G1
if this molecule becomes inactive, excessive cell proliferation can occur. In normal
cells, the p53 gene is responsible for temporarily arresting cell growth in response to
biochemical or molecular damage until the DNA damage can be repaired.
damage cannot be repaired, apoptosis (programmed cell death) occurs to prevent
genetically damaged cells from growing uncontrollably. Loss or mutation of a second
tumor suppressor gene, p53, is also common in human cancers and is associated with
the resistance of cancer cells to undergo cell cycle arrest or apoptosis.
Carcinogenesis is the process by which normal cells are transformed into cancer
cells. If the balance of stimulatory and inhibitory growth signals becomes
dysregulated, carcinogenesis may occur. In carcinogenesis, normal mechanisms such
as apoptosis and senescence (aging) do not function properly and cannot control
excessive cell division. Because abnormalities in the proto-oncogenes and tumor
suppressor genes regulating these processes are present in cancer cells, the balance
between cell renewal and loss of mature (senescent) cells is disrupted. Cancer cells
are also less dependent on receiving stimulatory signals from external growth
10 Furthermore, cancer cells possess unlimited replication potential, owing to
their ability to activate telomerase.
1,11 Telomerase is an enzyme that synthesizes
sequences of telomeres, thereby enabling cells to proliferate endlessly. The
expression of telomerase in most normal human cells is suppressed, but is
reactivated in most cancer cells.
occurs with each successive cell replication, and after a critical length is reached,
the cell undergoes irreversible growth arrest (replicative senescence).
normal cells, in which a finite telomere sequence regulates their life span, cancer
cells are capable of immortality through their ability to maintain their telomeres
the bone mass confirmed osteogenic sarcoma. A chest x-ray study showed three nodules that were also
S.T. does not have lung cancer. Tumor nodules in his lung are most likely
metastases from the sarcoma in his leg. The ability of cancer cells to disseminate and
form metastases represents their most malignant characteristic. Tumor metastases to
distant sites generally have a greater effect than the primary tumor on frequency of
complications and patient’s quality of life. Metastases also have a greater impact
Cancer cells must develop new blood vessels to obtain nutrients and spread to
distant sites (metastasize). In response to low oxygen supply (hypoxia) and other
factors, cancer cells and surrounding tissues secrete growth factors that stimulate
growth of new blood vessels (angiogenesis) from existing blood vessels in
factors needed for sustained endothelial cell growth. Once released by tumor cells,
these growth factors bind to tyrosine kinase receptors on the surface of endothelial
cells of existing blood vessels and activate a series of intracellular relay proteins
that transmit signals to genes in the nucleus to produce factors required for new
12 Once older endothelial cells become activated by growth
factors, they begin making matrix metalloproteinase (MMP) enzymes. These enzymes
destroy the extracellular matrix of surrounding cells, allowing older endothelial cells
to invade the extracellular matrix and begin cell division.
and proliferation is repeated several times until new blood vessels are formed.
Tumor cells can use these newly formed blood vessels to facilitate their spread to
distant locations. Cells must break away from the primary tumor and travel to other
sites in the body to form metastases. Normally, cells adhere to one another and the
extracellular matrix. The cell-to-cell adhesion molecules are called cadherins, and
the cell-to-extracellular matrix molecules are called integrins. In cancer cells, these
molecules are often absent, allowing tumor cells to easily move away from the
Once a tumor cell leaves the primary mass, it travels through the blood vessels and
lymphatic system within the body to form metastatic site(s). Usually, tumor cells
spread to the first capillary bed they encounter after their release from the primary
tumor. If the primary site drains its blood supply into the vena cava, the cancer cells
will reach the capillary bed in the lung. Similarly, if the primary site drains its blood
supply into the portal circulation, the cancer cells will reach the capillary bed in the
liver. In addition, cancer cells can potentially pass through the first capillary bed they
encounter and enter the arterial circulation where they can distribute to other organs
and tissues throughout the body.
Growth conditions (e.g., growth factors, physiologic conditions) within a tissue or
organ also can determine the location of a metastatic site. After a cancer cell
establishes a metastatic site, it must again undergo angiogenesis to ensure continued
growth. Together, angiogenesis and hematogenous or lymphatic spread help cancer
cells invade healthy tissues and increase morbidity and mortality associated with the
Cigarette smoking is probably the single largest factor that contributes to cancer
development, increasing risk for multiple cancer types including lung, head and neck,
gastrointestinal, bladder, and cervical cancers.
5 Therefore, tobacco cessation and
abstinence play an important role in prevention of cancer. For more information, visit
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