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 e- module 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 . 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 network. Understanding the role that the 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 1. differ slightly from other lymph nodes in the body in that they lack a. efferent collector vessels. b. afferent vessels. c. . d. macrophages. 2. True or False: Because of their locations within the 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 . 4. The ______is a large that is positioned along blood vessels. a. medulla b. thymus c. d. 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8 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 or that had a previous 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9 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 or ; 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11 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 at- risk 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 .18 The condition typically involves the spleen and the bone marrow and it often resembles hairy cell leukemia in several of its features. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12 The marginal zone describes the boundary between lymphoid and non- lymphoid 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 , 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15 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 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16 A review by Sauce and Appay in Current Opinion in Immunology evaluated studies about the effects of thymus disease, abnormal fetal thymus development, or 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22 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 non- existent 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 . 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 . 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 23 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25 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 fat- soluble 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29 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 , as these are considered sentinel lymph nodes nearest to the breast tissue; alternatively, 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 30 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31 Lymphangiogenesis, or the formation of new lymph vessels from pre- existing 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 32 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 33 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34 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 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 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 36 Lymph Node

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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37 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 and is considered a surgical procedure. Excisional biopsy requires at least 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 38 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 39 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 40 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 41 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 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 42 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 to be tested, sometimes while the surgical team waits for results. The nodes are

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 43 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 44 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 45 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 46 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 47 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 48  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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 49  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,

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 50 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 51 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 52 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 53 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 54 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 55 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 56 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 57 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 58 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 slow- growing 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 59 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 slow- growing 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 60 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 61 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 non- Hodgkin 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 62 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 63 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 64 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 65 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 66 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 67 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 68 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 69 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 70 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 non- Hodgkin 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 71 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 72 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 73 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 74  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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 75 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 slow- growing 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 76 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 77 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 78 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 79 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 80 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 non- Hodgkin 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 81 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 82 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 83 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 84 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 85 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 86 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 87 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 88 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 89 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 , 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 90 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 91 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 92 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 93 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,

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 94 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%

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 95 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 96 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 97 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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nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 98 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 99 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 100 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 101 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 102 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 103 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 104 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 105 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 106 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 107 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 108 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 109 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 non- Hodgkin 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.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 110 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 111 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 112 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

nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 113 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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nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 114 of Biological Chemistry 281, 934-944. Retrieved from http://www.jbc.org/content/281/2/934.abstract 8. 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 10. 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. Retrieved from http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html 12. Buddiga, P. (2013, Sep.). Lymphatic system anatomy. Retrieved from http://emedicine.medscape.com/article/1899053-overview#a2 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 http://www.sciencedirect.com/science/article/pii/S0952791511000550 17. National Institute of Neurological Disorders and Stroke. (2015, Jul.). Myasthenia gravis fact sheet. Retrieved from

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