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Cancer And Lymphatics:
Part II
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor,
professor of academic medicine, and
medical author. He graduated from Ross
University School of Medicine and has
completed his clinical clerkship training in
various teaching hospitals throughout New
York, including King’s County Hospital
Center and Brookdale Medical Center,
among others. Dr. Jouria has passed all
USMLE medical board exams, and has
served as a test prep tutor and instructor
for Kaplan. He has developed several medical courses and curricula for a variety of
educational institutions. Dr. Jouria has also served on multiple levels in the academic field
including faculty member and Department Chair. Dr. Jouria continues to serves as a Subject
Matter Expert for several continuing education organizations covering multiple basic medical
sciences. He has also developed several continuing medical education courses covering
various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the
University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an emodule training series for trauma patient management. Dr. Jouria is currently authoring an
academic textbook on Human Anatomy & Physiology.
ABSTRACT
In the human body, cells receive nutrition and oxygen from lymph, a fluid
that is recirculated through the body via an extensive network of vessels.
Upon arriving at one of many nodes found within the body, the lymph is
filtered to discern healthy cells from those carrying disease or infection.
White blood cells then flood infected cells to eradicate illness. However,
cancer can either develop in the lymph nodes around the body, or it can
travel there via the lymphatic vessel network. Understanding the role that
the lymphatic system plays in the development, treatment, and prevention
of cancer is vital for medical professionals who want to provide their patients
with cutting-edge care. This is the second of a two-part series on Cancer and
Lymphatics that discusses normal and disease states.
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Continuing Nursing Education Course Planners
William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,
Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner
Policy Statement
This activity has been planned and implemented in accordance with the
policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's Commission on
Accreditation for registered nurses. It is the policy of NurseCe4Less.com to
ensure objectivity, transparency, and best practice in clinical education for
all continuing nursing education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 5.5 hours. Nurses may only claim
credit commensurate with the credit awarded for completion of this course
activity.
Pharmacology content is credited for 1 hour.
Statement of Learning Need
Understanding the role of the lymphatic system is vital for all health
professionals, especially nurses who deliver care to patients with a disorder
involving the lymph system. There exist many misconceptions of the role of
the lymphatic system; including prevention and the treatment of disease.
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Course Purpose
To provide nurses with knowledge of the lymphatic system, and
corresponding diseases, prevention and treatment.
Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses and
Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,
Susan DePasquale, CGRN, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Activity Review Information
Reviewed by Susan DePasquale, CGRN, MSN, FPMHNP-BC
Release Date: 12/28/2015
Termination Date: 12/28/2018
Please take time to complete a self-assessment of knowledge, on
page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned
will be provided at the end of the course.
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1.
Tonsils differ slightly from other lymph nodes in the body in that
they lack
a. efferent collector vessels.
b. afferent vessels.
c. lymphocytes.
d. macrophages.
2.
True or False: Because of their locations within the thymus
gland, these white blood cells (lymphocytes) may be referred to
as thymocytes.
a. True
b. False
3.
Lymphopoiesis refers to
a. poor immune or thymic function.
b. the activation or initiation of the immune response.
c. the movement of lymphocytes through circulation.
d. the creation of lymphocytes in the bone marrow.
4.
The __________ is a large lymph node that is positioned along
blood vessels.
a. medulla
b. thymus
c. spleen
d. tonsil
5.
Lymphoid organs are those that
a. develop lymphocytes and other cells that protect the body.
b. house the immune system cells.
c. contain macrophages and lymphocytes.
d. All of the above.
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Introduction
The lymph system protects against edema by gathering excess interstitial
fluid and proteins into the lymph vessels where they circulate and eventually
return to venous circulation. This system prevents excess fluid build up in
the interstitial space and excess edema formation, which otherwise leads to
swelling and imbalanced fluid collection when there is a shift out of the
intravascular and interstitial spaces. If too much fluid remains out of blood
circulation, the affected person may experience hypotension because of
decreased intravascular volume. The individual may also experience
decreased oxygenation of the peripheral tissues when less fluid in the blood
leaves a lesser amount in circulation, thereby diminishing the amount of
oxygen and nutrients being transported through the bloodstream. The
lymphatic system plays a key role in preventing fluid imbalances that can
otherwise lead to such complications.
Within the gastrointestinal tract, the lymphatic system plays an important
role in supporting nutrition because it is also responsible for absorbing a
certain amount of fats and fat-soluble vitamins. The villi, present on the
interior mucosal wall of the small intestine where most absorption takes
place, are tiny projections that contain capillaries within their centers. Each
villus contains blood capillaries to absorb most nutrients directly into the
bloodstream, but it also contains lymph capillaries, called lacteals, which also
play a role in nutrient absorption.1 The lacteals absorb fats from the
bloodstream that are otherwise too large to be absorbed through the blood
vessels. The endothelial layer of the lacteals has large enough gaps that the
larger fat molecules in the digestive tract can pass through the wall of the
lacteal and then pass into lymph circulation. The fats eventually do enter the
bloodstream after they are transported through lymphatic circulation and are
deposited into the venous system.
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The lymphatic system plays a role in immunity and in defending the body
against invading pathogens and microorganisms. The lymph nodes and the
lymphatic vessels each have a part in protecting the body by filtering lymph
fluid to remove foreign particles. The lymphatic organs, including such
organs as the spleen, the thymus, and the tonsils and adenoids, work by
filtering particles or actively attacking microorganisms when they enter the
body. Some lymphatic organs contain lymphocytes that foster immunity by
attacking and destroying invading organisms.
Organs Of The Lymphatic System
Various organs of the lymphatic system contribute to immune defense and
the development of immune cells to further protect the body. A major
element of their work is to house the immune system cells while they
prepare to attack those substances that could harm the body.
Lymphoid organs are those that contain lymphoid tissue, which is a
collection of developing lymphocytes and other cells that protect the body.
Once lymphocytes have formed in the bone marrow, they undergo a period
of maturation and then travel to the organs of the immune system. The
lymphatic organs contain combinations of these lymphocytes as well as
other immune system cells, such as macrophages.
When the body is exposed to foreign particles and the immune system is
stimulated, the lymphocytes multiply and increase their numbers before
leaving the lymphatic organs to travel to the site of infection or injury. This
is how lymphatic organs play key roles in the immune system process.
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Spleen
The spleen is a complex organ that has several functions related to the
immune and hematologic systems. The spleen is located in the left upper
quadrant of the abdomen; it is positioned below the diaphragm and behind
the stomach. The spleen is the largest of the lymphatic organs. It is actually
a large lymph node that is positioned along blood vessels instead of being
located along the lymph vessels. The spleen has sometimes been referred to
as the lymph node of the bloodstream.8 Because of its work with the blood’s
circulatory system and with red blood cells, the spleen has a large and rich
blood supply. At its normal size, the spleen contains approximately 500 mL
of blood at any one time.21 While the spleen does play many roles in
maintaining health and managing blood cells, a person can live without the
spleen if it must be removed, although the affected person may be at higher
risk of infection because he or she is missing the protection the spleen
provides.
The spleen has a capsule exterior that
is made up of connective tissue. Its
center is divided into lobules that
contain the splenic pulp in its interior.
The spleen consists of substances
known as red and white pulp. The red
pulp is the location where aged, red
blood cells are destroyed, while the
white pulp contains lymphocytes. When
blood enters the spleen, it flows
through the pulp, where the spleen
then filters foreign substances. The
spleen contains macrophages and lymphocytes within its pulp, which filter
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foreign particles and destroy those that are foreign (non-self), as well as old
cells that are no longer useful.
The spleen filters blood in a manner similar to how the lymph system filters
lymph fluid. The spleen has several important roles. The lymphocytes within
the spleen respond to foreign antigens and to pathogens and destroy them
to be able to protect the body. Once destroyed, the macrophages that are in
the spleen then engulf the pathogens and other cellular debris. The spleen is
also responsible for disposing of aged blood cells and taking them out of
circulation so that their parts can be reused. Although it destroys red blood
cells that have aged, the spleen saves the iron found in hemoglobin in the
erythrocytes. In this way, the spleen is important for red blood cell and iron
metabolism, which are essential for supplying the body’s tissues with oxygen
through hemoglobin molecules.12
If there is damage or infection anywhere in the body, the spleen may send
some cells of immunity to respond. The spleen itself contains many
monocytes, which are transformed into macrophages when foreign particles
invade the body. Once the cells have changed into macrophages, they engulf
the foreign cells through phagocytosis. When infection occurs, the spleen
dispatches these monocytes as a defense mechanism to destroy the foreign
cells.
Some people have a certain amount of red blood cells that have pits in their
outer membranes. These pitted red blood cells are more commonly seen
among those with hematologic conditions, including sickle cell disease
(SCD), which is a group of inherited red blood cell disorders where affected
individuals have abnormal hemoglobin. A “pit count” describes the process of
counting the number of pitted red blood cells within a blood sample viewed
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microscopically. The pits or craters on the surface of the red blood cell are
actually vacuoles that contain leftover particles from cells, including ferritin,
hemoglobin, mitochondria, and some parts of cell membranes.63 Part of the
normal function of the spleen is to remove these pits when they appear on
the surface of the erythrocyte cell membrane.
A review by di Sabatino, et al., in The Lancet noted that people who have
poorly functioning spleens or that had a previous splenectomy are more
likely to have pitting red blood cells.64 Persons who have more pitted red
blood cells may be at higher risk of illness or disease because the spleen
may not be working well enough. Performing a pit count to determine the
number of pitted red blood cells is actually a test that can determine
functionality of the spleen, as increased numbers of pitted cells indicates
that the spleen is not adequately removing these abnormalities from the
cells.
Splenomegaly
Splenomegaly describes a condition of the spleen being enlarged. The spleen
normally sits next to the lower ribs on the left side of the ribcage; it is
therefore usually not palpable upon physical examination of the abdomen.
An enlarged spleen may be palpable as it extends below the costal margin.
Splenomegaly is technically defined as a spleen weight of at least 400 g to
500 g.
The normal size of the spleen is approximately 11 cm in length. Moderate
splenomegaly is defined as spleen length between 11 cm and 20 cm, while
severe splenomegaly is present if spleen length is over 20 cm.13
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Splenomegaly may develop as a result of a number of conditions, although it
should be noted that many individuals have enlarged spleens that may be
palpable on exam but who are not suffering from any type of infection or
disease process. For some people, an enlarged spleen is a normal part of the
anatomy and, as long as it is noted and recognized, it should not cause
concern. When the spleen is enlarged because of disease or damage, the
cause of splenomegaly may stem from multiple conditions, including certain
infectious processes such as mononucleosis. Additionally, splenomegaly may
be associated with conditions that affect circulation of blood through the
spleen, including portal hypertension or splenic vein thrombosis, as well as
certain types of cancer, such as leukemia or lymphoma; or with conditions
that result in increased destruction of red blood cells, including
thalassemia.13 Some other causes of splenomegaly include abdominal
trauma, use of certain medications, formation of cysts in or around the
spleen, abdominal abscess, or cancer metastasis.
Splenomegaly that develops as a result of an inflammatory condition
typically occurs because the spleen is working harder to defend the body.
When there is an increased need for defense activities, the spleen may grow
in size in response. When the body senses more antigens and a greater need
for defense, it responds by increasing antibody production. The result is a
condition called lymphoid hyperplasia, in which there is a rapid increase in
the number of lymphocytes in the spleen.
When splenomegaly occurs in response to a disease process, the overall
circulation of red blood cells may drop within the bloodstream. As the spleen
enlarges, it may sequester red blood cells and keep them contained within
its borders; sometimes up to 50 percent of red blood cells in the body are
sequestered at a time.14 This can significantly impact oxygenation and
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transport of nutrients throughout the rest of the body where red blood cells
are needed. As more red blood cells are sequestered in the spleen, the rate
of their destruction is also increased, which only further potentiates the
effects of decreased red blood cells in the rest of the body.
An individual with splenomegaly is also at risk of splenic hemorrhage, the
spleen may be more likely to become damaged or may rupture because of
its enlarged size. A person with splenomegaly should understand the
potential risks of splenic rupture and should take protective measures to
prevent this complication, such as by avoiding contact sports or other
activities that would increase the risk of injury.
Splenomegaly may need to be treated through removal of the spleen;
however, this is not always desirable as it puts the patient in a position
where he or she is at increased risk of infection. Other measures, such as
treatment through medications, including antimicrobials for infection or
drugs that prevent the spread of cancerous cells may be the first choice for
treatment rather than removing the entire spleen. The decision on whether
to remove the spleen is actually based on its size, its effects on the patient’s
health, and the cause of spleen enlargement in the first place. Depending on
the underlying cause of the splenomegaly, removal through splenectomy
may be the only option.
For those whom splenectomy is a treatment option for splenomegaly,
hematologic changes and an increased risk of infection are potential
complications. While most people undergo the surgical procedure for spleen
removal without complications, it is the effects of asplenia afterward that
sometimes cause more problems. After spleen removal, the red blood cells
change in appearance and tend to become thinner and broader in diameter.
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The white blood cell count increases following surgery and then stabilizes at
a level that is approximately 40 percent higher than pre-surgery levels.14
The affected individual is also at greater risk of thrombosis due to the
increase in platelet counts that occurs following surgery. Platelet counts tend
to rise after surgery and then remain elevated for the rest of the person’s
life.
Because any type of surgery increases the patient’s risk of infection due to
its invasive nature, a patient undergoing splenectomy is considered an atrisk individual not only because of the surgical procedure, but also because
the surgery is removing a significant organ of the lymphatic system
responsible for protection of the body against infection and illness. When the
spleen is removed, the patient is at higher risk of infection related to the
surgical procedure and may develop infection during the post-operative
period. Without adequate management, post-operative infection following
splenectomy can lead to overwhelming sepsis and organ failure.
If the spleen is damaged due to injury and trauma, it can cause severe
hemorrhage if it is not treated quickly. Because the spleen normally contains
almost a pint of blood at any one time and serves as a reservoir of blood for
the cardiovascular system, splenic hemorrhage can cause rapid blood loss in
the injured person. When this occurs, splenectomy is needed to prevent any
further loss of blood.
Splenic Lymphoma
A specific type of cancer that affects the spleen, splenic marginal zone
lymphoma is a rare form of cancer that occurs in approximately 1 percent of
all lymphomas.18 The condition typically involves the spleen and the bone
marrow and it often resembles hairy cell leukemia in several of its features.
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The marginal zone describes the boundary between lymphoid and nonlymphoid tissue within the spleen. Splenic marginal zone lymphoma (SMZL)
occurs as a tumor that originates from B lymphocytes and that develops
within this zone. The marginal zone is part of the spleen and of lymph tissue
classified as mucosa-associated lymphoid tissue, which is not typically seen
among other lymph nodes in the body.19
Most patients with SMZL develop significant splenomegaly, as noted upon
physical examination. The condition does not necessarily cause pain or
discomfort, although when massive spleen enlargement is present and the
spleen compresses surrounding tissues, the patient may experience pain.
Splenomegaly associated with SMZL is often discovered after the affected
patient has sought treatment for another condition, such as with altered
blood cell counts that lead to symptoms of anemia. The spleen sequesters
red blood cells and not only becomes enlarged, but the condition also causes
anemia due to the decrease in red blood cells in the rest of circulation. Other
hematologic disorders that may also be present with diagnosis of SMZL and
that have developed because of the condition include such illnesses as
thrombocytopenia and von Willebrand disease.
The treatment of SMZL depends on the amount of splenomegaly and
whether the patient has massive splenomegaly present and is experiencing a
level of pain, or any other pertinent symptoms present. Treatment often
involves watchful waiting, in which the patient is monitored for changes that
indicate tumor progression or further hematologic complications. According
to Thieblemont, et al., in the journal Oncology, the process of watchful
waiting among asymptomatic patients with SMZL does not affect the course
of the disease, as many patients with asymptomatic splenomegaly due to
SMZL often have a stable form of the disease that remains constant for up to
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10 years.19 This type of splenic lymphoma has been more commonly
associated with hepatitis C infection. If the patient with SMZL has concurrent
hepatitis C infection, then antiviral treatment should be administered to
control progression of the viral infection.
If the patient with SMZL becomes symptomatic, whether because of pain or
due to hematologic changes as a result of sequestering, treatment typically
involves chemotherapy, splenectomy, or both. Patients who undergo both
chemotherapy and surgical splenectomy have been shown to have an
increased rate of remission, although chemotherapy or splenectomy alone
each has positive benefits as well. Splenectomy, in particular, corrects much
of the anemia present, as the patient is no longer sequestering red blood
cells within the spleen. Splenectomy has also been shown to correct other
hematologic abnormalities associated with the condition and it corrects the
patient’s pain from splenomegaly as well. Although there has been much
success in treatment areas for this specific type of cancer, research is
ongoing about the optimal forms of disease management for SMZL.
Thymus Gland
One of the primary organs of the lymphatic system, the thymus gland is a
triangular-shaped structure that is made up of two lobes and located in the
chest at the level of the superior mediastinum and behind the sternum. In
addition to the bone marrow and the fetal liver, the thymus is classified as a
primary organ because of its role in the production of lymphocytes.
Alternatively, other organs of the lymph system, such as the spleen, lymph
nodes, and the tonsils, are considered secondary lymphatic organs because
they receive lymphocytes through circulation but do not necessarily produce
them.45 Instead, the secondary lymphatic organs are responsible for
initiating the immune response.
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The thymus gland is composed of two segments: the cortex and the
medulla. The cortex is made up mostly of lymphocytes; because of their
locations within the thymus gland, these white blood cells may be referred to
as thymocytes. In contrast to the cortex, the medulla contains few
lymphocytes and is made up of more epithelial cells.15 The medulla also
contains cells called Hassall corpuscles, which are a type of structure that
contain mature endothelial cells and which divide into many small cavities
within the thymus. Other types of cells found in the thymus gland include
macrophages and myoid cells.
Lymphocytes are originally created in the bone marrow in a process known
as lymphopoiesis. These lymphocytes then enter the thymus, where most of
them are sent to the cortex to develop into immature T lymphocytes.
Immature lymphocytes develop, are processed and age, within the thymus
to become T lymphocytes before they can transfer to other organs. When T
lymphocytes are still in the thymus, they do not respond to antigens to
protect the body. Instead, they must be processed and grow into mature
cells before they can provide a source of defense for the body.
A group of hormones, known as thymosins, are secreted by the thymus
gland and influence the overall development of T lymphocytes. The
endothelial cells that make up the thymus are responsible for assisting with
maturation of the T lymphocytes to bring them to the point at which they
are ready to transfer to other organs. Because of their work with assisting T
lymphocytes, these endothelial cells within the thymus are sometimes called
nurse cells.15
The thymus decreases in size as a person ages. It is large just after birth
and during infancy, growing to its largest size during early adolescence when
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it reaches approximately 35 g to 40 g in weight.21 Following puberty, the
size of the thymus continues to decrease until it is much smaller, in a
process known as involution, where the weight and overall size of the
thymus is diminished. Eventually, the thymus gland becomes a small mass
of lymphatic tissue with significant adipose and connective tissue once a
person has reached adulthood. However, evidence suggests that despite the
decrease in size of the thymus, it still continues to function.
The approximate size of the thymus is 1.1 cm among children and
adolescents, but it decreases to about half this size by the time an individual
reaches age 50.15 By age 80, the thymus has been reduced in size to the
point that it is almost completely gone.21 The need for continuous
maturation and production of T lymphocytes starts to decrease with age.
Over time, the thymus slowly decreases the rate at which it generates T
cells. However, despite this change that occurs with advancing age, the
thymus remains the primary site of T lymphocyte maturation in the body.
Disease of the thymus gland or removal
of the thymus because of illness or poor
health results in potentially significant
changes in an individual’s immune
status. Although the thymus gland
normally shrinks over time, removal of
the thymus at an early age, or in the
rare condition where an individual is
born without a thymus gland, results in
early immunosenescence, or the aging
of the immune system that normally
occurs as part of growing older.
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A review by Sauce and Appay in Current Opinion in Immunology evaluated
studies about the effects of thymus disease, abnormal fetal thymus
development, or thymectomy at a young age as a result of disease. The
review focused on research that showed that decreased thymic function at
an early age leads to early immunosenescence.16 Poor thymus function or
lack of a thymus gland is associated with poor immune function and causes
effects that are similar to premature aging of the immune system. Poor
thymic function may develop as a result of congenital conditions or of other
diseases that develop over time and that damage the thymus gland.
Two of the more common conditions associated with poor thymic function
are thymoma, which occurs as a tumor arising from the thymus gland, and
thymic hyperplasia in which the thymus gland becomes enlarged. Thymoma
is most often associated with myasthenia gravis, a neuromuscular
autoimmune disorder characterized by skeletal muscle weakness that
increases with activity and improves after resting.17 The antibodies that
normally protect the body against antigens instead attack acetylcholine
receptors at the neuromuscular junction, which prevents skeletal muscle
contraction.
Among adults who have myasthenia gravis, the thymus gland remains
abnormally large when it should instead shrink gradually with age.
Thymomas may also develop in the thymus gland as well; these are usually
benign tumors, but they can also become malignant and can cause cancer.
Between 10 and 20 percent of patients with myasthenia gravis develop
thymoma.15 It is not entirely clear why persons with myasthenia gravis
develop thymus problems and immune system dysfunction. It is associated
with the myoid cells normally present in the thymus gland. Research has
also shown that as the cells of the immune system develop abnormally, they
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somehow receive the message to attack acetylcholine receptors, resulting in
neuromuscular problems.
Thymic hyperplasia occurs as enlargement of the thymus gland. There are
two causative types of hyperplasia: true thymic hyperplasia and lymphoid
hyperplasia. With each condition, the thymus gland enlarges symmetrically
within the chest. True thymic hyperplasia typically occurs after a period of
significant stress on the body, such as with administration of chemotherapy
for the treatment of cancer. It has also been associated with certain
autoimmune conditions, such as scleroderma, rheumatoid arthritis,
Hashimoto thyroiditis, or Addison’s disease. In this condition, the thymus
gland grows to an abnormally large size relative to the person’s age.
Rebound hyperplasia describes the shrinkage of the thymus gland during
periods of treatment, only for it to grow back to its large size or an even
greater size when treatment is discontinued.
Lymphoid hyperplasia is also commonly associated with myasthenia gravis;
it develops when there is a significant increase in the number of lymphoid
follicles within the thymus gland. The thymus gland enlarges symmetrically,
as opposed to enlargement of one area of the gland as would be seen with
thymic cancer. The condition has also been associated with autoimmune
disorders such as Graves’ disease, vasculitis, thyrotoxicosis, and systemic
lupus erythematosus.
Thymus cancer is relatively uncommon, however, when it does develop it
can impact the abilities of the immune system in addition to causing
potentially disabling signs and symptoms for the affected patient. Thymomas
describe tumors that arise from the thymus gland. Although historically
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some of these tumors were considered to be benign, researchers now
believe that all thymomas at least have the potential to be malignant.
Thymomas are classified according to their histologic appearance and their
classifications range from being fairly normal in appearance with a relatively
good prognosis (Type A) to a type known as thymic carcinoma (Type C) in
which the cells appear very abnormal and have high risk of metastases.65
The exact cause of thymic cancer is still unknown, although there have been
some noted DNA changes that lead to cancer that are associated more often
with thymic cells when compared to other types of cells. Because it is
difficult to determine what factors are associated with an increased risk of
thymic cancer, it is difficult to prevent. Thymoma is more commonly
associated with myasthenia gravis; a thymoma is more likely to develop
when the cells of the thymus gland begin to multiply abnormally, possibly
because of the condition of myasthenia gravis. When the cells multiply and
proliferate, they form a tumor that may either stay within the boundaries of
the thymus gland or it may multiply and extend beyond the borders of the
gland.
Almost 50 percent of people with thymoma do not experience any
symptoms.66 When symptoms do develop, they are often similar to thymic
hyperplasia when the enlarged thymus gland compresses surrounding
structures. Consequently, thymoma may cause chest pain or tightness, a
hoarse voice, difficulty swallowing, or chronic cough, because of the location
of the thymus gland within the chest cavity.66 The main form of treatment
for thymoma is surgical removal of the thymus gland. If the tumor has
spread beyond the boundaries of the thymus gland, radiation or
chemotherapy may also be necessary.
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Researchers have investigated the effects of thymectomy on immune
function in patients where thymectomy was required for reasons such as
cancer or due to congenital conditions. Because the thymus gland decreases
in size with age, studies regarding the effects of thymectomy generally focus
either on the immune effects of thymectomy on very young children and
neonates or on thymectomy among adults. Among infants, thymectomy
does not seem to drastically affect immune function and it is possible that
surrounding tissues may take over many of the immune system functions in
the absence of the thymus. However, thymectomy should still be avoided in
these patients, if at all possible.
A study by Turan, et al., in Acta Cardiologica found that certain subgroups of
T lymphocytes were most affected by thymectomy when the procedure was
performed among infants born with congenital heart conditions. The
researchers in the study recommended that when performing cardiac
surgery for congenital defects for infants and thymectomy is a possibility, it
should still be avoided if at all possible; even though a child can live without
a thymus, it may still hinder the strength of the child’s immune system.67
Among adults, thymectomy does not appear to have a large effect on the
immune system’s abilities. Theoretically, the memory of the immune cells in
other parts of the body may take over many of the immune defenses once
held by the T cells of the thymus gland. T lymphocytes that were “seeded”
out from the thymus gland often take over in immune defenses when the
thymus is removed. However, it is possible that the body maintains immune
defenses for a period of time following thymectomy but that it may
eventually lose some of its immune responsiveness after several years.
Unfortunately, there are no studies available on the long-term effects of
thymectomy on the adult immune system.68 If thymectomy is required in the
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adult patient because of thymoma or invasive thymus cancer, it is generally
considered best to remove the thymus for the benefit of the patient,
regardless of the long-term effects on immune system function.
Tonsils and Adenoids
Tonsils play an important role in filtering lymph to destroy microorganisms
that might be dangerous to the body. The tonsils are collections of lymph
tissue that are located in the back of the mouth at the beginning of the
throat and on either side of where the tongue attaches at its root. The mass
of tonsillar tissue forms a ring around the opening of the respiratory and
digestive tracts. Because potential pathogens can easily enter the body
through the digestive or the respiratory tracts, the presence of the tonsils as
lymph tissue near the opening of these structures can prevent many
microorganisms from entering the body in the first place and further prevent
illness or disease. The tonsils are called mucosa-associated lymphoid tissue
(MALT) because of their composition as lymphoid tissue and because of their
location in the mucosa of the gastrointestinal tract at the back of the mouth
and near the opening of the digestive and respiratory systems.10
Tonsils differ slightly from other lymph nodes in the body in that they lack
afferent vessels. The tonsils have compartments that contain lymph tissue
instead of being in a position where lymph fluid is delivered to them through
the lymphatic vascular system. The lymph tissue within these compartments
determines when foreign pathogens are entering the body through the
respiratory or gastrointestinal tracts and destroys them before they can
cause illness. Tonsils still contain lymphocytes and macrophages within their
borders so that if harmful substances enter the body through the nose or the
mouth, these cells can provide protection immediately before the substances
can get very far.
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There are actually three sets of tonsils: the palatine tonsils, the lingual
tonsils, and the pharyngeal tonsils. The palatine tonsils are the most well
known type and are typically what people refer to when they talk about the
tonsils. They are located on either side of the mouth at the back of the oral
cavity at the beginning of the pharynx and they prevent potentially harmful
microorganisms from entering the body. It is the palatine tonsils that are
typically removed during a tonsillectomy procedure because they have
become infected or swollen due to tonsillitis.
The lingual tonsils are also composed of lymphatic tissue; they are found at
the base of the tongue and are also responsible for filtering potential
pathogens and destroying them before they can enter the body to cause an
infection. The lingual tonsils are the least likely set of tonsils to be removed,
although they may be surgically removed if they consistently become
infected and swollen. Lingual tonsils, when swollen, may grow large enough
that they could potentially block the airway or the pharynx, which would
necessitate their removal. Some people who suffer from sleep apnea have
particularly large lingual tonsils, the tissues of which have hypertrophied to
the point that they occlude the airway because of their position in the back
of the mouth when the individual sleeps in the supine position.
The pharyngeal tonsil is also referred to as the adenoids. Although its
reference is typically stated as plural, there is actually only one adenoid,
which is a mass of lymph tissue at the back of the throat. As with other
lymph nodes, the adenoid tissue is part of the immune system. In children,
the adenoids play a key role in protecting the body from infection from
pathogens that enter through the mouth and the nose. As a person grows
older, though, the adenoids shrink in size and they are less involved in the
immune response in adulthood; and, with growth, other elements of the
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immune system take over in the body’s defenses and the adenoids are not
as important. By adolescence, adenoids have almost completely
disappeared.
As with other types of tonsils, the adenoids can become infected and can
swell. Because adenoids are larger among infants and children, adenoid
infection is also more common among young children and is almost nonexistent in adults. Adenoid infection causes the tissue to swell, which can
make breathing difficult and it may cause snoring. The affected child may
also complain of a sore throat and may have difficulty swallowing. Note that
among some children, enlarged adenoids are normal and are not necessarily
indicative of an infection.
Chronic infection of the tonsils or the adenoids often requires tonsillectomy
with adenoidectomy. The procedure is most often performed among children
and adolescents; however, there are some adults who require tonsillectomy
as well. The procedure is generally short and can be done on an outpatient
basis. The patient typically experiences pain in the back of the mouth and a
severe sore throat for several days, which can cause difficulties with
swallowing and an increased risk of dehydration following the surgery.
Because the tonsils are lymphatic organs and they serve to protect the body,
tonsillectomy could potentially affect a person’s immune system and lead to
an increased risk of infections. However, the effects are not necessarily
known to be significant enough to avoid tonsillectomy and adenoidectomy
when these procedures are needed.
A literature review in Otolaryngology — Head and Neck Surgery found that
only a few studies demonstrated a negative effect on immune system
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function following tonsillectomy, while the majority of studies showed no
effect on the immune system after the procedure. The review considered
studies published between 1971 and 2010, which included over 1660
patients who had undergone tonsillectomy.67 Because tonsillectomy and
adenoidectomy are not considered elective procedures, and are typically
performed because the affected patient has had medical issues and would
benefit from the procedure, such as due to chronic sleep apnea, tonsillitis, or
tonsillar abscess, tonsil removal tends to be beneficial for the patient rather
than detrimental because of potential immune system dysfunction. It is
generally advisable to remove the tonsils when necessary, rather than
waiting to perform the procedure because of ill effects on the immune
system.
Small Intestines: Peyer’s Patches
The lining of the small intestine contains a
certain amount of lymph tissue known as
Peyer’s patches. These areas are
responsible for preventing harmful
microorganisms from invading the
bloodstream when they enter the gut.
Similar to the tonsils in the back of the
throat, Peyer’s patches are known as MALT
because they are lymphoid tissue in the
mucosa of the gastrointestinal tract that
provides protection from foreign antigens.
The gut contains a large number of
microorganisms, some of which are
considered beneficial and some are potentially harmful. The specific MALT
tissue of the intestine can discriminate between the different types of
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microorganisms to determine what is helpful and what needs to be
destroyed.
Originally named after Johann Conrad Peyer when they were discovered in
1677, Peyer’s patches are composed of various cells of the immune system
that are contained within follicles of lymphatic tissue.69 They are most
commonly found in the ileum of the small intestine. Instead of being
classified as lymph nodes, Peyer’s patches are called lymphatic nodules;
they have a similar size and shape as lymph nodes and they are made up of
lymphatic tissue, but they are not encapsulated as are lymph nodes.
Peyer’s patches contain epithelial cells that line their sides facing the
intestinal wall; these epithelial cells are called microfold cells. The other side
of the mass, opposite the microfold cells, contains lymphoid cells and
lymphatic vessels. The microfold cells absorb antigens in the gut and send
them to the lymphoid tissue. Once the antigens reach the lymphoid tissue,
they come into contact with the macrophages, B lymphocytes,
T lymphocytes, and dendritic cells found within the Peyer’s patches. Some of
these cells produce antibodies against specific antigens and they destroy the
harmful microorganisms.
The Peyer’s patches seem to contain the most tissue during childhood,
adolescence, and young adulthood. The amount of tissue present then starts
to decline with advancing age. They are connected to the rest of the body
through lymphatic vessels and small veins of the cardiovascular system. As
with other areas of the lymphatic system, Peyer’s patches have efferent
vessels that distribute lymphocytes out of the tissue and return them to
lymphatic circulation. As described, the microfold cells that are present
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within Peyer’s patches have the ability to discriminate between beneficial
and harmful bacteria.
Studies have shown that when larger numbers of harmful bacteria are
present in the gut, the number of microfold cells within Peyer’s patches
actually increases.69 While the role of Peyer’s patches within the immune
system continue to be discovered, it is known that these areas of specialized
tissue are important for protecting the body from some harmful pathogens
that invade the digestive tract. Because there are multitudes of bacteria and
other kinds of microorganisms within the gastrointestinal tract, Peyer’s
patches play a crucial role in adaptive immunity.
Lymphatic System
As described, the lymphatic system consists of a number of different cells
and tissues that are designed for various tasks. The lymphatic system plays
an important role in the transport of fluids throughout the body and in
defending the body against foreign pathogens. The network of lymphatic
vessels is an efficient pathway for lymph fluid to carry pathogens to the
lymph nodes and to carry fluid away from the interstitial spaces and return it
to venous circulation. When it works properly, the lymphatic system typically
performs all of its functions of controlling fluid levels, absorbing fats and fatsoluble vitamins, and protecting the body through immune system cells; as
with many other body systems, most of this work is done quietly and
without obvious detection unless complications develop and the system does
not work normally.
Most people are unaware of how much their lymphatic system protects them
from potentially harmful sources and they often do not consider the complex
system of fluid balance and physical defense that describes the efforts of the
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lymphatic system. Because of the intricacies of the lymphatic system and its
involvement in almost every area of the body, the lymphatic system may
also be tested and evaluated when bodily functions go awry. When certain
diseases develop — often because foreign pathogens have invaded the body
and could not be contained or when abnormal cells proliferate to cause
certain types of diseases — the lymphatic system plays a role in determining
the extent of the spread of the disease. For example, if an infectious
organism has invaded the body and the immune system attempted
unsuccessfully to destroy it, the invading cells may proliferate to cause an
infection.
The lymphatic system still acts as a system of identifying when and where
the infection is present, even if the immune system was unable to
adequately contain the pathogen and prevent it from causing the infection.
Another example is when malignant cells form a tumor within the body.
Normally, the cells of the immune system destroy abnormal cells to prevent
them from growing into cancerous tumors, but obviously this is not always
completely successful because of the numbers of people diagnosed with
cancer. In the case of cancer, despite the fact that the immune system did
not contain the cancerous cells and a malignant tumor, the lymphatic system
still plays a role in identifying whether cancerous cells have spread beyond
their original site of growth.
The lymph channels often provide a mechanism of transport of cancerous
cells to travel from the site of the primary cancerous growth to a new
location as part of metastasis. The cells of the immune system that are part
of the lymphatic system also multiply and increase their defense
mechanisms when cancer cells are proliferating. Based on the body’s
response to these cells, lymph nodes and lymph fluid can also be tested to
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check for immune responses, which may indicate whether cancerous cells
have spread through the lymphatic channels, or whether the body has
initiated the immune response in an attempt to defend itself against the
cancerous cells.
Cancer Metastasis
When an individual develops cancer, a significant part of determining the
extent of the disease is finding out whether metastasis has occurred.
Metastasis describes the movement of cancer cells from the original site of
tumor growth to areas beyond the primary site. A cancerous tumor may
originally develop in a particular site as a primary tumor. Tumor cells
develop, often from body cells that somehow developed abnormally. The
immune system is often aware of various cells that have developed
abnormally and strives to attack them before they can proliferate. However,
there are some cases in which abnormalities continue to grow and spread,
eventually forming a tumor. The cells are typically associated with their
initial area of growth; for instance, malignant cells that proliferate in breast
tissue are referred to as breast cancer, while tumor cells that develop within
the lung tissue are known as lung cancer, and so on.
Uncontrolled growth of tumor cells can eventually lead to the spread of these
same cells to other parts of the body. The cells from the original tumor can
break off and travel to other areas of the body to grow and develop there.
The tumor cells may travel through the bloodstream or they may pass
through the lymphatic system to relocate in a distant area of tissue, typically
in another organ or in a lymph node. Metastatic spread of tumor cells from
the primary site is the main cause of mortality associated with cancer.
When tumor cells relocate to other areas of the body by traveling through
the bloodstream, they often end up in lymph nodes along the way. When
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this occurs, the cancerous cells can remain in the lymph node and may grow
there. With enough cancerous growth, the lymph node may become
enlarged and, if it is close to the surface of the skin, the enlarged node can
be felt on palpation. Many cancerous cells die, especially when they are
exposed to lymphocytes present in the lymph nodes; however, those that
are not killed and are able to grow and continue to multiply can eventually
form metastatic tumors.
Once cancerous cells reach a new area of growth as part of metastasis, they
must be able to penetrate the wall of the organ or the lymph node to be able
to grow. This means that when the cancerous cells reach another organ,
they attach to the wall of a blood vessel or a lymph vessel and then
penetrate the wall to be able to enter the circulation. Once they arrive at
their new location, the cells must also grow and expand in order to survive,
holding off attacks from the cells of lymphocytes and other components of
the immune system. Because of this, not all cancerous cells are able to
metastasize and cancer is often not able to spread, either because of the
characteristics of the cells or because of the defenses provided by the
immune system.
A complication that often develops with metastasis is that when cancerous
cells travel to other locations and grow, they may be slightly different than
the original primary tumor. The cells that are growing in the new location
may not be exactly the same as those in the source location from where
they migrated. Consequently, they may also not respond to treatment in the
same way and may require variations in therapy or medication. The
treatment may be prescribed based on the primary tumor characteristics and
the primary tumor may actually respond well to treatment, but the
metastatic cancer cells may or may not respond in the same way.
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Unfortunately, the patient may then need to undergo more than one type of
treatment to be able to manage cancerous growths in various locations.
Sentinel lymph nodes describe those nodes that are the closest to the
growing tumor. When cancer cells spread through the lymphatic system,
they often become trapped in the sentinel lymph nodes near the tumor and
they may be detected there when these lymph nodes are tested. For
example, breast cancer cells often travel to the axillary lymph nodes, as
these are considered sentinel lymph nodes nearest to the breast tissue;
alternatively, melanoma that develops in the leg may metastasize to sentinel
lymph nodes in the groin when these are closest.
The benefit of knowing about how cancerous cells spread to sentinel lymph
nodes is that healthcare providers can often determine where cancer cells
are more likely to spread based on the original location of the tumor. Certain
types of cancer are more likely to metastasize to specific areas, hence, when
a primary tumor is found in a location, the physician typically knows where
to look for metastasis. For example, breast cancer typically metastasizes to
the bone, the lung, or the brain, while colorectal cancer often metastasizes
to the liver, the lung, or the peritoneum.53
Because cancerous cells often use lymph vessels to metastasize, spread of
cancerous cells into the lymphatic system is one of the earliest signs of
metastasis and, when detected at an early stage, tumor cell metastasis can
potentially be thwarted and prevented from spreading much further if it is
well controlled. It is well known that tumor cells can travel through both the
blood vessels and through lymphatic vessels to disseminate and metastasize
to various locations beyond the original tumor. What is often unknown is
how these tumor cells enter the lymphatic system and why they are able to
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move past the lymphocytes of the lymph nodes to expand and proliferate in
distant tissues.
Researchers have looked at the effects of transforming growth factor beta
(TGF-) on the potential for certain cancerous cells to metastasize.
Transforming growth factor beta is a type of cytokine protein that controls
the proliferation of certain types of cells and is involved in the work of the
immune system; altered levels of TGF- have been implicated in a variety of
medical conditions, including Marfan syndrome, heart disease, diabetes, lung
disease, and Parkinson’s disease. Elevated levels of TGF- have also been
seen in many patients with breast cancer. These elevated levels also seem
to have an association with cancerous states that involve lymph node
metastasis.
A study by Pang, et al., in the journal Oncogene looked at the potential for
tumor cells to enter the lymphatic system and to metastasize to distal
tissues and lymph nodes as well as the effects of TGF- on certain cells’
abilities to spread. The study found that TGF- actually gives cancerous cells
some of the same receptors as white blood cells in the immune system so
that their cell surfaces appear to be similar. When this occurs, the cancerous
cells are able to bypass some of the lymphocytes that would normally attack
them because they are somewhat disguised as white blood cells through a
similar cell membrane receptor.70 The research was conducted by examining
the cells of breast cancer patients and how TGF- specifically is able to travel
through the lymphatic system in patients with breast cancer. Through this
research, clinicians are better able to understand how some types of
cancerous cells can travel through the lymphatic system and can grow within
lymph nodes without being destroyed.
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Lymphangiogenesis, or the formation of new lymph vessels from preexisting lymphatic vessels, is another element that may be involved with
cancer metastasis and the ability of cancerous cells to spread through the
lymphatic system. It was once thought that lymphatic vessels served only as
pathways for tumor cells to travel through during metastasis. It is now
known that lymphatic vessels are more involved in metastasis of tumor cells
and they play important roles in dissemination of metastatic cancer cells as
they move from one location to another in the body.
Initial vessels of the lymphatic system are highly permeable where they
begin in the epidermis, consisting of a single layer of squamous cells with
gaps in between, which allows larger molecules and proteins to enter the
lymphatic system from the interstitial space. Lymph fluid is propelled
through the lymphatic vessels through external pressure because there is no
central pump in the lymphatic system, which means that pressure from such
sources as the skeletal muscles or the movement of the diaphragm force
fluid to move through the lymphatic system - segment by segment.
While the structure and integrity of the lymphatic vessels and its methods of
moving lymph fluid are appropriate and practical for the movement of lymph
fluid, cancerous cells may also take advantage of these mechanisms and
enter lymphatic circulation where they can then be transferred fairly
effortlessly to other areas of the body. For instance, larger protein particles
in the interstitial space are easily able to enter the lymphatic vessel through
openings in the vascular wall, but cancerous cells may also enter the
lymphatic network in a similar manner and insert themselves into lymphatic
circulation in this method.
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Lymphangiogenesis is another method associated with tumor cell
proliferation and tumor growth. Normally, the formation of new lymph
vessels only occurs during fetal development when other organs, tissues,
and blood vessels are also forming. However, research has also discovered
that lymphangiogenesis now also occurs during certain pathologic conditions,
including disease processes that require tissue repair, or with tumor
growth.112
When the lymphatic system forms new lymph vessels, there are several
specific molecular markers involved that promote the new growth. Many of
these markers are variations of vascular endothelial growth factor (VEGF),
which is a type of protein produced by cells that stimulates the formation of
new vessels. VEGF is also involved with the development of new blood
vessels during angiogenesis in addition to lymphangiogenesis of lymphatic
vessels. When lymphangiogenesis occurs because of tumor growth, it is
activated by certain types of VEGF and in some cases there may be
overexpression of growth factor, which leads to a marked increased in
lymphatic vessel growth as well as an increase in tumor cell metastasis to
lymph nodes.112 Further research has shown that VEGF not only stimulates
tumor lymphangiogenesis, but it also contributes to enlargement of the
overall size of the lymph vessel, which can contribute to more efficient
transport of tumor cells during metastasis.
Another factor, known as a prolymphangiogenic factor because it supports
lymphangiogenesis, is called neuropilin-2 and it is normally associated with
formation of new lymphatic vessels during the fetal period. Neuropilin-2 has
also been discovered with lymphangiogenesis of tumor-associated lymphatic
vessels. It is therefore more closely associated with increased tumor growth
and metastasis when present in increased quantities; alternatively, blocking
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the effects of neuropilin-2 may decrease cancer cells’ abilities to form new
lymphatic vessels and to spread through metastasis.112
Although the process of lymphatic vessel formation may seem similar when
comparing normal lymphangiogenesis as part of physiological development
and lymphangiogenesis as part of tumor development, there are a number
of molecular differences between the two processes. An article by
Christiansen and Detmar in the journal Genes and Cancer stated that when
the RNA profiles of normal lymphatic vessels were compared with the
vasculature of an aggressive form of fibrosarcoma, over 790 differences in
gene expression were found between the two samples.112 This suggests that
although the two processes appear to be similar, they are actually quite
different. Their physical properties of forming new lymphatic vessels are not
only different, but their ultimate purposes are different as well. Normal
lymphangiogenesis is performed to develop new lymphatic vessels that will
support the body through regulation of fluid levels and transport materials,
while lymphangiogenesis associated with tumor formation is done to
distribute tumor cells and to promote the spread of cancerous cells.
The metastatic spread of cancerous cells often means that a specific type of
cancer has gone from being localized and potentially treatable to spreading
to other areas, causing physiological complications and creating more
difficulties with treatment. Unfortunately, tumor cells have devised ways of
inserting themselves into the lymphatic vascular system so that they can
travel more easily to distant sites. When tumor cells form within the
lymphatic system, causing lymphoma, they may also metastasize and
spread to different sites away from their primary site of growth.
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Metastatic lymphoma does not necessarily present in the same manner as
other forms of metastatic cancer. When cancer metastasizes, its cells break
off to grow as another tumor in a secondary site. With lymphoma, where
tumor cells do not always form a bulky tumor, metastasis of cancer cells
often takes place when cells migrate through the lymph system and grow
within distant lymph nodes. Notably, this is not the case with all patients and
some persons with lymphoma may have a bulky mass that can grow within
the lymph system, sometimes large enough to compress surrounding
tissues.
The cancerous cells of lymphoma may metastasize to various points in the
body where they travel through the lymphatic system. Lymphoma has also
been seen with metastasis to the central nervous system. A case study by
Slam, et al., in the Internet Journal of Neurosurgery discussed a case of a
patient with a history of Hodgkin lymphoma that had tumor metastasis to
her brain. The patient had been diagnosed with Hodgkin lymphoma two
years prior and had gone through successful chemotherapy at that time. The
patient later presented to the emergency department with severe headache
and neurological symptoms, where it was found that she had developed a
brain meningioma. Pathological investigation of the tissue revealed that it
was a Hodgkin lymphoma tumor that had metastasized to her brain.
Although the condition was treated surgically and she underwent radiation
therapy, her lymphoma continued to spread and additional nodules were
found in her lung tissue.113
Brain metastasis occurs in approximately 25 percent of cancers that form
solid tumors, including lung cancer, breast cancer, and malignant melanoma.
It is less common in hematologic and lymphatic cancers, including leukemia
and lymphoma.
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At one time, it was thought that the brain and central nervous system lacked
lymphatic vessels, which could partially explain why lymphoma metastasis to
the brain is rare. However, researchers have recently discovered the
presence of vessels that contain markers of the lymphatic system in the
brain meninges of mice. The vessels carry fluid and immune cells through
their pathways and eventually connect with the cervical lymph nodes.
Similar vessel structures have also been found upon autopsy of human
patients.114
As discussed, in order for tumor cells to metastasize, they must not only
circulate to the new site of metastasis, but they must also be able to
penetrate the lining of the new organ and be able to grow in the new site.
Lymphoma cells, as with many other cancerous cells, are able to metastasize
when they are transported through lymphatic vessels and then enter the
structure of another organ at a distal site where they are able to grow and
proliferate.
When lymphoma metastasizes, it most often develops cancerous cells in
other portions of the lymphatic system, including within other lymph nodes,
as well as in other lymphatic vessels such as the spleen. It also may be
more likely to travel and grow in the bone marrow or in the lungs. It should
be recognized that the term “metastasis” is not always used when describing
lymphoma, as metastasis describes the movement of tumor cells to a new
location to start a new tumor. While this certainly can occur with lymphoma,
it is more common that the cancer cells from the primary site are
disseminated through the lymph vessels to grow in other areas of the
lymphatic system, but they do not necessarily form a new tumor and they
are often similar to the primary cancer cells from where they started.
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Lymph Node Biopsy
When cancerous cells travel through the lymphatic system to spread to distal
tissues, their presence can be detected through biopsy of nearby lymph
nodes. There are various methods of extracting tissue for biopsy of lymph
nodes; some methods involve removal of the entire lymph node, while
others involve extraction of a small sample of tissue. Although lymph nodes
contain lymphocytes that are designed to destroy foreign particles and
cancerous cells, tumor cells may still be able to survive the attacks of the
immune system cells and still proliferate in the lymph nodes.
Fine needle aspiration is a type of biopsy procedure that involves removing a
small amount of tissue by drawing it into a syringe with a very large, hollow
needle. It can be used to take a tissue sample from a lymph node or from a
larger tumor. When used to examine a lymph node, fine needle aspiration
does not necessarily collect enough of a sample to always rule out the
presence of cancerous cells since the amount aspirated is only a small
portion of the lymph node. For example, fine needle aspiration is typically
not used to diagnose primary lymphoma, however, it may be used to sample
part of a tumor to detect whether it is benign or malignant. When used for
tumor biopsy, the provider can aspirate a tissue sample directly through the
skin if the tumor is close to the skin surface. Aspiration of tissue from a
deeper tumor or lymph node requires ultrasound to specifically locate the
tissue and to extract the appropriate amount.
Core needle biopsy is a test similar to fine needle aspiration in that the
provider uses a needle to extract tissue; however, the needle is actually
much larger in diameter with this type of procedure. Core needle biopsy
removes approximately ½ inch of a cylinder of tissue. Because of the larger
needle size, core biopsy is typically performed under local anesthesia to
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reduce pain and discomfort for the patient, although it can still be performed
in an outpatient clinic or in a medical provider’s office in a manner similar to
fine needle aspiration. As with fine needle aspiration, core biopsy does not
always take a large enough sample of tissue to provide a positive diagnosis
of cancer, but it is still a useful method of lymph node biopsy for diagnosing
many different types a cancer.
A research study by Ganott, et al., in the journal International Scholarly
Research Notices Oncology compared the outcomes of lymph node biopsy
when performed through fine needle aspiration versus core needle biopsy in
patients with ipsilateral breast cancer. The patients in the study all
underwent both fine needle aspiration and ultrasound-guided core needle
biopsy of the same axillary lymph nodes and the tissue samples were
evaluated for the presence of metastatic cancer cells. The results showed
that core biopsy was more sensitive in detecting the presence of cancerous
cells in nearby lymph nodes when compared to fine needle aspiration. The
core biopsy was able to detect more cases of cancer that had invaded
surrounding lymph nodes when compared to fine needle biopsy.115 Although
this does not negate the use of fine needle aspiration for detecting cancer
cells within lymph node tissue, core needle biopsy may be a better
alternative because it typically removes more tissue for sampling.
Alternatively, fine needle biopsy may be more likely to be performed in
cases where the lymph node is small.
Excisional biopsy describes the process of removing a lymph node for
analysis; it is much more involved than needle biopsies and is considered a
surgical procedure. Excisional biopsy requires at least local anesthetic to
remove the tissue, as the process requires a skin incision. This type of
biopsy is easier to perform when the lymph node is enlarged and near the
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surface of the skin. Alternatively, removal of deeper lymph nodes requires
anesthesia and involves a surgical procedure that is more extensive. It
typically requires imaging studies to guide the surgeon to the exact location
of the node; ultrasound is often used during the actual procedure. Excisional
biopsy is the standard for use when diagnosing lymphoma, as it allows the
clinician to view the full structure of the affected lymph node where the
cancer has started.
In some cases, such as in breast cancer, excisional biopsy is done to actually
remove some of the cancerous cells. If the cancer has spread beyond the
primary tumor site and has entered nearby lymph nodes, removal of the
node through excisional biopsy will actually remove many of the cancerous
cells. Historically, healthcare providers believed that removing as many
lymph nodes as possible would rid the body of much of the cancer. However,
removing too many lymph nodes at once tends to lead to other
complications, such as lymphedema of surrounding tissue because of
destruction of the lymph vessels; it has also not always been shown to
remove enough of the cancerous lymph nodes. Excisional biopsy may now
be used to remove some cancerous cells that have infiltrated lymph nodes,
but it is not a sole source of treatment for eliminating cancerous tissue from
the body.
When a lymph node obtained through excisional biopsy shows the presence
of cancerous cells, the surgeon must then consider the tissue margin
surrounding the node. The margin is a ring of healthy tissue that is extracted
at the same time as the lymph node during the biopsy. The surgeon tries to
remove a large enough margin around the tissue that does not have
cancerous cells to know that the cancer is contained within the tissue that
was taken out. Alternatively, it is important not to remove too much of a
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tissue margin, because the patient can suffer from other complications
associated with a larger amount of tissue extraction.
The margins are assessed with the lymph node tissue to determine if
cancerous cells are present. If the margins are clear, it means that the
cancer has not moved into the space surrounding the cancerous tissue.
Margins that are not clear or that are considered involved mean that
cancerous cells are in the tissue and there may be more cells still in the area
of the biopsy. The surgeon may then need to remove more tissue if the
biopsy margins are not clear.
Excisional lymph node biopsy is often very effective in determining the
presence of cancerous cells and it provides enough of a tissue sample to
positively identify and diagnose cancer when it is present. Excisional biopsy
also allows the clinician to stage cancer when it is present, which shows the
extent of spread of cancerous cells and helps to determine the most
appropriate course of treatment. Compared to needle biopsy, excisional
biopsy is more involved and more painful for the patient, as it requires an
incision. It requires more time for the patient to recover from the process
and it may need to be repeated if enough tissue has not been retrieved.
Incisional biopsy describes cutting out a small portion of a tumor to assess it
for the presence of cancerous cells. If a tumor is very large, incisional biopsy
is preferable for removing tissue when the entire tumor cannot be resected.
This type of biopsy is not as common when assessing lymph nodes, as an
entire lymph node can often be removed for the purpose of examination. It
is beneficial in some cases since it does not involve extracting as much
tissue as with an excisional biopsy, which can be more comfortable for the
patient. As with an excisional procedure, an incisional biopsy involves an
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incision and typically requires at least local anesthesia for patient comfort,
depending on the area being examined.
Lymph node biopsy is also beneficial to make a diagnosis of lymphoma,
however, sometimes accessing certain lymph nodes can be difficult. Because
the lymphatic system consists of many pathways that travel throughout the
body and there are various lymph nodes that are both superficial and deep
within tissues, lymphoma cells can disseminate almost anywhere. If an
enlarged lymph node is superficial, it can most likely be removed with
relative ease for biopsy. However, if a suspected lymph node is in deep
tissue, such as within the chest or the abdomen, it may be more difficult to
gain access to the node for removal, necessitating anesthesia and surgical
incision in some cases. In some situations, removal of smaller lymph nodes
that are superficial and easier to access may suffice for performing biopsy
and to diagnose the spread of lymphoma.
In a study published in the American Journal of Hematology, researchers
examined five patients with suspected lymphoma and excised superficial
lymph nodes that were considered smaller than what is normally optimal for
diagnosis of lymphoma. They extracted these lymph nodes to spare the
patients the pain and procedure of undergoing surgical biopsy of deep lymph
nodes and to determine if removing superficial, smaller nodes would yield
similar results. The study showed that, among all five patients, removal of
lymph nodes that would normally be considered smaller than desirable for
diagnosis was actually beneficial in terms of providing enough information
through biopsy to be able to facilitate treatment for the involved patients.116
In routine cases, removal of the largest lymph node for biopsy is desirable
for the diagnosis of lymphoma. Although a patient may undergo various
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imaging studies to determine whether lymph nodes are affected within
deeper tissues, excision of deeper lymph nodes to detect lymphoma still
requires a surgical process that can be painful for the patient or, in some
cases, may be contraindicated according to the patient’s medical condition.
Although the study described was very small, further research may discover
similar results showing that the removal of smaller (superficial) nodes can be
just as beneficial in providing a diagnosis of lymphoma as removing deep
nodes that are more difficult to access.
Typically, when removing a lymph node to examine for biopsy, the
healthcare provider selects the sentinel lymph node as the closest node to
the actual site of the tumor. The sentinel lymph node is one that receives
lymph fluid directly from a tumor site. Sentinel lymph node biopsy is part of
the diagnostic process that determines if cancer has spread past the initial
tumor and has entered the lymphatic system. Because the sentinel nodes
are the first location where lymph fluid drains from a tumor, a biopsy of the
tissue can help to determine if fluid has moved directly past the primary
tumor. Typically, if a tumor has already been identified, it is removed during
the sentinel node biopsy. The goal of the process is to not only remove a
potentially cancerous tumor from the patient’s body, but also to remove
surrounding tissue that may contain malignant cells as well.
A sentinel node biopsy is beneficial because it does not require removal of
too many lymph nodes during the early stages of tissue procurement for
biopsy. Because the lymph nodes cannot be removed for testing and then be
replaced, it is preferable to remove as few as possible. Alternatively,
removing too few may not provide a clear enough picture as to the spread of
the cancerous cells and the physician could potentially miss some cancer
cells that have spread through the lymph system. Because the sentinel
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nodes are closest to the tumor, sentinel node biopsy initially requires
removal of only one node, which to begin with includes the node most likely
to have cancer cells if they have spread from the tumor. If cancerous cells
are present, further tissue can be removed to determine cancerous spread.
If cancer cells are not present, the surgeon will most likely not need to
remove more lymph nodes.
To perform a sentinel node biopsy, the surgical provider injects a tracer
material. The tracer may be radioactive solution or a blue dye that helps to
locate the tumor and the surrounding lymph nodes. The radioactive solution
is injected into the tissue near the tumor. The solution enters the lymphatic
system and travels to the nearby lymph nodes so that they can be identified.
The injection is done several days before the actual biopsy is performed.
Instead of radioactive material, the provider may also choose to use blue
dye to locate the sentinel lymph nodes. The dye is a specialized combination
of materials that are designed to reveal vessels so that they can be
visualized with imaging procedures. A common type of dye used to locate
the sentinel lymph nodes for biopsy is PATENT BLUE V®. The dye is injected
into the tissue near the tumor just prior to the start of the surgical
procedure. As with the radioactive solution, the dye also travels through the
lymphatic system to identify the appropriate lymph nodes to test. Use of
either type of tracer has its own advantages and disadvantages, but it
ultimately helps the clinician to identify the sentinel nodes so that they can
be removed for biopsy.
Once the sentinel lymph nodes are identified according to the tracer
material, the surgeon can usually reach them by making a skin incision near
the site to extract the node. The affected node is sent to pathology to be
tested, sometimes while the surgical team waits for results. The nodes are
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tested for the presence of malignancy, which then helps the provider to
determine the next best course of action. If the sentinel nodes contain
malignant cells, then it is likely that the cancer has spread from the primary
tumor. The cancerous cells have spread beyond the tumor to the sentinel
lymph node but they may also be present in other nearby tissues as well. If
these results have been found during the surgical procedure, the surgeon
may remove more tissue or other lymph nodes during the same procedure
instead of starting a new process later. If a tumor is present but there are
no malignant cells in the sentinel lymph node, then the cancer may be more
likely contained within the tumor tissue.
Sentinel node biopsy is routinely performed as part of diagnostic testing for
metastatic breast cancer and melanoma. It is also commonly used for
diagnosing other types of cancer as well; some types include esophageal
cancer, colon cancer, stomach cancer, thyroid cancer, and non-small cell
lung cancer. The patient undergoing sentinel node biopsy is at risk of slight
complications associated with the procedure, although the process is
generally determined to be safe. Potential risks associated with sentinel node
biopsy include pain or bruising from the biopsy site, bleeding from the
biopsy site, infection, if microorganisms are introduced into the skin or
surrounding tissue, or an allergic reaction to the tracing material. The
patient is also at risk of lymphedema development in the surrounding tissues
when the affected lymph nodes are removed.
Lymph node biopsy is actually also performed to protect against
development of lymphedema, even though lymphedema is a potential
complication of this type of procedure. As discussed, lymphedema is a
painful, debilitating condition that most often occurs following surgical
procedures for breast cancer surgery, although it can also develop following
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surgical intervention for other types of solid-tumor cancers, including head
and neck cancer, melanoma, sarcoma, and some urologic or gynecological
surgeries.117 Lymphedema can develop anywhere from a few days to years
following lymph node extraction and there is usually no cure for the
condition. Instead, affected patients must make attempts to control swelling
and to continue to use the affected area despite grossly enlarged tissue,
pain, and stiffness.
It is possible that sentinel lymph node biopsy can decrease the incidence of
lymphedema for some patients who must undergo excisional biopsy.
Because lymphedema often occurs with occlusion of lymphatic vessels,
generally following removal of one or more lymph nodes from an area, the
patient who has several lymph nodes removed at a particular site may be
more likely to develop lymphedema because of the disruption in that
particular area of lymphatic vessels. Sentinel lymph node biopsy is designed
to target the specific lymph node that is closest to the tumor and most likely
to contain cancerous cells if they have spread through the lymphatic system.
By targeting the lymph node that is most likely affected, the surgical
provider may then only remove that one lymph node for biopsy and for
potential cancer diagnosis. Removing one lymph node for biopsy is beneficial
and causes much less tissue trauma for the affected patient. If the lymph
node is superficial, it can even be removed under local anesthesia in contrast
to procedures required for removal of deep tissue. By decreasing the amount
of tissue trauma and lessening the potential obstruction of lymphatic
pathways by removing only one lymph node at a time, the patient may be
less likely to develop lymphedema following the biopsy.
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Sentinel lymph node biopsy was actually developed to reduce the risk of
lymphedema and many healthcare centers focus on this type of procedure to
be able to spare some of the pain and disability associated with
lymphedema.118 Particularly among patients with breast cancer, in whom the
risk of lymphedema seems to be the greatest, sentinel node biopsy has been
shown to decrease the risk of lymphedema development when compared to
axillary node dissection, in which several lymph nodes are removed at once
for biopsy.119 With continued development of diagnostic techniques, imaging
studies, and histologic analysis, researchers may be able to use the methods
associated with sentinel node biopsy to further restrict incidences of
lymphedema development in some patients.
Staging Cancer
Lymph node biopsy is useful as a diagnostic test in staging cancer and the
extent of its spread. The stage of cancer describes how much it has spread
in the body and it helps the provider to better determine the patient’s
prognosis. In general, cancer that has spread further from its original site of
development is more difficult to contain and has a poorer prognosis in
comparison to cancer that is contained within its original location of growth
and has not spread beyond its primary borders. The lymph node biopsy can
help to determine how much and how far cancerous cells have been
distributed through the body.
Cancer cells may spread through the bloodstream when they utilize
angiogenesis to develop their own small amount of blood supply to be able
to continue to grow and develop. Cancerous cells may also separate from
the primary tumor and may spread through either the bloodstream or
through lymph circulation. This is a typical method of metastasis and how
cancer spreads from the primary tumor site to distant organs. If the cancer
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cells travel through the lymph system and enter the lymph nodes, some of
them may be destroyed by the lymphocytes present there; however, if they
remain or are even able to grow within a lymph node, the node should be
tested.
It is difficult to determine if lymph nodes contain cancerous cells and the
extent at which cancerous cells have spread. A lymph node that contains
malignant cells may or may not be enlarged. Even if the lymph node does
become enlarged because of cancer, it may be a deep lymph node that is
not outwardly obvious right away. It can be quite complicated to determine
how many lymph nodes to test based on the potential spread of cancer, and
removing many lymph nodes for biopsy purposes can lead to its own set of
complications. Sentinel lymph node biopsy, described above, is a common
method of extracting the lymph nodes closest to the primary tumor to
reduce the need for removing too many nodes at once.
For some types of cancer, removal of only one lymph node is not enough to
determine the spread of cancerous cells and, at times, several lymph nodes
need to be removed all at once. The American Society of Clinical Oncology
recently updated practice guidelines for sentinel lymph node biopsy and
dissection. The committee updated their practice standards to reflect current
practice since the last set of standards was published in 2005. The
recommendations are that women who undergo sentinel lymph node biopsy
for breast cancer and who are not found to have sentinel lymph node
metastases should not undergo lymph node dissection. Furthermore, women
with breast cancer who have 1 to 2 sentinel lymph nodes with metastases
also do not require lymph node dissection when they are planning to
undergo breast-conserving surgery with whole-breast radiotherapy.50
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When necessary, lymph node dissection may be needed to assess for and to
stage cancer. Lymph node dissection refers to the removal of several lymph
nodes at the same time; it may be performed if an initial sentinel lymph
node biopsy shows the presence of cancer cells and more tissue must be
extracted for examination if the tissue margins are not clear. The cancer is
staged depending on the presence and characteristics of the cancerous cells
found in the lymph nodes.
Staging is done to determine the size of the initial tumor, the extent of the
spread of cancer cells, and whether metastasis has occurred in distant
organs or in the lymph nodes. There are various cancer staging systems
used to detect cancer growth, many of which vary, depending on the type of
cancer involved and the understanding of how it spreads. For example, the
Brigham Staging System is a method used to determine the extent of
mesothelioma to determine the best course of its treatment and whether
lymph nodes are involved. Most types of cancer can be staged according to a
general system that assesses involvement of the primary location of cancer
development, whether the cancer has spread to surrounding tissues and the
extent of its growth.
The tumor, nodes, and metastasis (TNM) staging system is one of the most
frequently used assessments for staging the extent of cancer and it involves
identification of malignancy in certain lymph nodes near the primary tumor
site. The system assesses whether the tumor, lymph node involvement, and
metastasis components are present and then uses numerical subtypes to
clarify the extent. Increasing numbers indicate further involvement of tissue
and a more complex diagnosis. The TNM staging system includes:49
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
Primary tumor (T):
The primary tumor describes the initial location where the cancer
cells developed. The tumor classification is further described
according to the presence and size of the primary tumor.

T0:
No evidence of a primary tumor.

TIS:
Carcinoma in situ.

T1, T2, T3, T4:
A tumor is present and is numbered according to present size. A
larger number indicates a larger size of tumor.

TX:
The primary tumor cannot be assessed.

Regional lymph nodes (N):
This is a description of regional lymph node involvement, which
dictates whether the tumor has spread to nearby lymph nodes.

N0:
No regional lymph node involvement.

N1, N2, N3:
Regional lymph nodes are involved. The number given indicates the
degree and the amount involved.
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
NX:
The regional lymph nodes cannot be assessed.

Distant metastasis (M):
Assessment of metastasis determines if the cancer has spread to
distant lymph nodes or to remote organs.

M0:
No distant metastasis noted.

M1:
Distant metastasis is noted.

MX:
Distant metastasis cannot be assessed.
As with other diagnostic procedures
for cancer, staging that uses lymph
node involvement have benefits and
disadvantages. There are times
when staging can be very clear and
the treatment methods are obvious;
in other situations, staging may be
done but the patient’s condition
progresses so that it is no longer
applicable and further testing is
required. Staging procedures, such
as through the TNM staging system,
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provide a guide for the clinician to understand the extent of the disease,
which then provides direction about the best course of treatment. By
understanding how lymph nodes are involved in the spread of cancerous
tissue, healthcare providers have been better able to devise strategies that
can also impede some of the spread of cancer by providing treatments that
specifically target the patient’s condition.
Immune System And T Cell Function
Regulatory T cells (Tregs) are essential components of maintaining
homeostasis within the immune system. Regulatory T cells, also known as
suppressor T cells, are essential for regulating lymphocyte activity and for
preventing uncontrollable autoimmune responses. Normally, when antigens
are present and the T cells attack, the body’s immune system is being
upheld by preventing potential infection and disease. However, when the
body attacks its own cells, such as during an autoimmune condition, Tregs
can suppress some of the functions of effector T cells and prevent them from
attacking their own tissues. Many autoimmune disorders, including
rheumatoid arthritis and type 1 diabetes have been associated with
decreased levels of Tregs, in which they are unable to stop the work of
effector T cells in attacking their own tissues.
Cancer immunosurveillance describes the work of certain immune cells as
they recognize and destroy cancer cells. Some cancer cells are able to avoid
immunosurveillance because they contain variants that enable them to resist
attack from antibodies produced by B lymphocytes or from the cell-mediated
immunity of T cells. Unfortunately, when chronic inflammation develops, as
associated with some medical conditions, the immune system may be unable
to control growth of cancerous cells as well. Research has shown that
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cancerous tumor growth is associated with an increase in immunosuppressor
cells and in T cells.120
In regards to cancer, regulatory T cells also play a role in tumor
progression.120,121 Because a regulatory T cell is responsible for controlling
effector T cells — typically as part of control of inflammation or to contain an
autoimmune response — the Treg can then also prevent effector T cells from
controlling cancerous tumor growth. While decreased amounts of Tregs have
been found in autoimmune disorders, the converse is often true when it
comes to cancerous cells; elevated levels of Tregs are often found in
cancerous conditions, including in cases of lung, pancreatic, and breast
cancers.122 Furthermore, continued immune suppression because of tumor
growth may explain why some cancer treatments are ineffective to the
extent that they are unable to work against the elevated levels of Tregs.
Tumor cells may actually recruit some regulatory T cells to do some of their
work for them, so to speak. These Tregs that are recruited by tumor cells in
the tumor microenvironment become known as tumor Tregs. Tumor Tregs
then promote tumor growth and they act as an obstacle for the immune
system to defend itself against tumor growth. During the early stages of
cancer, tumor Tregs are more often found in the tumor mass, which allows
the tumor to continue to grow because the tumor Tregs have suppressed
effector T cell responses. When cancer has progressed to an advanced stage,
the numbers of tumor Tregs increases significantly, and antitumor activity
from effector T cells is diminished.123 Therefore, destroying these tumor Treg
cells may play a role in supporting immunity against cancer and may
improve some of the efforts of cancer treatment that are available.
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Immunotherapy is a method of cancer treatment that works by stimulating
the immune system to be able to fight off cancer cells. Research is
considering the potential for destroying Treg cells as part of immunotherapy
for cancer treatment, since several types of cancer have been associated
with elevated levels of Tregs. The T cells are essential for supporting
immunity to control cancer growth, in that they travel to the sites of growing
tumor cells and release cytokines to destroy the cells and to prevent their
proliferation. When tumor Tregs are present, the responses of the effector T
cells is suppressed. An article by Byrne, et al., in the journal Cancer
Research, noted that depletion of Tregs, when combined with
immunotherapy treatment, has been shown to contain some types of
tumors, including those associated with metastatic melanoma and
sarcoma.123
Strategies used to diminish Tregs in the tumor environment have focused on
using certain toxins that will specifically destroy those cells, as well as
utilizing targeted antibodies that are intended for specific Treg cells.
Unfortunately, while these strategies have been useful, they are also not
permanent, so that Treg numbers decline initially with their application;
however, the decline is only temporary and they eventually return to their
normal counts.
There have been some trials in which regulation of Treg cells through
immunotherapy has slowed the spread of cancerous cells and has induced a
response in some patients in advanced stages of cancer.123 At the very least,
some of these treatments have provided a little more time for some patients
who were otherwise succumbing to advanced cancer growth when Tregs
were controlled. Research in this area continues to look for the best methods
of administering immunotherapy to control cancerous growth and to control
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the work of regulatory T cells. The regulatory T cells actually play a
paradoxical role in immunity when it comes to cancer growth; therefore,
finding a way to restrain their activity against other cells in the immune
system seems to be the key to controlling some types of cancer.
Immune System And Dendritic Cell Maturation
The lymphatic system and its immune system cells also have important roles
in controlling maturation of dendritic cells. As previously noted, dendritic
cells are those that are antigen-presenting cells, which introduce antigens to
immune system cells so that they can form antibodies. Dendritic cells (DCs),
as major antigen-presenting cells in the immune system are important
components that initiate the immune response when antigens are present.
Dendritic cells, like many other cells of the immune system, have immature
stages and mature stages. It is during the mature stage of life that DC cells
exhibit their antigen-presenting activity. The DC cells must become mature
cells in order to stimulate T cell activity.
During the maturation process, DCs go through several changes that affect
their function, including alterations in their major histocompatability complex
markers on their cell surfaces and morphological changes. They are able to
secrete cytokines and certain proteases and their cell membranes develop
the capacity to express chemokine receptors. Immature DCs are found in the
bone marrow and in the lymphatic system; they are triggered to mature
when invading pathogens recruit their presence in the areas of invasion.
Once the dendritic cells recognize the antigens, they travel to the lymphatic
organs to present the antigens to T cells; it is during this process of
migration that the DC cells mature.
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Conversely, immature DCs can present self-antigens to T cells, which
promote the activity of Tregs and inhibits an autoimmune response. The
type of response generated by the T cell and how the T cell differentiates
after coming into contact with the DC is largely based on the type of DC that
presents the antigen.125 For instance, in response to DC presenting antigens,
the T cell may develop into effector T cells that fight the antigens, they may
become helper T cells that work with B lymphocytes or could differentiate
into regulatory T cells.
In some lymph tissue, mature DCs can be found, even when infection or
inflammation is not present. Further, inflammatory mediators that are
present with cancer promote tumor growth and prevent much of the work of
anti-tumor immune system cells. Tumor cells are able to immobilize DC cells
and prevent them from maturing, thereby keeping them in an immature
state and preventing them from their work of antigen-presenting activity.
Other types of cells have also been able to inhibit the maturation of DCs,
which can ultimately promote tumor activity and could lead to cancer
progression.
A study by Lui, et al., in the journal PLOS One researched the effects of
mesenchymal stem cells on maturation of DC cells. Mesenchymal stem cells
are cells that can differentiate into various cell types, including bone cells,
fat cells, and cartilage cells. The study looked at the ability of mesenchymal
stem cells to disrupt the maturation of DC cells by secreting factors that
interrupt the transition between mature and immature states.51 The
mesenchymal stem cells (MSCs) disrupted the process by secreting
interleukin-10 (IL-10), which is a type of cytokine that regulates several
functions of the immune system. The IL-10 plays various roles in
immunosuppressive and anti-inflammatory functions in the body to control
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cytokine production by macrophages and to restrain some of the functions of
macrophages during T-cell activation.52 It also plays a role in inhibiting the
maturation of DC cells, as well as some other cells involved in the
inflammatory process.
The JAK/STAT pathway transmits information and chemical signals from
outside the cell to the cell nucleus and to portions of cell DNA. This pathway
is also important for regulating communication between cytokine receptors.
A part of the JAK/STAT pathway, known as STAT3, is potentially associated
with abnormal DC cell differentiation and development of cancerous cells.
The JAK/STAT pathway plays an important role in cell signaling between
cytokines associated with maturation of DC cells. The described study
concluded that there is a link between the release of IL-10 by MSCs and the
JAK/STAT pathway that inhibits the maturation of DC cells.51
The various roles of interleukin-10 are complex and multifaceted in its
association with immune system functioning. The IL-10 is important for
regulating inflammatory processes, and in its absence, the body is at risk of
the complicated and significant effects of autoimmune disease; and, it is also
responsible for inducing some Treg responses so that effector T cells can be
suppressed when needed during the autoimmune response. As stated, IL-10
is also associated with suppression of maturation of dendritic cells. When
dendritic cells are prevented from maturing, they are unable to present
antigens to T cells and to therefore stimulate T cell differentiation. This
affects the immune system because the T cells are not necessarily able to
secrete their own enzymes that would destroy foreign particles and protect
against certain invading pathogens. Alternatively, when DC cells are
prohibited from maturing, they may not stimulate differentiation of T cells,
some of which could evolve in the regulatory T cells. While Tregs are
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important for suppressing excessive autoimmune functions, too many Tregs
are also associated with cancerous states and tumor formation. Controlling
DC maturation is one step in thwarting a process that eventually controls the
formation of Treg cells, which if produced in excess, can ultimately depress
some of the functions of the immune system.
The information regarding immune system functions and properties is very
complex. Some elements of the immune system work together in their
protective mechanisms in a smooth manner that focuses on the same goal of
preventing the excess growth of infectious pathogens or tumor cells. On the
other hand, when some processes go awry, other cells of the immune
system are in place and are designed to control immunity and to prevent the
body from destroying itself. Unless the cells of the immune system are in
balance and are working correctly, there is potential for development and
growth of harmful products that can destroy the tissues and can shorten the
life of the affected individual. The process of regulating immune system
functions requires a distinct process that equalizes cell functions and that
maintains appropriate cell roles.
Immune System Diseases
As raised in the previous discussion, when the mechanisms of the lymphatic
system do not work appropriately, disease can develop from proliferation of
either foreign particles that have invaded the body or from the growth of
abnormal cells that have transformed into cancerous tumors. Many diseases
develop as the result of insufficient immune system functioning, either
because the cells of the immune system are not working properly, or
because the abnormal, disease-causing cells are out of control and cannot
be contained. Cancer is an example of a situation where body cells are
abnormal. The T cells normally recognize and destroy abnormal cells before
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they can multiply, however, in some cases, the abnormal cells still
proliferate and grow out of control to form cancerous tumors, which can
eventually take over normal body processes.
Lymphoma refers to a condition where one or more tumors have developed
in the lymphatic system. The individual with lymphoma typically develops
enlarged lymph nodes that are initially painless. The enlarged nodes are
often found in areas where there are clusters of lymph nodes, such as in the
neck or the axillae, although an enlarged and painless lymph node may also
develop in an isolated area. Eventually, the affected individual develops
other signs and symptoms of the cancer’s effects on the body, including
fever, weight loss, anemia, and weakness. As the cancer spreads, more and
more lymph nodes become enlarged and are palpable upon examination. In
most cases, lymphoma is a malignant condition that requires treatment to
prevent the cancer from spreading; however, there are some rare cases
where lymphoma is a benign condition. The two main types of lymphoma are
non-Hodgkin lymphoma and Hodgkin lymphoma (also referred to as Hodgkin
disease).
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) describes a type of cancer that originates in
the lymphatic system. As stated, lymphoma refers to cancer of the lymphatic
system, rather than cancer that has started in a specific organ but that has
spread to other lymph nodes as a result of metastasis. Non-Hodgkin
lymphoma is much more common when compared to Hodgkin lymphoma;
NHL is seen in five times as many cases of lymphoma as Hodgkin
lymphoma.26
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There are a number of different types of non-Hodgkin lymphoma, and it can
sometimes be difficult to detect the exact kind upon diagnosis. The various
subtypes that have been identified demonstrate the complexity of the
disease and its variations in cell behavior and clinical manifestations. There
have been various classification systems used to categorize the different
subtypes of NHL; one of the more recent systems is the 2008 World Health
Organization (WHO) classification system, which was designed to identify
cancers of the lymphoid system.29 Because there are so many lymph nodes
and several organs of the lymphatic system, the potential variations in
cancer cell development within lymph tissues are quite numerous.
Because lymphoma is a cancer of the lymphatic system, the affected cells
are most often those of the immune system. Approximately 85 percent of
non-Hodgkin lymphomas originate in B lymphocytes. For this reason, these
types of lymphomas are called B-cell lymphomas.27 T-cell lymphomas can
also occur, in which the T cells of the immune system are primarily affected;
however, T-cell lymphomas are not as common despite their harmful effects
on the body. The 2008 WHO system of classification does make a distinction
between B-cell lymphomas and T-cell lymphomas.
Types of Non-Hodgkin Lymphoma
Within the types classified as B-cell lymphomas, there are indolent or slowgrowing lymphomas, aggressive lymphomas, and very aggressive forms of
lymphomas.30 Indolent lymphomas are those types that grow slowly and
may be better contained through treatment as compared to some of the
more aggressive forms. In general, lymphomas of small lymphocytes tend to
be indolent and to grow more slowly, while lymphomas that consist of larger
cells grow more rapidly and are more aggressive. Types of indolent
lymphomas include the early stages of follicular lymphoma, splenic marginal
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zone lymphoma, lymphoplasmacytic lymphoma, and chronic lymphocytic
leukemia with small lymphocytic lymphoma.
Follicular lymphoma describes a specific type of cancerous growth that forms
within the lymph nodes. It is so named because of the circular pattern of
clumps that develop with its formation. Follicular lymphoma occurs in
approximately 1 in 5 types of lymphoma in the United States.31 Although
follicular lymphoma is considered a slow-growing form of NHL, it is classified
as such when it is in its early stages; either stage 1 or stage 2 of the
disease. If allowed to grow and if not managed well, follicular lymphoma
may eventually become much more aggressive. Earlier stages of the disease
are more often diagnosed during the sixth decade of life and it more
commonly affects older adults instead of the very young.
Splenic marginal zone lymphoma (SMZL), as described when discussing the
lymphatic organs and the spleen, is a specific type of lymphoma that forms
in the marginal zone between lymphoid and non-lymphoid tissue in the
spleen. Although it is relatively rare, SMZL can cause significant
splenomegaly as to affect the surrounding tissues and to cause anemia when
the spleen sequesters red blood cells. However, because SMZL is a slowgrowing form of cancer, spleen enlargement may not develop until much
later in the course of the disease. However, when SMZL is contained within
the spleen and does not disseminate to other tissues, it responds well to
treatment and often offers a positive prognosis. The condition is more likely
to affect older adults as opposed to younger patients.
Lymphoplasmacytic lymphoma, also called Waldenström macroglobulinemia,
is a rare form of lymphoma. When this type of lymphoma develops, the
cancer cells in the lymph system create macroglobulins, which are
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monoclonal antibodies that build up and that eventually lead to its
symptoms. The abnormal cells typically grow in the bone marrow; because
of their abnormal production of macroglobulins, the cells that normally
belong in the bone marrow, including red and white blood cells, are then
crowded out. When this occurs, the affected person often develops signs of
infection or anemia because of depletion of these cells.32 The cancer may
also lead to liver and spleen enlargement, which further increases the risk of
complications associated with this type of cancer.
Two conditions known as chronic lymphocytic leukemia (CLL) and small
lymphocytic lymphoma (SLL) are illnesses that are very closely related in
terms of the types of cells associated with their cancer growth. Both
diseases involve cancerous cells known as small lymphocytes. In CLL, the
small lymphocytes develop in the blood and in the bone marrow, while in
SLL, the small lymphocytes grow in the lymph nodes and in the spleen. Both
types of cancer are very slow growing. Although they are not curable,
treatments often include watchful waiting and comfort measures. The
treatments available for CLL and SLL have been shown to keep these two
conditions under control for a long time; among some affected patients,
symptom remission may last up to ten years.
Aggressive lymphomas are those that grow more quickly and progress from
their initial stage to the next at a rapid rate as compared to indolent
lymphomas. The benefit of developing these types of lymphoma over
indolent forms is that they often respond to treatment measures, such as
chemotherapy or radiation. Despite being considered aggressive forms of the
disease, these types of lymphoma often have relatively good five-year
survival rates. According to the WHO, forms of aggressive NHLs include
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diffuse large B-cell lymphoma, grade 3 follicular lymphoma, and mantle cell
lymphoma.30
Diffuse large B-cell lymphoma (DLBCL) is the most common type of nonHodgkin lymphoma in the United States, appearing in approximately 1 out of
every 3 diagnosed cases.31 Diffuse large B-cell lymphoma is so named
because of the appearance of the B cells when viewed under a microscope,
as they grow to become quite large. The affected person with DLBCL
typically develops an enlarged lymph lode, which grows quickly. In some
cases, the affected lymph nodes are deep nodes and cannot be felt with
palpation. However, once they swell to become large enough, they compress
surrounding structures and can cause associated symptoms. For example,
DLBCL may develop as an enlarged lymph node in the chest, which is deep
enough that it is not felt with palpation. As the lymph node grows, it can
compress the vena cava, causing superior vena cava syndrome, leading to
shortness of breath, swelling in the face and neck, headache, dizziness, or
changes in level of consciousness.
Diffuse large B-cell lymphoma may be further classified into subtypes.
Primary mediastinal B-cell lymphoma is more likely to develop in younger
patients, especially in women. The affected lymph nodes are often
surrounded by areas of fibrosis, as has been seen when they are viewed
microscopically. The lymph nodes near the mediastinum are those that are
affected first, although the cancer typically has not spread much beyond the
chest cavity by the time most cases are diagnosed. Intravascular large B-cell
lymphoma is quite rare; the cancerous cells grow in the bloodstream instead
of in the lymph nodes. Because it still involves cancerous growth of
lymphoma cells, it is treated in the same manner as DLBCL.31
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Although DLBCL is an aggressive form of lymphoma and it may spread
quickly, it also responds very well to treatment and is often able to be cured.
Follicular lymphoma, when found during the early stages of the disease, is
classified as an indolent form of the cancer. However, once it reaches stage
3, it may change into a more aggressive form of the cancer. In stage 3 of
cancer classification, the affected lymph nodes have been found both above
and below the level of the diaphragm. The survival rate among those
diagnosed at this stage is worse than if the cancer was found during early
stages of the disease.
Researchers have found that when the cancerous cells reach stage 3 of
follicular lymphoma, they behave more aggressively. The reasons may be
because once the cancer cells reach a larger size and their locations in the
body are enough to warrant a grade 3 classification, the cells become quite
similar to those of DLBCL, which is an aggressive form of lymphoma.
According to a research study performed by Horn, et al., and published in
the journal Hematologica, follicular lymphoma grade 3, which is actually
further divided into subtypes 3a and 3b (with cells that are categorized as
being grade 3b) are actually different from those found in groups 1, 2, and
3a. Cells of category 3b have fewer translocations of certain genes when
compared to other cells in staged follicular lymphoma.33 According to this
study, the cells of type 3b follicular lymphoma should actually be classified
as a different category of lymphomas completely, based on their variations.
This may better explain why follicular lymphoma, once it has reached stage
3, behaves differently and is a more aggressive form of cancer.
Mantle cell lymphoma is a rare form of NHL, affecting between 5 and 10
percent of cases.34 Mantle cell lymphoma is more likely to develop in
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patients over 60 years of age, and primarily in men. It is referred to as
“mantle cell” lymphoma because of the region within the lymph node where
this type of cancer develops. Microscopically, mantle cell lymphoma appears
similar to indolent forms of lymphoma; however, it behaves more
aggressively. It is often not diagnosed until it is in a later stage of the
disease, when the affected lymph nodes have spread beyond the initial area
of growth. Mantle cell lymphoma often causes symptoms similar to those of
other forms of NHL, including enlarged, painless lymph nodes in various
areas; as well as non-specific symptoms of weight loss, night sweats, and
fever. It is difficult to cure because it often spreads quickly. Most people
undergo chemotherapy and/or radiation therapy as part of treatment, but
these measures may be more likely to put the cancer into a type of
remission, rather than curing it completely. Unfortunately, this kind of NHL
often returns after a period of treatment.
Beyond the aggressive forms of non-Hodgkin lymphoma, there are some
other types of NHL that are considered to be highly aggressive. The B-cell
types include Burkitt lymphoma and lymphoblastic lymphoma. Burkitt
lymphoma is named after Denis Burkitt, a British surgeon who first
discovered the specific types of cells associated with the disease in 1956
while working with children in Africa. Unfortunately, for those who are
diagnosed with this type of lymphoma, it is so aggressive that it can quickly
cause death if not promptly treated, as it has been recognized as the fastest
growing human tumor.35 Burkitt lymphoma is more commonly associated
with a previous infection involving the Epstein-Barr virus; it is thought that
infection with Epstein-Barr may weaken the cells to the point that the
cancerous cells are more likely to grow and spread.
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Burkitt lymphoma is rare in the United States; it is diagnosed in about 1200
people each year. There are actually three forms of the disease. The
endemic form, which occurs in Africa and more commonly affects young
boys ages 4 to 7 years; the sporadic form, which is found throughout the
world and affects both children and adults; and the third form being the
immunodeficiency-associated Burkitt lymphoma, which occurs primarily
among patients infected with HIV.35 Within the United States, the sporadic
form of the disease typically begins in the abdomen near the gastrointestinal
tract and causes a large abdominal tumor. The affected patient may have
symptoms of bowel obstruction if the tumor blocks a portion of the
gastrointestinal tract. A large retroperitoneal mass could also compress the
ureters and then cause symptoms of obstruction and hydronephrosis.26 It
typically involves the spleen, the liver, and the bone marrow as well, and it
can quickly spread to the central nervous system.
Treatment of Burkitt lymphoma requires intensive chemotherapy with
additional treatment aimed at the brain and spinal cord through intrathecal
chemotherapy, if these areas are affected. Fortunately, outcomes are
relatively good for those patients with Burkitt lymphoma when it is caught
early. When it develops among children, it is often cured with intensive
chemotherapy. Among adults, intensive chemotherapy leads to long-term
survival rates of up to 80 percent.35 Without prompt treatment of Burkitt
lymphoma, the condition otherwise spreads so quickly that it is fatal within a
short period of time.
Lymphoblastic lymphoma is a condition that is similar to acute lymphoblastic
leukemia (ALL); it primarily affects children and adolescents and is
considered to be very rare among adults.36 Abnormal lymphocytes most
often grow in the thymus gland or in various lymph nodes throughout the
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body; it spreads to other organs of the lymphatic system, including the
spleen and the bone marrow, as well as to the liver, skin, or brain. It is a
highly aggressive form of lymphoma that must be treated quickly;
otherwise, as with many cases of ALL, it is rapidly fatal. Lymphoblastic
lymphoma is predominantly a form of T-cell lymphoma, however, it can also
grow within B cells.
Approximately 15 percent of cases of non-Hodgkin lymphoma are classified
as T-cell lymphomas, in which the cancerous cells arise out of T cells. These
types of lymphoma are often more aggressive when compared to some
forms of the B-cell tumors. As mentioned, lymphoblastic lymphoma can be a
type of T-cell lymphoma; it is very similar to lymphoblastic leukemia and is
classified according to how much of the tumor grows in the bone marrow. It
often develops in the thymus, where T cells develop and mature. Because
the thymus is larger in young children, this may be why lymphoblastic
lymphoma is more common among children. In addition to non-specific
symptoms associated with NHL, lymphoblastic lymphoma can cause
symptoms when a tumor grows large enough to compress surrounding
structures in the mediastinum, such as with superior vena cava syndrome or
breathing difficulties if the tumor compresses the trachea.31 If the cancer has
not spread to the bone marrow, as with acute lymphoblastic leukemia, the
prognosis for lymphoblastic lymphoma is much better and often responds to
treatment with chemotherapy.
Cutaneous lymphoma is a form of T-cell cancer that primarily affects the
skin. Cutaneous T-cell lymphoma is the most common form, although any
kind of cutaneous lymphoma is rare when compared to other types.37
Cutaneous T-cell lymphoma is similar in appearance to eczema and causes
patches of red, scaly skin that can be itchy or that can lead to skin
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breakdown. As it spreads, it involves the lymph nodes, the blood vessels,
and other organs. This type of lymphoma is considered an indolent form; it
is typically slow growing and responds well to treatment when it is caught
early on.
Anaplastic large cell lymphoma (ALCL) often starts in the lymph nodes and
then spreads to the skin. It is much more common among young people and
older adults. There are two main forms of ALCL; one form affects only the
skin, while the other form is systemic.31 The type that affects the skin begins
with small tumors in the skin, which may eventually develop into ulcers. It
has a good prognosis with intensive treatment and typically does not spread
beyond the skin.
There are also other types of cutaneous lymphomas that begin primarily in
the skin and together account for approximately 5 percent of all
lymphomas.31 Mycosis fungoides causes patchy lesions on the surface of the
skin that can be itchy and that can be easily confused with some other types
of skin conditions, such as eczema. If the disease progresses, it forms solid
tumors on the skin surface.38 Despite its beginnings as a type of cancer
affecting the skin, it typically requires treatment with chemotherapy and
radiation to completely eradicate the disease and to prevent it from
spreading. When mycosis fungoides is not treated, it may spread to
underlying lymph nodes and it can spread to the liver, although it is
considered a slow-growing form of T-cell lymphoma.
Sezary syndrome is similar to mycosis fungoides except that it involves most
of the skin rather than just patchy areas. The main symptom is generalized
erythroderma, in which large areas of skin are covered with a red, itchy rash
that looks like a sunburn.38 The condition is characterized by abnormal
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lymph cells, called Sezary cells, which may invade the bloodstream and the
lymph nodes. Sezary syndrome spreads more quickly when compared to
mycosis fungoides. It also requires treatment with chemotherapy or
radiation to destroy the cancerous cells and to prevent their further
proliferation. Because it spreads quickly, the prognosis is more favorable
when the condition is caught as early as possible to be able to begin
treatment.
Adult T-cell lymphoma is a type of NHL that typically develops following
infection with human T-lymphotropic virus, type 1 (HTLV-1). It consists of
four basic subtypes: smoldering, which typically affects the lungs and the
skin and grows slowly; chronic, which affects the skin, lungs, liver, and
lymph nodes and that also grows slowly; acute, which causes enlargement
of lymph nodes, the liver, and the spleen and that causes high numbers of T
cells; and, lymphoma type, which grows more quickly, causes enlarged
lymph nodes, but does not result in increased T-cell counts.
There are many other types of T-cell lymphomas that can be classified as
non-Hodgkin lymphoma. Some may be slow growing, while others can
spread rapidly. Their symptoms typically develop based on the affected area,
such as within the skin, chest cavity, or abdomen. Most patients also
develop many of the same non-specific symptoms of fever, anorexia,
fatigue, night sweats, and weight loss. Some other types of T-cell
lymphomas include angioimmunoblastic T-cell lymphoma, extranodal natural
killer/T-cell lymphoma, enteropathy-associated intestinal T-cell lymphoma,
and peripheral T-cell lymphoma, unspecified.
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Causes and Risk Factors
Non-Hodgkin lymphoma is one of the more common types of hematologic
cancers and is one of the leading causes of cancer deaths in the United
States, accounting for almost 20,000 estimated deaths per year, according
to the National Cancer Institute.28 It most commonly affects adults between
the ages of 40 and 70 years, although it can develop in anyone of any age.
The exact cause of NHL is not entirely clear. Because the cancer originates in
the lymphocytes, it is uncertain exactly how these white blood cells are
transformed into cancer cells.
Various risk factors have been associated with an increased risk of
developing NHL, including a previous diagnosis of an autoimmune disorder,
such as rheumatoid arthritis or lupus, HIV infection, infection with certain
pathogens, including H. pylori and Epstein-Barr virus; and, exposure to
certain environmental chemicals, including formaldehyde, benzene, lead,
and some pesticides, as well as with advancing age and male gender.27
Introduction of some types of viruses, such as Epstein-Barr virus or HTLV-1,
can alter the lymph cells so that cancer is more likely to develop. As
previously discussed, B cells undergo changes in their structures, which adds
antibodies to cells that match specific antigens during their time of
development. Tumors that develop within the lymph system have cells that
have corresponding antigens to various portions of the B cells; these various
tumors have also been shown to be associated with various stages of B-cell
development. For instance, lymphoid tumor cells that eventually grow to
become follicular lymphoma have similar gene characteristics that match the
memory cells that develop as part of the clone reproduction of B cells have
matching antibodies.
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Chromosome translocations are a common cause of NHL cancers, although
different translocations are associated with different subtypes of lymphoma.
A chromosome translocation occurs when DNA from a pair of chromosomes
separates and attaches to a different chromosome. For example, the
t(14;18)(q32;q21) translocation is more commonly seen with follicular
lymphoma, while t(11;14)(q13;q32) translocation is more likely a cause of
mantle cell lymphoma. Other types of lymphomas that are known as being
caused by chromosome translocations include anaplastic large cell
lymphoma, Burkitt lymphoma, and with lymphomas that develop within
MALT tissue. These chromosome abnormalities may be identified through
cytogenetic studies that reveal abnormalities in the affected cells and that
provide details about chromosomal irregularities.
Cytogenetic studies are important components of diagnostic methods for
identifying the specific chromosome abnormalities and their corresponding
cancer cells. Once clinicians understand the connection between specific
chromosome translocations and certain subtypes of NHL, they can better
isolate the exact type of NHL present, which can lead to more rapid planning
and execution of treatment measures.
As stated, viral infections with some specific pathogens may also increase
the risk of lymphoma development. In addition to infection with HTLV-1 and
Epstein-Barr virus, hepatitis C virus has been associated with SMZL.
Immunodeficiency caused by HIV infection can also increase the risk of
lymphoma development; HIV infection has been present with some specific
types of lymphomas, including Burkitt lymphoma. There are also some other
immunodeficiency states that are not associated with viral infections but that
increase the risk of lymphoma development, such as with chronic use of
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immunosuppressive drugs. Celiac disease is also associated with an
increased risk of malignant lymphoma.26
Lymphomas that arise out of MALT tissue may be more likely to develop due
to chronic inflammation, particularly that associated with autoimmune
disorders. Sjögren’s syndrome, which affects the mucous membranes, may
lead to chronic inflammation that increases an individual’s risk of developing
MALT-associated lymphoma. Studies have shown that Hashimoto thyroiditis,
an autoimmune condition in which the body attacks the thyroid gland, is
present in up to 56 percent of patients with primary thyroid lymphoma.26
On average, most people who develop lymphoma are over 50 years of age,
except in certain subtypes of lymphoma that primarily affect children and
adolescents. Men are more likely than women to develop most types of nonHodgkin lymphoma, although there are some subtypes that affect women
more frequently than men. However, although these risk factors are
associated with greater potential for NHL development, there are always
individuals who have none of these factors and yet who still develop NHL;
alternatively, there are those who develop NHL and who also have several of
these risk factors, which is why the exact causative factors behind this type
of cancer still remain somewhat elusive.
Signs and Symptoms
Non-Hodgkin lymphoma presents with signs and symptoms associated with
a disease process that has affected the lymphatic system. The symptoms
may be mild or significant, depending on the location of the cancer, how
quickly the tumor is growing, and whether surrounding tissues or organs are
affected. The characteristic sign of NHL is the presence of enlarged, painless
lymph nodes, which can develop in any of the lymph nodes of the body. The
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nodes are non-tender when compared to the painful nodes associated with
bacterial infection. Instead, lymph nodes associated with NHL grow in size
without necessarily being detected until they become large enough that they
are easily palpable. The enlargement lasts for weeks and does not resolve on
its own. Other symptoms may be non-specific and include anorexia, night
sweats, weight loss, weakness or fatigue, easy bruising, and an increased
rate of infections.
The patient who develops lymphoma in lymph nodes within certain areas of
the body, such as in the chest or abdomen, may also demonstrate
symptoms associated with lymph node enlargement in these areas. For
example, a lymph node in the chest cavity may become large enough
because of NHL that it compresses surrounding structures, such as the
bronchus or the lung tissue, causing cough or difficulty breathing.
Enlargement of the thymus gland in the chest can cause chest pain if it
presses on the sternum bone.27 Hepatomegaly or splenomegaly may also be
noted upon exam, particularly with more aggressive forms of lymphoma.
Skin lesions, rash, and itching are characteristic signs associated with
cutaneous lymphomas.
Diagnostic Measures
Excisional lymph node biopsy is the standard method of removing tissue for
examination for potential lymphoma. As previously discussed, excisional
lymph node biopsy involves removal of a lymph node to assess its structure
and to evaluate any changes that may have occurred within the tissue
because of the effects of the tumor. When diagnosing lymphoma, this type
of biopsy is the only acceptable method that will obtain enough tissue for
adequate analysis.26 Fine-needle aspiration and needle core biopsies
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typically do not provide enough tissue samples to be able to make a
diagnosis with certainty.
Immunophenotyping is a diagnostic method that identifies specific proteins
on the surface of cells and that can be employed to identify the types of
lymphoid tumors present. This is a valuable diagnostic method when
working with non-Hodgkin lymphomas, as there are so many types and
subtypes of the disease. Immunophenotyping not only identifies the correct
type of tumor, but it also assists with classifying the stage of the disease.
Each tumor cell contains various cell surface markers; when appropriately
identified, these markers pinpoint the type of tumor present and can then
guide the healthcare provider toward the best method of treatment for the
patient’s condition.
Flow cytometry is a process of identifying cell markers present on tumor
cells, as well as recognizing the number of cells present within an area. It is
useful for locating the specific types of cells to be able to stage the cancer,
based on location of the cells in the body. Flow cytometry exposes cells to
antibodies that are tagged with fluorescent markers and that bind to their
matching antigens on the tumor cells. The markers can then be identified
when bound to antigens, which distinguishes the location and the number of
cells with a particular antigen, including tumor cells. The fluorescent markers
that are used cause the affected cells to give off light when they are passed
in front of a laser. This particular type of cell identification is useful in
pinpointing the exact type of lymphoma, especially when the patient’s
symptoms and clinical signs indicate other possible diagnoses. For instance,
enlarged lymph nodes may be indicative of some other type of disease
process, including Hodgkin lymphoma, which is similar but still requires a
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different type of treatment. Use of flow cytometry can better isolate the
exact type of cell antigen to be able to guide treatment.
Immunohistochemistry is another method of identifying cell phenotypes to
identify certain B cells within a sample. The process uses labeled antibodies
to distinguish certain biomarkers expressed from abnormal B cells that could
be cancerous. The antibodies that are labeled have corresponding antigens
that can be identified, if they are present. When present, the marked
antibodies appear as different in color when viewed microscopically. This
method of analysis is often employed to identify the specific subtypes of NHL
when lymphoma has been diagnosed but the exact type of lymphoma must
still be determined.30
When a patient presents with enlarged lymph nodes that could be indicative
of NHL, a CT scan of the affected area may be warranted to visualize the
lymph nodes and to assist with staging of the disease after biopsy results
have been obtained. The CT may also be included when the patient presents
with a tumor that has affected certain body regions, such as the abdomen or
the chest, and if the patient is having abnormal symptoms in that area, such
as enlarged abdominal girth, hepatomegaly, or splenomegaly.
Once the type of lymphoma is confirmed through biopsy or lymph node
dissection, the cancer is staged according to the amount of tissue involved
and whether it has spread beyond its initial location of tumor growth.
Staging is typically done through the Ann Arbor staging system as listed
below.
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
Stage 1:
Non-Hodgkin lymphoma is found in the initial lymph node or it is
found in a lymph organ, such as the spleen or the thymus; or the
cancerous tissue has been found in one organ outside of the lymph
system.

Stage 2:
Non-Hodgkin lymphoma is found in a region near to the initial site
where the cancer was found. This is described as cancerous tissues
in two or more lymph nodes on the same side of the diaphragm;
and means that at least two lymph nodes above the diaphragm are
affected or at least two lymph nodes below the diaphragm are
affected. Alternatively, stage 2 may be considered if the cancer has
spread from its initial lymph node to a nearby organ.

Stage 3:
Non-Hodgkin lymphoma is found in lymph nodes both above and
below the diaphragm, and it may have spread to either a nearby
organ from the original site or it has spread to the spleen.

Stage 4:
Non-Hodgkin lymphoma has spread to one or more organs outside
the lymphatic system, or it is found in at least two areas that are
distant from the initial site (not just in the lymph nodes closest to
the original site); or it has been found in an area such as the liver,
the bone marrow, or the lungs.
Staging requires analysis of lymph nodes beyond the initial site of tumor
development. This may require further biopsies to determine the extent of
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the illness, including biopsy of other tissues beyond the lymph nodes. Biopsy
to determine the degree of cancer present may involve taking tissue
samples from surrounding organs or performing a bone marrow biopsy to
check how far the malignant cells have spread.
Treatment
There are several types of treatment options for non-Hodgkin lymphoma.
The method of choice will depend on the patient’s health status, the stage of
the disease, and whether the cancer is considered to be aggressive, very
aggressive, or indolent. Other factors to consider include the phenotype of
the lymphoma, such as whether it is B cell or T-cell lymphoma, the patient’s
age, and any other complications that have occurred as a result of the
cancer or underlying disease processes, including patient history of HIV
infection or the presence of autoimmune diseases. The most common forms
of treatment are through chemotherapy, radiation, immunotherapy, and
certain types of medication.
Among patients with indolent forms of lymphoma, studies have shown that
radiation treatment alone is just as effective and provides positive overall
outcomes as compared to combined radiation with chemotherapy.26
Radiation, when given for local control of non-Hodgkin lymphoma, is the
first-line course of treatment and is the most effective modality in slowgrowing lymphomas that have not spread far beyond their initial site of
growth. According to an article in the International Journal of Radiation
Oncology that explains treatment guidelines from the International
Lymphoma Radiation Oncology Group, radiation treatment alone can be
curative for those patients with localized indolent lymphoma and it is also
considered for those with more aggressive forms of lymphoma that is
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refractory to chemotherapy or for those who cannot undergo chemotherapy
because of serious comorbid conditions.39
Chemotherapy may also be used successfully for some patients with indolent
forms of lymphoma, although it should be noted that long-term use of
chemotherapy for this type of cancer, because it is slow growing,
progressively becomes less effective over time. The repeated administration
of chemotherapy may eventually cause resistance in the patient’s body.26
This may explain, in part, why many forms of indolent lymphomas are
actually not curable, but are instead managed. Their slow growth still can
lead to a long-term favorable prognosis if the tumor does not progress far
beyond the initial lymph node site. However, for those with indolent forms of
lymphoma who are not diagnosed until late stages of the disease, the
prognosis is not as favorable and the condition cannot be cured.
Chemotherapy is a standard form of treatment for non-Hodgkin lymphoma.
It is typically administered intravenously, although there are some forms
that are given as oral formulations. Chemotherapy is administered in cycles,
in which the patient receives one or more agents, typically on an outpatient
basis and on a schedule over several weeks; the patient then undergoes a
rest period. Each cycle may be repeated, depending on the prescribed
course of the treatment and whether the patient’s body is responding to the
treatment. The patient may also receive a combination of drugs for several
cycles, but if the chemotherapy is not having much of an effect on the
cancer, the healthcare provider may change the formulation and may
prescribe a different combination of chemotherapeutic agents. Some forms
of intensive chemotherapy are administered intravenously over a shorter
period of time, but they require hospitalization for the affected patient.
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A single type of chemotherapy is often used to treat lymphomas that are
found within stages 1 or 2. Some agents used as single therapy include
doxorubicin and chlorambucil. As the cancer progresses and reaches stage 3
or 4 of the disease, chemotherapeutic agents are combined and
administered during the same treatment session. Combination
chemotherapy may be used as one of several types, which often involves
combining different forms of drugs to administer them together. For
instance, some chemotherapy drugs are classified as alkylating agents,
some are anti-metabolites, and some are purine analogs. Combination
chemotherapy may use one or more drugs from these different categories to
treat lymphoma.
Currently, there are various combinations of chemotherapy used to manage
indolent lymphoma, including CHOP (cyclophosphamide,
hydroxydaunomycin, Oncovin®, and prednisone), and CVP
(cyclophosphamide, vincristine, and prednisone). The goal of chemotherapy
in patients with indolent lymphoma is to achieve a state of remission so that
the affected patient can continue to live a normal and healthy life once the
chemotherapeutic regimen is complete.
External beam radiation therapy is a second method that can be successfully
used to manage indolent forms of lymphoma. Once the location of the tumor
has been identified, radiation is used to target and destroy the cancerous
cells. It is advantageous in that it can be administered as outpatient therapy
for several sessions and it typically produces fewer side effects when
compared to chemotherapy, although many patients who undergo radiation
treatments can have skin changes or may have discomfort following the
radiotherapy. Although the actual procedure is typically painless, the effects
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of instilling radiation into the patient’s body for the purposes of eradicating
tumor cells can cause long-standing consequences.
Treatment of more aggressive forms of lymphoma typically involves
combination chemotherapy with CHOP. Early stages of aggressive
lymphomas often involve combination chemotherapy and external beam
radiation therapy. Although CHOP is the main type of chemotherapy
combination used for management of more aggressive forms of lymphoma,
other combinations of drug therapy may also be successfully employed as
well, depending on the type of lymphoma.
A 2014 study published in the journal Leukemia & Lymphoma considered a
regimen of chemotherapy agents that is highly effective but with the least
toxicity for treatment of relapsed and refractory diffuse large B-cell
lymphoma. The patients in the study were treated with a combination of
cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin
(COAD-B). The overall response rate of the patients who received this
combination was 70.7 percent, while the average remission rate was 13
months.40 The study indicates that other forms of chemotherapy are
available and could be successfully used in place of CHOP; the type and
amounts of drugs to include are based on whether the patient has previously
been treated with chemotherapy or if there are contraindications to using
specific formulations.
The CHOP combination, along with intravenous rituximab, is recommended
for patients with more advanced stages of aggressive lymphomas. Those
who are given rituximab along with CHOP, a monoclonal antibody specifically
directed to target cells with CD20 antigens, have been shown to have better
outcomes when compared to those who have not been given rituximab.27
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Again, this further supports the idea that combination therapies tend to be
more successful than using a single agent, however, because each patient is
different in terms of location of the primary tumor site and of cancerous
spread, as well as because of the many different subtypes of non-Hodgkin
lymphoma that are possible, combination therapy may work for a majority
but may not necessarily be beneficial for everyone.
Immunotherapy is another form of treatment that may be included in
addition to or in place of chemotherapy and radiation for some forms of
lymphoma. Monoclonal antibody therapy, which targets specific antigens on
cancer cells so that they can be destroyed, has been shown to be helpful
with some forms of lymphoma. As stated, rituximab (Rituxan®) is a type of
monoclonal antibody that may be administered with chemotherapy because
it targets lymphoma cells with CD20 antigens. Alemtuzumab (Campath®) is
another type of monoclonal antibody that is administered to target CD52
antigens. It is used in some types of T-cell lymphomas as well as with
treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.
CD30 is a type of molecule that is sometimes seen on the surface of
lymphoma cells. Brentuximab vedotin (ADCETRIS®) is a drug given that
acts against CD30; it has been approved for treatment of patients who have
undergone stem cell transplant to get rid of any remaining cancer cells.42
Monoclonal antibodies can be quite beneficial for some patients with specific
types of lymphoma, however, they can also cause some side effects,
including neuropathy, an increased risk of infection, fatigue, and fever.
When combined with chemotherapeutic agents, use of monoclonal antibodies
is favorable but side effects must be considered and accounted for as well.
Monoclonal antibodies may also be used as a type of radioimmunotherapy,
in which the antibody is bound to an isotope. These two items work in
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tandem to kill lymphoma cells; the antibody searches out the antigens of the
cancerous cells and the isotope destroys the cells once they are found.
Types of immunotherapy drugs used specifically for the treatment of nonHodgkin lymphoma include ibritumomab tiuxetan (Zevalin®) and
tositumomab (Bexxar®).
Interferon alpha is another form of immunotherapy that may be
incorporated into treatment of some types of non-Hodgkin lymphoma.
Interferon alpha is a synthetic form of interferons that are made by the
immune system and that reduce the growth and spread of cancer cells. This
type of immunotherapy does not kill the tumor cells; instead, it boosts the
immune system to reduce the growth of tumor cells. While still considered
experimental, interferon alpha may be a potential method that could be used
to successfully treat certain types of lymphoma.
A study by Gyan, et al., in the Annals of Hematology showed that
administration of interferon alpha to patients with relapsing follicular
lymphoma resulted in an overall response rate of 68 percent. The interferon
alpha was administered alone in some cases and combined with rituximab in
others; the average time of progression-free survival was 20.9 months for
those who received interferon alpha only, and 48.7 months for those who
received it combined with rituximab.41 There are some further promising
studies directed at treating non-Hodgkin lymphoma that are being met with
some success, but many new and experimental therapies require additional
testing and research to be deemed effective.
When high doses of chemotherapy destroy cancerous cells, they may also
destroy healthy cells as well. The affected patient is then at risk of such
problems as anemia, bleeding, or infection if blood cells are destroyed as
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part of lymphoma treatment. Bone marrow or stem cell transplantation can
be included as part of treatment to replace some of the healthy cells that
have been destroyed. Samples are often harvested prior to high-dose
chemotherapy and then are stored until needed. Autologous transplant uses
the patient’s own stem cells for transplant, while an allogeneic transplant
uses stem cells from a donor. When allogeneic transplant occurs, the patient
is at greater risk for transplant rejection; the cell markers on the donor cells
must be compatible with the antigens on the recipient.
Following high-dose chemothearpy, many of the cancer cells have been
eliminated, but because of the strength of the chemotherapy, many normal
cells in the bone marrow have been killed as well, and the body has
difficulties forming new blood cells. This is why stem cell transplant would be
necessary; to replace many of the cells that were destroyed by
chemotherapy. The patient receives the transplant through an infusion of the
stem cells. If an allogeneic transplant occurred, the patient would most likely
receive some form of anti-rejection drug as well. The patient is also at
significant risk of infection, and may require isolation for a period of time
following the transplant until he has recovered enough and is able to
maintain a normal number of white blood cells again.
In some cases of indolent lymphoma, watchful waiting is a potential
management strategy. This holds true among asymptomatic cases and
particularly within older adults. Watchful waiting defers therapy for a period
of time to monitor the patient’s condition, unless the cancerous cells spread
or the patient develops signs or symptoms of disease progression. In most
cases, watchful waiting is not a complete type of cancer management; it can
only be done for a limited time before the patient will need to undergo actual
cancer treatment. However, the amount of time to wait varies between
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patients depending on the rate of cancer growth. Some patients may defer
treatment for months or years because they have a type of lymphoma that
is very slow to spread. Alternatively, some patients may start out with
watchful waiting but then may need to start treatment after only a few
weeks or months.
The International Prognostic Index (IPI) is a clinical tool that has been
designed to determine the prognosis of patients diagnosed with non-Hodgkin
lymphoma. The IPI was developed in 1993 by a group of oncologists to
identify those factors that would affect the prognosis of a patient diagnosed
with aggressive non-Hodgkin lymphoma. It was initially developed to
determine prognoses of patients diagnosed with aggressive forms of NHL,
but it has since been found that the IPI is also useful for determining the
outlook for patients with other, slow-growing forms of lymphoma as well.
The IPI considers several factors that can impact a patient’s prognosis when
diagnosed with lymphoma. The factors include:27
1. Patient age Those over age 60 have less positive of prognosis when compared to
younger patients.
2. Lymphoma stage Persons diagnosed with stage 1 or stage 2 lymphoma typically have a
better prognosis, as opposed to those who are diagnosed in later
stages (stage 3 or stage 4) of the disease.
3. Involvement of extra nodal sites This describes the extent of how far the cancer has spread. In general,
those who have developed lymphoma that has stayed within the
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primary site of growth and that has not spread to other areas have a
more favorable prognosis when compared to others who have had
lymphoma cells spread to other lymph nodes and to other organs,
such as the spleen, the liver, or the bone marrow.
4. The patient’s performance status This describes the effect the lymphoma has had on the patient’s ability
to continue with normal activities. If the cancer has affected an
individual’s activities of daily living, his or her performance status is
lower, and the prognosis is not as favorable as compared to someone
whose cancer symptoms have not affected his activities.
5. Serum lactate dehydrogenase (LDH) levels Elevated serum LDH levels can be indicative of an aggressive form of
lymphoma. Persons with lymphoma who have normal LDH levels have
a better prognosis than those who have elevated LDH levels.
To score the IPI, each factor receives a score of “1” when it is a poor factor.
For instance, a patient with an elevated LDH level would receive a score of
“1” for that factor, but someone under age 60 would not receive a score for
that factor. The scores are totaled and the patient’s prognosis is assigned to
a category, depending on the final score. The scores and their subsequent
risk factors are as follows:
Low Risk: IPI score of 0 to 1
Low/Intermediate Risk: IPI score of 2
Intermediate/High Risk: IPI score of 3
High Risk: IPI score greater than 4
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A lower score indicates a lower risk of complications and is therefore
associated with a greater prognosis and a better five-year survival rate.
Alternatively, a higher IPI score indicates a higher risk of problems and is
associated with a less favorable prognosis and a poorer five-year survival
rate. A revised version of the IPI has also been developed, which takes into
consideration some of the more recent forms of treatment that have been
developed for lymphoma, such as some types of immunotherapy. The
revised IPI uses the same prognosis factors but narrows down the scores to
only three:

Very good prognosis (no poor prognostic factors)

Good prognosis (0 to 2 prognostic factors)

Poor prognosis (3 or more prognostic factors)
Although the IPI is useful for many types of NHL, it has not been shown to
be quite as accurate when dealing with follicular lymphomas. As a result,
similar efforts were made to specifically address factors associated with this
type of lymphoma. The Follicular Lymphoma International Prognostic Index
(FLIPI) was developed to better determine outcome for patients with
follicular lymphoma. The prognostic factors for FLIPI include those listed
below.
1. Age:
As with IPI, persons younger than age 60 have a more favorable
prognosis than those over age 60.
2. Stage of lymphoma:
Those with stage 1 or stage 2 lymphoma at diagnosis have a better
prognosis than those with later stages of the disease.
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3. Blood hemoglobin levels:
Patients with serum hemoglobin levels at or above 12 g/dL have a
better prognosis than those with levels less than 12 g/dL.
4. Number of lymph nodes affected:
When fewer than 4 lymph nodes are affected, the patient has a
better prognosis than when 4 or more lymph nodes are affected.
5. Serum LDH levels:
Lower serum LDH is associated with a good prognosis; and,
elevated LDH levels are associated with a poor prognosis.
Similar to IPI, FLIPI assigns a point to each poor prognosis factor and
calculates the total score to determine the patient’s overall outlook:

Low risk: 0 to 1 poor prognostic factors

Intermediate risk: 2 poor prognostic factors

High risk: 3 or more poor prognostic factors
As with determining prognosis based on IPI factors, the FLIPI score is also
associated with overall patient outcome and five-year survival rate. A low
risk with fewer poor prognostic factors is associated with a better five-year
survival rate when compared to a high risk of complications and 3 or more
poor prognostic factors. Over the years, much progress has been made in
determining the causes, risk factors, diagnostic methods, and appropriate
forms of treatment for non-Hodgkin lymphoma. Researchers have made
considerable advancements in the field of treatment for this type of cancer
and although risk factors and complications remain, many people who are
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diagnosed with NHL at an early stage are able to complete treatment and go
on to live healthy lives.
Hodgkin Lymphoma
Hodgkin lymphoma is a specific type of cancer that develops in the
lymphatic system. It differs from non-Hodgkin lymphoma in how the cells
act and in how they spread. The condition can begin almost anywhere in the
body where there are lymph nodes or lymphatic vessels, although it most
commonly develops in the upper part of the body, including in the axillae,
chest, and neck. According to the American Cancer Society, over 9000 new
cases of Hodgkin lymphoma were identified in the United States in 2015 and
the condition led to about 1150 deaths.25 Hodgkin lymphoma typically
spreads through the lymph system and rarely enters the bloodstream to
circulate. If the cancerous cells do eventually circulate in the bloodstream, it
occurs during a late stage of the disease. When this happens, the cancerous
cells then metastasize through the bloodstream to ultimately grow and
spread in other organs beyond the lymphatic system.
Types of Hodgkin Lymphoma
Hodgkin lymphoma is actually classified according to one of two different
types, depending on the appearance and behavior of the affected cells:
classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin
lymphoma. Classic Hodgkin lymphoma originates from Reed-Sternberg cells,
which are almost always abnormal B cells that have developed and are no
longer able to produce antibodies. They differ in appearance from regular B
cells and are typically much larger in size. Rarely, Reed-Sternberg cells may
develop from T cells that have also developed abnormally; this presentation
occurs in up to 2 percent of cases of Hodgkin lymphoma.52
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The classic form of Hodgkin lymphoma is further subdivided into four
different classifications, as listed below.54
1. Nodular sclerosis Hodgkin lymphoma (NSHL):
This is the most common form of classic Hodgkin lymphoma,
comprising up to 80 percent of all cases. The condition is more
likely to affect adolescents and young adults in comparison to
middle-aged or older adults. Tissue samples analyzed from NSHL
often show characteristic nodule patterns with thickened bands of
tissue. Its most common site of development is in the mediastinum
and in areas above the diaphragm, with many affected lymph nodes
becoming enlarged in the face or in the neck.
2. Mixed cellularity Hodgkin lymphoma (MCHL):
Although it can occur at any age, this type of classic Hodgkin
lymphoma is more commonly seen among older adults. It occurs in
15 to 30 percent of total cases of Hodgkin lymphoma and frequently
appears in the lymph nodes in the abdomen or in the spleen. MCHL
is also more commonly seen among patients with HIV infection who
have immunosuppression.
3. Lymphocyte-rich Hodgkin lymphoma (LRHL):
This type does not usually spread very far from its initial lymph
nodes. It may present in a manner similar to that seen with MCHL,
which is why it requires distinctive diagnostic testing to clarify
between the two types in order to facilitate the most appropriate
treatment. LRHL makes up approximately 5 percent of cases of
Hodgkin lymphoma.
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4. Lymphocyte-depleted Hodgkin lymphoma (LDHL):
This type of the condition is more commonly seen among older
adults. It may involve lymph nodes in various locations throughout
the body and it is often not detected until later in the course of the
disease. As with MCHL, this form of lymphoma is also more
commonly seen among patients with HIV infection who are
immunosuppressed and it is also associated with Epstein-Barr virus
infection. It is not as common as other types of classic lymphoma
and it typically accounts for less than 1 percent of all cases.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is the second
form of Hodgkin lymphoma in addition to the classic form of the disease. In
many cases, this type of lymphoma does not contain any Reed-Sternberg
cells at all; instead, its cells are made up of a variation of cells called
popcorn cells, which are so named because of their appearance. NLPHL
makes up approximately 5 percent of total cases of Hodgkin lymphoma. It is
similar in appearance to LRHL and so tissue samples must be examined
microscopically to verify the presence of its specific type of cells before
making a diagnosis.
Causes and Risk Factors
Studies have shown that certain risk factors increase a person’s chance of
developing Hodgkin lymphoma, including age during adolescence or young
adulthood as well as older adulthood, male gender, and family history. Some
people who have had a previous infection with Epstein Barr virus have also
been shown to be at higher risk of the condition. The reasons for this
connection are not entirely clear, although some people who have been
diagnosed with Hodgkin lymphoma have also had evidence of Epstein Barr
virus within their Reed-Sternberg cells. This has not been seen in all patients
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with Hodgkin lymphoma, and not all people who contract the Epstein Barr
virus will develop Hodgkin lymphoma. Research has shown that the
association between the two conditions is approximately 30 percent of
cases.54
There are no generalized screening tests that can specifically identify
Hodgkin lymphoma before it develops. To appropriately diagnose the
condition, a thorough history and physical examination and imaging studies
are necessary, as well as histologic examinations following biopsy to verify
the characteristics of the Reed-Sternberg cells. These cells actually only
make up approximately 1 to 2 percent of the total tumor mass, with the rest
of the tumor cells comprising a variety of reactive inflammatory cells.53
Reed-Sternberg cells express specific antigens on their cell surfaces, so that
immune cells can recognize and attack them when they develop. However,
when these cells proliferate to the point that they cannot be controlled, the
lymphoma condition is said to have developed and it must be managed
through external treatment. The Reed-Sternberg cells typically express
either CD30 or CD15 antigens, which are often targeted through specific
types of treatment interventions.
Signs and Symptoms
People who develop Hodgkin lymphoma demonstrate the characteristic sign
of asymptomatic lymphadenopathy, which occurs as enlarged, painless
lymph nodes in one or more areas of the body. The appearance of a
painless, enlarged lymph node differs from that of an enlarged node
associated with infection or inflammation, which often feels tender and
painful when illness is present. Other symptoms that may be associated with
Hodgkin lymphoma are often non-specific and could be caused by another
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condition. Examples include fever, which may be intermittent but is
unrelated to another condition, such as a fever, weight loss of at least 10
percent of total weight over the past six months, and night sweats, which
together are referred to as “B” symptoms. The patient may also experience
general feelings of fatigue or anorexia. Other features may be associated
with the disease developing within specific regions, including cough, chest
pain, shortness of breath, back pain, splenomegaly, hepatomegaly, or
neuropathy.
Diagnostic Measures
Following diagnosis, the physician then determines whether the cancerous
tissue has spread to other areas. Because it is rare for Hodgkin lymphoma to
spread to the bloodstream, it is more likely that if the condition has spread,
it has moved through the lymphatic vessels. The healthcare provider will test
surrounding lymph nodes and lymph tissue to determine if there is evidence
of Hodgkin lymphoma in these cells as well. A complete blood count can
determine if the patient has low white or red blood cell levels, further
laboratory testing may also reveal changes in lactate dehydrogenase, in
which an elevated level has been associated with greater incidence of the
disease; as well as for the presence of infectious diseases, including HIV
infection and previous infection with Epstein Barr virus. When combined with
an evaluation of the patient’s prognostic factors, the diagnosing medical
provider can then stage the extent of the illness.
Once diagnosis has been made, the condition is staged to determine the
extent of involvement. The staging system most often used is the Ann Arbor
staging system, which is divided into four levels, according to the extent of
the disease and whether it has spread to surrounding areas. The staging
system is the same as what was described for staging of non-Hodgkin
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lymphoma and it describes each stage in terms of the location and the
number of lymph nodes involved. For the purposes of staging, it should be
noted that the spleen is considered to be a lymph node area that would be
included if tumor cells have infiltrated the organ.54
Treatment
There are various methods of treatment commonly used for management of
Hodgkin lymphoma, including chemotherapy, radiation, stem cell transplant,
or other types of medications. The overall goal of treatment is to place the
patient into a state of long-term remission, and based on current medical
therapies, there is often a relatively good chance of this occurring for many
patients. Even for those patients who do not achieve complete remission,
long-term control of the disease without its further spread is a viable goal for
many individuals and may lead to years of stable health and control of
symptoms.
Chemotherapy and radiation are the two most common methods. They may
be used individually or may be combined. Combination chemotherapy
protocols for this specific form of cancer often follow a method known as
ABVD, which refers to the types of drugs administered and the order of their
administration. The order of the drugs in the protocol includes Adriamycin®,
bleomycin, vinblastine, and dacarbazine.26 While administration of
chemotherapy is often quite effective in treating Hodgkin lymphoma,
chemotherapy also typically produces various side effects, some of which
can be severe, including thrombocytopenia, nausea and vomiting, hair loss,
mouth sores, fatigue, and an increased risk of infection. Most of the time,
these infections resolve after a short period of time, however, some patients
struggle with side effects so much that they discontinue treatment
prematurely.
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Those who undergo the ABVD protocol are at greater risk of long-term
complications, including infertility, cardiac and lung damage, and an
increased risk of developing another form of cancer, such as leukemia. There
are also other potential regimens that may be used instead of ABVD,
depending on the patient’s stage and the location and bulk of the tumor.
Other available therapies used include BEACOPP (bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone);
MOPP (mechlorethamine, vincristine, procarbazine, prednisone), and the
Stanford V (doxorubicin, vinblastine, mustard, bleomycin, vincristine,
etoposide, prednisone).54 Each of these combinations are administered
intravenously and each has their own benefits and disadvantages; each
combination must be considered for individual patient selection as the most
appropriate form of treatment based on the patient’s condition.
Radiation therapy is another form treatment for Hodgkin lymphoma,
although it is most frequently combined with chemotherapy, either during
each phase of chemotherapy administration or immediately following the
chemotherapy cycle. Radiation is typically administered as external beam
radiation, which is delivered through frequent sessions over a short period of
time. It is most often administered in conjunction with chemotherapy, as the
combination of the two types of treatments has been shown to be more
effective than either treatment used alone.25
Radiation, while effective, can cause many uncomfortable side effects,
including skin burns, fatigue, nausea, diarrhea, and low blood cell counts,
which could lead to anemia or an increased risk of infection. Depending on
the area of the body, radiation may cause side effects associated with a
particular body system. For example, a person who has enlarged lymph
nodes due to lymphoma in the neck may receive radiation in that area, but
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this form of treatment can also later cause swallowing problems and chronic
xerostomia because of damage to the salivary glands in the jaw. Because of
the associated side effects, a patient with Hodgkin lymphoma often first
requires imaging studies to closely pinpoint the location of the tumor so that
the radiation can be directed to the specific site in order to minimize side
effects. Termed involved field radiation or involved site radiation therapy,
the external beam directly pinpoints the affected lymph nodes to minimize
damage from the radiation to the surrounding tissues.
As with non-Hodgkin lymphoma, Hodgkin lymphoma may also be
successfully managed with medications such as monoclonal antibodies,
including ADCETRIS® and rituximab. As stated, these drugs are synthetic
versions of the antibodies created by the body to fight off the effects of
antigens. Monoclonal antibodies are designed to attack specific antigens
because they can identify certain molecules on the cell surfaces. For
instance, ADCETRIS is an anti-CD30 drug that identifies tumor cells with the
CD30 molecule on their cell surface; when it targets these specific cells, it
kills them when they try to divide. Rituximab has also been used with
success among Hodgkin lymphoma patients, as it specifically attacks
antigens with the CD20 molecule on their cell surfaces. Rituximab may be
more commonly used among patients with nodular lymphocyte-predominant
Hodgkin lymphoma (NLPHL) form of the disease.
When a patient undergoes chemotherapy with or without radiation and does
not achieve complete remission or his or her disease or is unresponsive to
treatment, the next step is to administer high-dose chemotherapy and then
prepare for stem cell transplant. When lymphoma has not responded to
initial chemotherapeutic regimens, it is of little value to continue another
cycle of the same or similar regimen. Instead, high-dose chemotherapy,
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which will eradicate the tumor cells as well as the healthy cells of the bone
marrow, has been shown to be more effective in treating refractory Hodgkin
lymphoma.54 The patient who undergoes this type of chemotherapy as part
of treatment must then have a bone marrow stem cell transplant, whether
through previously collected samples of the patient’s own tissues or through
a donor, which will replace many of the blood cells that were destroyed
through high-dose chemotherapy.
The International Prognostic System (IPS) uses various prognostic factors to
determine a patient’s risk of developing Hodgkin lymphoma. The IPS uses
the following patient characteristics at diagnosis to consider prognosis:

Age over 45 years

Albumin < 4 g/dL

White blood cells > 15,000 mm3

Hemoglobin < 10.5 g/dL

Lymphocyte count < 6,000/mm3 or < 8% of the differential

Male gender

Stage 4 disease
Each factor, when present, is assigned one point. The amount of points is
calculated and the total number of points determines the risk.55 Based on
the IPS classification system, five-year survival rates for patients with the
applied risk factors are as follows:

0 factors: 84%

1 factor: 77%

2 factors: 67%

3 factors: 60%

4 factors: 51%

5 or more factors: 42%
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A patient’s prognosis may also be related to the stage of disease at which he
or she was diagnosed and started treatment. Patients who are diagnosed at
later stages of the disease have added risk of poor prognosis when
compared to those diagnosed at earlier stages. Rates of survival for patients
diagnosed with Hodgkin lymphoma are related to the stage identified at
diagnosis. Persons diagnosed in earlier stages of 1 or 2 have better
prognoses that those who are not diagnosed until the later stages, however,
Hodgkin lymphoma typically has a good overall prognosis and is often quite
curable.
The American Cancer Society has given the following five-year survival rates
for patients with Hodgkin lymphoma, based on the stage of diagnosis:25

Stage I: Approximately 90 percent

Stage II: Approximately 90 percent

Stage III: Approximately 80 percent

Stage IV: Approximately 65 percent
The survival rates for Hodgkin lymphoma are higher than they have ever
been due to continued advances in studies focused on its treatment. The
one-year survival rate of those diagnosed is 92 percent, while the ten-year
survival rate is 80 percent.25 When relapse does occur, it is most likely to
happen during the first three years after therapy, so frequent monitoring is
needed through patient history and physical examination, imaging
procedures, and laboratory studies to determine if signs or symptoms of the
disease has returned; and, if complications, whether due to the disease itself
or due to complications of treatment, have occurred so that they may be
quickly managed to prevent further consequences.
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Summary
The lymphatic system plays many important roles in maintaining normal
body function. The cells of the immune system are widely distributed
throughout the body and serve as defense mechanisms when foreign
organisms could potentially cause harm.
Through the lymphatic system, the body maintains surveillance for those
microorganisms that do not belong in the body or that increase the risk of
serious disease, such as with cancer cells. If cancer does develop, the
lymphatic system can serve as a channel for transporting cells from the site
of the original tumor to different areas for growth to continue, resulting in
metastasis. However, this is offset by the lymphatic system’s ability to fight
and destroy potentially harmful cells and to keep them from proliferating.
Healthcare providers play a key role to determine the extent of the spread of
cancerous cells when they have invaded the lymph nodes. Although the
lymph nodes may be affected by the spread of cancer and there are specific
types of cancer that grow within the lymphatic system, continued
improvements in diagnostic measures and in treatment methods have
increased the potential for long-term positive outcomes of those diagnosed
with cancer of the lymphatic system.
The prognosis for an individual diagnosed with a cancer of the lymph system
is multifactorial, including the type and stage of disease, when the disease
was diagnosed and treatment started. Survival rates for patients also relate
to the disease type and stage identified at the time of diagnosis. The
American Cancer Society provides helpful information to clinicians and
patients relative to cancer prevention, diagnosis and survival rates. In the
case of Hodgkin lymphoma, the survival rate is higher than in previous years
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due to continued advances in studies focused on its treatment. Initial
diagnosis, treatment and relapse rates continue to influence patient
outcomes in the diagnosis of lymphoma cancer, and is an evolving area of
medical research and science that impacts the role of health providers and
nurses caring for patients diagnosed with a type of lymphatic cancer.
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1.
Tonsils differ slightly from other lymph nodes in the body in that
they lack
a) efferent collector vessels.
b) afferent vessels.
c) lymphocytes.
d) macrophages.
2.
True or False: Because of their locations within the thymus
gland, these white blood cells (lymphocytes) may be referred to
as thymocytes.
a. True
b. False
3.
Lymphopoiesis refers to
a. formation of new lymph vessels.
b. the activation or initiation of the immune response.
c. the movement of lymphocytes through circulation.
d. the creation of lymphocytes in the bone marrow.
4.
The __________ is a large lymph node that is positioned along
blood vessels.
a. medulla
b. thymus
c. spleen
d. tonsil
5.
Lymphoid organs are those that
a. develop lymphocytes and other cells that protect the body.
b. house the immune system cells.
c. contain macrophages and lymphocytes.
d. All of the above.
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6.
Involution refers to a process where
a. T lymphocytes mature.
b. the weight and size of the thymus shrinks.
c. hormones known as thymosins are secreted in the thymus.
d. T lymphocytes are transferred to other organs.
7.
Thymoma, a tumor arising from the thymus gland, is most often
associated with
a. a process known as involution.
b. thymic cancer.
c. myasthenia gravis.
d. an enlarged thymus gland.
8.
True or False: Among adults, thymectomy does not appear to
have a large effect on the immune system’s abilities.
a. True
b. False
9.
The ___________ are called mucosa-associated lymphoid tissue
(MALT)
a. myoid cells
b. tonsils
c. adenoids
d. endothelial cells
10. Which of the following is classified as a primary organ because
of its role in the production of lymphocytes?
a. Adenoids
b. Spleen
c. Tonsils
d. Thymus gland
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11. Some people with sleep apnea have particularly large
a. adenoids.
b. palatine tonsils.
c. lingual tonsils.
d. thymus gland.
12. The adenoids are also referred to as the
a. palatine tonsil.
b. lingual tonsil.
c. mucosa-associated lymphoid tissue.
d. pharyngeal tonsil.
13. Peyer’s patches are called lymphatic nodules instead of being
classified as lymph nodes because
a. they are found in the small intestine.
b. they are contained within follicles of lymphatic tissue.
c. they are not encapsulated as are lymph nodes.
d. they different in size and shape from lymph nodes.
14. Peyer’s patches are responsible for preventing harmful
microorganisms from
a. entering the gut.
b. invading the bloodstream.
c. entering the stomach.
d. entering the gastrointestinal tract.
15. Cancer metastasis specifically describes
a. the movement of cancerous cells beyond the primary tumor site.
b. the abnormal development of cells forming a primary tumor.
c. the body’s immune response to defend against cancerous cells.
d. the lymphatic system’s role in identifying cancerous cells
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16. The lymphatic system typically performs the function of
a. controlling fluid levels.
b. absorbing fats and fat-soluble vitamins.
c. protecting the body through immune system cells.
d. All of the above.
17. When cancerous cells travel to other locations and grow,
a. they always spread the same cancer to the new organ or location.
b. they always spread to the nearest organ first.
c. the cells may be slightly different, spreading a different cancer.
d. the metastatic cancer cells respond to treatment in the same way.
18. True or False: Lymph nodes and lymph fluid can be tested to
check whether the body has initiated an immune response to
defend itself against the cancerous cells.
a. True
b. False
19. Sentinel lymph nodes specifically describe the nodes that
a. produce lymphocytes.
b. are the closest to the growing tumor.
c. defend against cancerous cells.
d. are “secondary” lymphatic organs.
20. Elevated levels of transforming growth factor beta (TGF-) help
cancerous cells bypass lymphocytes by
a. sequestering red blood cells.
b. disguising cancerous cells as white blood cells.
c. causing antibodies to attack healthy cells.
d. coding a message to attack acetylcholine receptors.
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21. Lymphangiogenesis refers to
a. the creation of lymphocytes in the bone marrow.
b. the absorption of fats by the lymphatic system.
c. the formation of lymph vessels from pre-existing lymphatic vessels.
d. development of macrophages within the “primary” lymphatic organs.
22. Which of the following is a consequence of the fact that initial
vessels of the lymphatic system are highly permeable?
a. There is no central pump in the lymphatic system.
b. Fluid moves through the lymphatic system segment by segment.
c. Fat-soluble vitamins are not absorbed through the lymphatic system.
d. Cancerous cells may also enter the lymphatic network.
23. Vascular endothelial growth factor (VEGF) is
a. a protein that stimulates the formation of new lymph vessels.
b. a method associated with tumor growth.
c. non-protein a process that repairs diseased tissue.
d. a non-protein particle in the interstitial space.
24. Neuropilin-2 is normally associated with
a. the formation of new lymphatic vessels during the fetal period.
b. decreased tumor growth when present in increased quantities.
c. anti-lymphangiogenic factors.
d. the formation of new lymphatic vessels during adulthood.
25. When tumor cells are in the lymphatic system, they
a. do not develop into the mass seen in bulky tumors.
b. rarely spread from their primary site of growth.
c. may migrate through the lymph system, causing lymphoma.
d. All of the above.
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26. Lymphoma metastasis to the brain is rare because
a. the brain meninges is devoid of lymphatic vessels.
b. the brain and central nervous system lack lymphatic vessels.
c. the cervical lymph nodes are not connected to the lymphatic system.
d. None of the above.
27. When extracting tissue for a biopsy of lymph nodes,
a. the entire lymph node may be removed.
b. a small sample of tissue may be removed.
c. both a and b are correct.
d. None of the above.
28. True or False: Although lymphatic vessels do not play an
important role in dissemination of metastatic cancer cells, they
do provide pathways for tumor cells to travel.
a. True
b. False
29. Fine needle aspiration is a biopsy procedure best suited
a. for obtaining tissue samples from larger lymph nodes.
b. to diagnose primary lymphoma.
c. for use on lymph nodes located deep within the body.
d. for taking a tissue sample from a larger tumor.
30. According to one study, in what way is a core needle biopsy
more effective than a fine needle aspiration biopsy?
a. It is typically performed without anesthesia.
b. It always takes enough tissue sample to provide a diagnosis.
c. It does not require an ultrasound to locate the tissue.
d. It detects more cases of cancer in surrounding lymph nodes.
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31. ___________________ is the standard when attempting to
diagnose lymphoma.
a. Excisional biopsy
b. Needle aspiration
c. Core needle biopsy
d. Complete node removal
32. Excisional biopsy may be used
a. for biopsy but not to remove cancerous cells.
b. a sole source of treatment for eliminating cancerous tissue.
c. to remove some cancerous cells.
d. only for removal of an entire lymph node.
33. When cancer is found in a lymph node, what is the “tissue
margin”?
a. It is a ring of healthy tissue that is extracted during a biopsy.
b. It refers to the organ or tumor.
c. It is the area involved in the biopsy.
d. It is the area that is cancer-free.
34. In a biopsy to determine if cancer has spread past an initial
tumor, the surgeon will first remove
a. the largest lymph node.
b. the sentinel lymph node.
c. as many potentially involved lymph nodes as possible.
d. the smallest lymph node.
35. In order to help a clinician identify the sentinel nodes, the
clinician may
a. remove as many lymph nodes as possible.
b. use fine needle aspiration.
c. use radioactive material or dye.
d. use ultrasound.
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36. A patient is at risk of _______________ developing in the
surrounding tissue when lymph nodes are removed.
a. bleeding from the biopsy site
b. lymphedema
c. infection
d. All of the above
37. True or False: Lymph node biopsy may be performed to protect
against development of lymphedema.
a. True
b. False
38. Lymphedema
a. is usually curable if treated early.
b. is best treated by the patient resting the affected area.
c. may develop days to years after lymph node extraction.
d. is most common after sentinel lymph node biopsy.
39. Staging of cancer is done to determine
a. the size of the initial tumor.
b. the extent of the spread of cancer cells.
c. whether metastasis has occurred.
d. All of the above.
40. True or False: VEGF can contribute to more efficient transport of
tumor cells during metastasis.
a. True
b. False
41. Under the TNM staging system
a. the size of the tumor is not considered.
b. lymph node involvement is assessed.
c. the lower number indicates further involvement of tissue.
d. the regional lymph nodes are not assessed.
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42. Regulatory T cells (Tregs) perform what function?
a. They recognize and destroy cancer cells.
b. They stop effector T cells from attacking their own tissue.
c. They increase the number of T cells.
d. They detect cancer in surrounding lymph nodes.
43. Some cancer treatments may be ineffective because
a. of increased effector T cell responses.
b. tumor Tregs are absent in the tumor mass.
c. of elevated levels of Tregs working against the treatment.
d. of the release of cytokines by T cells.
44. One reason it is difficult to know if lymph nodes have cancerous
cells is that
a. elevated levels of Tregs cannot be tested.
b. cancerous lymph nodes may or may not be enlarged.
c. sentinel lymph node biopsies are indeterminate.
d. superficial lymph nodes are difficult to evaluate.
45. The ______________ method is used to determine the extent
(“stage”) of mesothelioma and the best course of treatment.
a. Brigham Staging System
b. TNM staging system
c. sentinel lymph node biopsy
d. lymph node dissection
46. Cancer immunosurveillance describes
a. how cancer cells recognize and destroy B lymphocytes.
b. the production of B lymphocytes in lymph nodes.
c. how cancer cells avoid immune cells.
d. how immune cells recognize and destroy cancer cells.
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47. Once the dendritic cells recognize the antigens they
a. mature while in the bone marrow before migration.
b. go through several changes before migration.
c. express cytokine receptors.
d. mature during migration to the lymphatic organs.
48. True or False: Dendritic cells lose their antigen-presenting
activity once they mature.
a. True
b. False
49. Mesenchymal stem cells may disrupt dendritic cells (DCs”) by
secreting factors that
a. block the release of chemokine from DCs.
b. inhibit their migration.
c. interrupt their maturation.
d. block the release of interleukin-10 from DCs.
50. When comparing non-Hodgkin lymphoma (“NHL”) to Hodgkin
lymphoma,
a. NHL is limited to upper body organs, unlike Hodgkin lymphoma.
b. Hodgkin lymphoma spreads through the bloodstream.
c. NHL is 5 times more common than Hodgkin lymphoma.
d. 85% of NHL originates in the T-cell.
51. Which of the following is NOT a classification of B-cell
lymphomas?
a. Slow-growing lymphomas
b. Aggressive lymphomas
c. very aggressive lymphomas
d. Involved lymphomas
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52. In general, lymphomas of small lymphocytes tend to
a. grow more rapidly.
b. be indolent and to grow more slowly.
c. be involved lymphomas.
d. be very aggressive lymphomas.
53. Follicular lymphoma describes a type of cancerous growth that
a. is a slow-growing form of NHL at all stages.
b. forms a circular pattern of growths in the lymph nodes.
c. aggressive at all stages.
d. is more common in young people.
54. Splenic marginal zone lymphoma (SMZL)
a. may cause anemia.
b. is always symptomatic of an enlarged spleen.
c. first forms outside the spleen.
d. is a common form of lymphoma.
55. One type of lymphoma is called B-cell lymphoma
a. because lymphoma does not occur in T-cells.
b. to distinguish it from the more common T-cell lymphomas.
c. because 85% of NHL originate in B lymphocytes.
d. only because of the WHO classification system.
56. True or False: Lymphedema is a painful, debilitating condition
that most often occurs following surgical procedures for breast
cancer surgery.
a. True
b. False
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57. Chronic lymphocytic leukemia (CLL) is an illness that
a. develops in the spleen.
b. grows in the lymph nodes.
c. develops in the blood and bone marrow.
d. is extremely aggressive.
58. Which of the following characterizes an indolent lymphoma?
a. aggressive
b. generally slow-growing
c. progresses quickly to the next stage
d. usually curable
59. ____________________ is the most common type of nonHodgkin lymphoma in the United States?
a. Diffuse large B-cell lymphoma (DLBCL)
b. Chronic lymphocytic leukemia (CLL)
c. Splenic marginal zone lymphoma (SMZL)
d. Follicular lymphoma
60. Which of the following types of lymphoma is so aggressive that
it can quickly cause death?
a. Burkitt lymphoma
b. Chronic lymphocytic leukemia (CLL)
c. Small lymphocytic lymphoma (SLL)
d. Follicular lymphoma.
61. Lymphoblastic lymphoma often forms in the
a. bloodstream.
b. bone marrow.
c. spleen.
d. thymus gland.
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62. Lymphoblastic lymphoma is more common among children
possibly because
a. B-cell tumors are more prevalent in children.
b. it originate in B lymphocytes.
c. the thymus gland is larger in young children.
d. the thymus gland is smaller in young children.
63. Small lymphocytic lymphoma (SLL)
a. develops in patients diagnosed with Hodgkin lymphoma.
b. develops in the lymph nodes and in the spleen.
c. is curable unlike chronic lymphocytic leukemia (CLL).
d. has no known treatment.
64. Cutaneous lymphoma is a form of T-cell cancer that primarily
affects what part of the body?
a. the thymus gland
b. axillary lymph nodes
c. the skin
d. tonsillar tissue
65. True or False: When mycosis fungoides is not treated, it may
spread to the liver.
a. True
b. False
66. _______________ causes patchy lesions on the surface of the
skin that can be confused with skin conditions such as eczema.
a. Anaplastic large cell lymphoma (ALCL)
b. Mycosis fungoides
c. Small lymphocytic lymphoma (SLL)
d. Lymphoblastic lymphoma
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67. How is Sezary syndrome different from mycosis fungoides?
a. Mycosis fungoides looks more like a sunburn.
b. Mycosis fungoides is a skin disease.
c. Sezary syndrome spreads more slowly.
d. Sezary syndrome involves most of the skin, not just patchy areas.
68. Adult T-cell lymphoma is a type of NHL that typically develops
following infection with
a. Hepatitis C virus.
b. H. pylori.
c. Epstein-Barr virus.
d. human T-lymphotropic virus, type 1 (HTLV-1).
69. Among patients with indolent forms of lymphoma, studies have
shown
a. that radiation treatment alone may be effective.
b. combined radiation with chemotherapy is needed.
c. long-term use of chemotherapy is most effective.
d. immunotherapy treatment alone is effective.
70. Fine needle aspiration is the standard method of removing
tissue for examination for potential lymphoma.
a) True
b) False
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Correct Answers:
1. b
21. c
41. b
61. d
2. a
22. d
42. b
62. c
3. d
23. a
43. c
63. b
4. c
24. a
44. b
64. c
5. d
25. c
45. a
65. a
6. b
26. d
46. d
66. b
7. c
27. c
47. d
67. d
8. a
28. b
48. b
68. d
9. b
29. d
49. c
69. a
10. d
30. d
50. c
70. b
11. c
31. a
51. d
12. d
32. c
52. b
13. c
33. a
53. b
14. b
34. b
54. a
15. a
35. c
55. c
16. d
36. d
56. a
17. c
37. a
57. c
18. a
38. c
58. b
19. b
39. d
59. a
20. b
40. a
60. a
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References Section
The reference section of in-text citations include published works intended as
helpful material for further reading. Unpublished works and personal
communications are not included in this section, although may appear within
the study text.
Cancer and Lymphatics Part I and Part II References
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2.
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3.
Stillerman, E. (2016). Modalities for massage and bodywork (2nd ed.).
St. Louis, MO: Elsevier Mosby
4.
Wardlaw, G., Smith, A. (2002). Contemporary nutrition (5th ed.).
Boston, MA: McGraw-Hill
5.
Miller, M., Newberry, R. (2010, Oct.). Microanatomy of the intestinal
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Retrieved from
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6.
Bäckhed, F., Crawford, P., O’Donnell, D., Gordon, J. (2007, Jan.).
Postnatal lymphatic partitioning from the blood vasculature in the small
intestine requires fasting-induced adipose factor. Proc Natl Acad Sci
104(2): 606-611. Retrieved from
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Mandard, S., Zandbergen, F., van Straten, E., Wahli, W., Kuipers, F.,
Müller, M., Kersten, S. (2005, Nov.). The fasting-induced adipose
factor/angiopoietin-like protein 4 is physically associated with
lipoproteins and governs plasma lipid levels and adiposity. The Journal
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of Biological Chemistry 281, 934-944. Retrieved from
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French, R. (2012). The complete guide to lymph drainage massage (2nd
ed.). Clifton Park, NY: Cengage Learning
9.
Falvo, D. (2014). Medical and psychosocial aspects of chronic illness
and disability (5th ed.). Burlington, MA: Jones and Bartlett Learning
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Hull, K. (2011). Human form, human function: essentials of anatomy
and physiology. Baltimore, MD: Lippincott Williams & Wilkins
11.
Kimball’s Biology Pages. (2011, Feb.). Histocompatability molecules.
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Buddiga, P. (2013, Sep.). Lymphatic system anatomy. Retrieved from
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13.
Matacia-Murphy, G., Sacher, R. (2015, Oct.). Splenomegaly. Retrieved
from http://emedicine.medscape.com/article/206208-overview
14.
McCance, K., Huether, S., Brashers, V., Rote, N. (2014).
Pathophysiology: the biologic basis for disease in adults and children
(7th ed.). St. Louis, MO: Elsevier Mosby
15.
Nishino, M., Ashiku, S., Kocher, O., Thurer, R., Boiselle, P., Hatabu, H.
(2006). The thymus: a comprehensive review. RadioGraphics 26(2):
335-348. Retrieved from
http://www.thymic.org/uploads/mainpdf/thethymus.pdf
16.
Sauce, D., Appay, V. (2011, Aug.). Altered thymic activity in early life:
how does it affect the immune system in young adults? Current Opinion
in Immunology 23(4): 543-548. Retrieved from
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17.
National Institute of Neurological Disorders and Stroke. (2015, Jul.).
Myasthenia gravis fact sheet. Retrieved from
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http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthe
nia_gravis.htm
18.
Non-Hodgkin’s Lymphoma Cyberfamily. Splenic marginal zone
lymphoma. Retrieved from
http://www.nhlcyberfamily.org/types/smzl.htm
19.
Thieblemont, C., et al. (2012, Feb.). Splenic marginal zone lymphoma:
current knowledge and future directions. Oncology, 2012. Retrieved
from http://www.cancernetwork.com/leukemia-lymphoma/splenicmarginal-zone-lymphoma-current-knowledge-and-future-directions
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