Understanding Non-Hodgkin Lymphoma

Understanding Non-Hodgkin Lymphoma A Guide For Patients, Survivors, and Loved Ones Fourth Edition This guide is an educational resource compiled by the Lymphoma Research Foundation (LRF) that provides general information on adult non-hodgkin lymphoma. Publication of this information is not intended to take the place of medical care or the advice of a patient s doctor. Patients are strongly encouraged to talk to their doctors for complete information on how their disease should be diagnosed, treated, and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy. National Headquarters 115 Broadway, Suite 1301 New York, NY 10006 (212) 349-2910 phone (212) 349-2886 fax Helpline: (800) 500-9976; helpline@lymphoma.org Website: www.lymphoma.org Email: LRF@lymphoma.org This patient guide is supported through unrestricted educational grants from: Turning Insights into Hope 2012 Lymphoma Research Foundation. Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowledged to be the source.

ACKNOWLEDGMENTS The Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom, and advice, which have truly enhanced this publication. The review committee guided the content and development of this publication. Without their dedication and efforts, this publication would not have been possible. We hope those in the lymphoma community will now be better informed and have a better understanding of their illness because of the gracious efforts of those involved in the planning and execution of this comprehensive disease guide. Review Committee Bruce D. Cheson, MD, Georgetown University Hospital, Lombardi Comprehensive Cancer Center Morton Coleman, MD, Weill Cornell Medical College-NewYork Presbyterian Hospital Christopher R. Flowers, MD, Emory University School of Medicine Randy Gascoyne, MD, FRCPC, British Columbia Cancer Agency Stephanie A. Gregory, MD, Rush University Medical Center/ Rush University John P. Leonard, MD, Weill Cornell Medical College NewYork Presbyterian Hospital Oliver W. Press, MD, PhD, Fred Hutchinson Cancer Research Center, University of Washington Sonali Smith, MD, The University of Chicago Steven P. Treon, MD, PhD, Harvard Medical School Julie M. Vose, MD, MBA, University of Nebraska Medical Center Michael E. Williams, MD, University of Virginia School of Medicine ii Understanding Non-Hodgkin Lymphoma

TABLE OF CONTENTS Introduction...1 Part 1 Learning the Basics...2 Chapter 1: Understanding Non-Hodgkin Lymphoma...2 Chapter 2: Seeking Medical Help...17 Chapter 3: Getting a Diagnosis...20 Chapter 4: Work-up Before Treatment Can Begin...28 Part 2 Treatment of Non-Hodgkin Lymphoma...36 Chapter 5: What You Should Know Before Starting Treatment...36 Chapter 6: Treatments for Non-Hodgkin Lymphoma...47 Part 3 Side Effects and Living With Cancer...69 Chapter 7: Common Treatment Side Effects...69 Chapter 8: Managing Your Life During and After Treatment...86 Part 4 Clinical Trials and Advances in Treatment..91 Chapter 9: Overview of Clinical Trials...91 Chapter 10: Advances in Treatment of Patients With Non-Hodgkin Lymphoma...96 About the Lymphoma Research Foundation...99 Understanding Non-Hodgkin Lymphoma iii

INTRODUCTION The purpose of this booklet is to help patients with non-hodgkin lymphoma become active participants in their healthcare decisions. Chapters in this book address different issues faced by these patients, including: what to expect during diagnosis, work-up, and treatment; how to cope with treatment side effects; and what questions to ask doctors. 1 Understanding Non-Hodgkin Lymphoma

Part 1 Learning the Basics Chapter 1: Understanding Non-Hodgkin Lymphoma Non-Hodgkin lymphoma (NHL) is a type of blood cancer that affects specialized white blood cells called lymphocytes. Lymphocytes work together with other cells in the immune system to defend the body against invasion by bacteria, viruses, parasites, and other foreign substances. Lymphocytes travel in the bloodstream and in a separate network of vessels called the lymphatic system. Part 1 The sections in this chapter will explain these and other terms that will help you understand NHL and how it affects a person s health. A better understanding of the disease will help patients take a more active role in deciding the course of their treatment. What is cancer? Cancer is a group of diseases that develop when abnormal cells gain the ability to divide abnormally and to spread to areas in the body where they are not normally found. Your body is made up of many different types of specialized cells that are organized into tissues and organs to perform all the different tasks needed to stay healthy. To keep things running smoothly, the cells in your body grow, work, and divide in a very controlled fashion. All of these cells also have a limited lifespan. Normally, a self-destruct mechanism is triggered when a cell becomes too old or when it stops working properly. However, sometimes damage to the genetic material (DNA) of a cell gives it the ability to override this self-destruct mechanism, allowing these abnormal cells to live longer or divide more frequently than normal. Unless the body s immune system gets rid of them, these abnormal cells can multiply and cause cancer. Learning the Basics 2

HOW CANCER FORMS INSIDE THE BODY Abnormal Cells Evade the Immune System Abnormal Cells Multiply (Cancer) Tumors May Form (Groups of Abnormal Cells) Most cancers are named after the organ or cell type of origin. For example, a cancer that started in the pancreas is called pancreatic cancer and a cancer that started in lymphocytes is called a lymphoma. 3 Understanding Non-Hodgkin Lymphoma

Why is there no single cure for cancer? Cancer refers to a large group of very complicated diseases. A tricky aspect of cancer is that there are many different ways for a cell to become abnormal enough to develop into a cancer cell. Because of this, the path taken by a liver cell to become a cancerous liver cell is quite different from that taken by a lymphocyte to become NHL. This is why a treatment that works against one type of cancer may not necessarily work against another. There are also important differences between different kinds of NHL, and a treatment that works against one type of NHL may not necessarily be the best treatment choice for another type. Part 1 There are also smaller, but still important, differences in the cancer cells found in different patients diagnosed with the same type of cancer. Because of this, a treatment that may work very well in one patient may not have the same positive effect in another. These are some of the reasons why most cancers are much harder to treat or prevent than, for example, bacterial or fungal infections, which typically are caused by a single type of organism. What is the lymphatic system? As shown in the picture on page 5, the lymphatic system is a circulatory system that is made up of a spidery network of thin tubes called lymph vessels. Similar to blood vessels, lymph vessels branch out into all tissues of the body. While people can clearly see blood vessels, especially at their wrists and on the top of their hand, lymph vessels are invisible to the naked eye. Learning the Basics 4

ANATOMY OF THE IMMUNE SYSTEM The immune system is the body s defense against disease. Tonsil Thymus Lymph nodes Diaphragm Spleen Lymph vessels 5 Understanding Non-Hodgkin Lymphoma

Lymph vessels carry lymph, a type of liquid that contains lymphocytes. Within this huge network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found throughout the body, including the elbows, neck, armpits, chest, abdomen, and groin. Lymph fluid flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow, and thymus gland. Lymph nodes filter lymph fluid, removing bacteria, viruses, and other foreign substances from the body. If a large number of foreign substances are filtered through a node or series of nodes, swelling may occur and the nodes may become tender to the touch. Most swollen nodes are a reaction to infection and are not cancerous. Part 1 What is a lymphoma? A lymphoma is a cancer that affects lymphocytes, a type of white blood cell. Lymphocytes travel through the blood and lymphatic system to defend the body against foreign invaders like bacteria and viruses. There are 2 major categories of lymphomas: non-hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). NHL is approximately 8 times more common than HL; according to the American Cancer Society, each year in the United States over 70,000 adults are diagnosed with NHL and approximately 9,000 with HL. Both of these major categories of lymphoma are further subdivided into several types that are different in the way they develop and spread, and in how affected patients are treated. Lymphomas usually develop when a change, or mutation, occurs within a lymphocyte, causing the abnormal cell to replicate faster than, or live longer than, a normal lymphocyte. Like normal lymphocytes, cancerous lymphocytes can travel through the blood and lymphatic system and spread and grow in many parts of the body, including the lymph nodes, spleen, bone marrow, and other organs. This is why most types of NHL are found throughout the body by the time a patient is diagnosed with the disease. Learning the Basics 6

What is non-hodgkin lymphoma? NHL does not refer to a single disease, but to a large group of related cancers that occur in lymphocytes. NHL is the seventh most common type of cancer affecting adults of both sexes. The World Health Organization estimates that there are approximately 60 types of NHL. While these various types share many common features, certain characteristics set them apart from each other, including: n How they look when examined under a microscope. n Genetic characteristics and other molecular features. n How and where they grow in the body. n How their growth and spread affect patients. n How patients should be treated. How are non-hodgkin lymphoma types organized? NHL is divided into the following 2 major groups: n B-cell lymphomas These lymphomas develop from abnormal B-lymphocytes ( B because B-lymphocytes come from the bone marrow) and account for 85% of all NHL. n T/NK-cell lymphomas These lymphomas develop from abnormal T-lymphocytes ( T because normally T-lymphocytes spend part of their lifespan in the thymus gland, a small organ in the chest) or natural killer (NK) cells. These account for the remaining 15% of NHL. 7 Understanding Non-Hodgkin Lymphoma

RELATIVE FREQUENCIES OF B-CELL LYMPHOMAS Diffuse large B-cell 37% Follicular 29% MALT 9% Part 1 Mantle cell 7% Chronic lymphocytic/ small lymphocytic 12% Lymphoplasmacytic 1.4% Nodal marginal zone 2% Primary mediastinal large B-cell 3% High Grade B, not otherwise specified 2.5% Burkitt 0.8% Splenic marginal zone 0.9% RELATIVE FREQUENCIES OF T-CELL LYMPHOMAS Peripheral T-cell, not Angioimmunoblastic 18.5% otherwise specified 25.9% Extranodal natural killer/t-cell 10.4% Adult T-cell leukemia/ lymphoma 9.6% Anaplastic large cell, ALK+ 6.6% Other disorders 12.2% Unclassifiable peripheral T-cell 2.5% Subcutaneous panniculitis-like 0.9% Anaplastic large cell, ALK- 6.6% Enteropathy-type T-cell 4.7% Primary cutaneous anaplastic large cell 1.7% Hepatosplenic T-cell 1.4% Learning the Basics 8

NHL types are also often grouped according to how quickly they grow: n Indolent lymphomas (also called low-grade lymphomas) grow slowly and tend to cause few symptoms. While indolent lymphomas are usually not curable, patients can live a long time with these types of lymphomas because they respond well to treatment and may potentially remain in remission for many years (even decades). Over time, some indolent lymphomas may transform into aggressive lymphomas. n Aggressive lymphomas (also called intermediate-grade and highgrade lymphomas) grow and spread more quickly than indolent lymphomas. Aggressive lymphomas, while potentially lifethreatening, can often be cured with chemotherapy and other newer treatments. This table lists some of the main types of indolent and aggressive NHL. Indolent Non-Hodgkin Lymphomas Follicular lymphoma Chronic lymphocytic leukemia/ small lymphocytic lymphoma Marginal zone lymphoma Lymphoplasmacytic/Waldenström macroglobulinemia Mycosis fungoides/sézary syndrome (subtypes of cutaneous T-cell lymphoma) Aggressive Non-Hodgkin Lymphomas Diffuse large B-cell lymphoma (DLBCL) Burkitt lymphoma Lymphoblastic lymphoma Mantle cell lymphoma Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic lymphoma Blastic natural killer (NK)-cell lymphoma Pathologists (doctors who specialize in disease diagnosis) can distinguish among the many different types of NHL by examining biopsy tissue samples under a microscope and by carrying out various laboratory tests. This information is critically important in deciding how to treat the affected patient. 9 Understanding Non-Hodgkin Lymphoma

Common types of aggressive non-hodgkin B-cell lymphoma Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, accounting for up to one-third of newly diagnosed NHL patients. The median age at diagnosis is 57 years, but the disease is also seen in younger people. Part 1 DLBCL can arise in the lymph nodes or outside the lymphatic system. It may be localized or generalized (spread throughout the body). Despite being an aggressive lymphoma, DLBCL is curable. The first sign of DLBCL is usually rapid swelling in the neck, armpit, or groin caused by enlarged lymph nodes. Other symptoms include night sweats, chills, unexplained fevers, and weight loss. Mantle cell lymphoma Mantle cell lymphoma affects approximately 6% of all patients with NHL. This type of lymphoma usually affects men over 50 years. Often, patients with mantle cell lymphoma have many lymph nodes, 1 or more organs, and the bone marrow involved. The gastrointestinal tract is a very common extra-nodal site of involvement. Mantle cell lymphoma may sometimes follow an indolent, or slow-growing, course but more typically behaves as an aggressive disease and is, therefore, often treated as an aggressive lymphoma. For more information on mantle cell lymphoma, please visit LRF s Focus on Mantle Cell Lymphoma website at www.focusonmcl.org. Common types of indolent non-hodgkin B-cell and T-cell lymphoma Follicular lymphoma Follicular lymphoma (FL) is the second most common type of NHL. FL accounts for about 22% of all NHLs. FL typically occurs in middleaged and older adults, but it can also affect younger adults. FL usually appears in lymph nodes spread throughout the body. Often, one of the first signs of FL is a painless swelling in the neck, armpit, or groin caused by these enlarged lymph nodes. FL may eventually transform Learning the Basics 10

into a more aggressive form of the disease. For more information on FL, please visit LRF s Focus on Follicular Lymphoma website at www.focusonfl.org. Chronic lymphocytic leukemia/small lymphocytic lymphoma Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are B-cell malignancies involving lymphocytes. The main difference between the 2 diseases is where the cancer primarily occurs. If the cancer cells are found mainly in lymph nodes, the disease is called SLL. If the cancer cells are found in the bloodstream and bone marrow, the disease is called CLL, although the lymph nodes and spleen are often also involved. Approximately 16,000 new cases of CLL and 5,000 new cases of SLL are diagnosed annually. CLL/SLL are usually diagnosed in adults over age 50; more than half of the people with CLL are over age 70. Thinking of CLL/SLL as a lymphoma and not a form of leukemia is important because CLL has a clinical course and treatment regimen that is similar to other indolent lymphomas. Over time, CLL may progress to a more aggressive type of lymphoma (Richter s syndrome). The staging system for CLL is different from the staging system applied to other NHLs. For a more detailed description of CLL, visit www.focusoncll.org or request a copy of the Lymphoma Research Foundation s publication entitled Understanding CLL/SLL: A Guide for Patients, Survivors and Loved Ones. Marginal zone lymphoma Marginal zone B-cell lymphomas account for approximately 7% of all NHLs. The median age of diagnosis of this type of lymphoma is 65. These lymphomas include 3 basic types: (1) extranodal or mucosaassociated lymphoid tissue (MALT), occurring outside the lymph nodes; (2) nodal, occurring within the lymph nodes; and (3) splenic, occurring mostly in the spleen and blood. Skin-associated lymphoid- 11 Understanding Non-Hodgkin Lymphoma

tissue-related B-cell lymphoma (SALT) is also considered a form of MALT lymphoma. Marginal zone and MALT lymphomas vary from other types of B-cell NHLs in several ways: n Many people who develop MALT lymphoma have a history of inflammation, infection, or autoimmune disorders. n Chronic inflammation is associated with Helicobacter pylori (H. pylori), a microbial pathogen linked to chronic gastritis. n Sometimes, MALT lymphomas can be treated with antibiotics. Part 1 n Different infections have also been implicated in other forms of MALT lymphoma. n Hepatitis C virus infection has been associated with splenic marginal zone lymphoma. Waldenström macroglobulinemia Waldenström macroglobulinemia (also known as lymphoplasmacytic lymphoma or immunocytoma) is a rare B-cell lymphoma that occurs in less than 2% of people with NHL. There are about 1,500 new cases of Waldenström s each year. The disease usually affects older adults and is primarily found in the bone marrow, although lymph nodes and spleen may sometimes be involved. People with Waldenström s have a high level of a protein called immunoglobulin M (IgM) in the blood. These high levels of IgM can cause a thickening of the blood, resulting in symptoms such as nosebleeds, headaches, dizziness, and blurring or loss of vision. Cutaneous T-cell lymphoma Cutaneous T-cell lymphomas (CTCL), a group of lymphomas that originate in the skin, are a subset of peripheral T-cell lymphoma (PTCL). However, CTCL types are generally less aggressive, have a different prognosis, and have different treatment approaches than the aggressive PTCLs. Mycosis fungoides is the most common type of CTCL. Sézary syndrome is an advanced, variant form of mycosis fungoides, and affects both the skin and the peripheral blood. Learning the Basics 12

Common types of aggressive non-hodgkin T-cell/natural killer cell lymphoma Peripheral T-cell lymphomas PTCL refers to a large number of different T-cell lymphomas that together affect 5-10% of all patients diagnosed with NHL. This type of lymphoma can occur anytime during adulthood. Some varieties of PTCL are rare in the United States but can more commonly be found in Asia, notably Japan, where an infection with a virus called HTLV-1 is prevalent. Its presence makes it more likely for an individual to develop a specific type of PTCL. It has also been found in individuals coming from Caribbean countries. For more information on PTCL, please visit LRF s Focus on Peripheral T-Cell Lymphoma website at www.focusonptcl.org. Anaplastic large-cell lymphoma Anaplastic large-cell lymphoma (ALCL) is rare, affecting about 3% of adults with all types of lymphomas and 10-30% of children with all types of lymphomas. ALCL occurs either systemically (meaning in organs in the body) or cutaneously (meaning on the skin surface). Systemic ALCL can respond well to chemotherapy and is potentially curable. The cutaneous (skin) ALCL is a less aggressive disease that is associated with a rare condition called lymphomatoid papulosis (LyP), which is often a precursor to the development of cutaneous anaplastic large-cell lymphoma. Patients with systemic ALCL are divided into 2 groups, depending on the expression of a protein called anaplastic lymphoma kinase (ALK). The prognosis for ALCL depends on whether a patient is ALK positive (expresses the protein) or ALK negative (does not express the protein). ALK positive disease responds well to chemotherapy, putting most patients in long-term remission or cure. A majority of ALK negative patients will relapse within 5 years and are treated more aggressively, often with transplant. For more information on ALCL, please visit LRF s Focus on Anaplastic Large Cell Lymphoma website at www.focusonalcl.org. 13 Understanding Non-Hodgkin Lymphoma

Angioimmunoblastic lymphoma Angioimmunoblastic lymphoma (AITL) affects 1-2% of all patients with NHL in the United States. Symptoms include high fever, night sweats, skin rash, and some types of autoimmune disorders, such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), in which the body does not recognize its own cells. Because of this, the body makes antibodies against and destroys its own cells or tissues, such as platelets (ITP) and red blood cells (AIHA). Part 1 Initially, AITL may be treated with steroids. However, the disease often progresses and patients require chemotherapy and other medications. In advanced cases, transplantation may be used. Lymphoblastic lymphoma Lymphoblastic lymphoma can appear in both B cells and T cells but is much more common in T cells (which are affected in 80% of all lymphoblastic lymphomas). This lymphoma is most often diagnosed in children. With intensive chemotherapy, the complete remission rate can be very high. The disease is often treated similarly to acute lymphoblastic leukemia. Blastic natural killer-cell lymphoma Blastic natural killer (NK)-cell lymphoma is a very rare form of lymphoma that affects the NK cells of the immune system. NK cells are a type of lymphocyte that attack and destroy viruses and tumor cells. This type of lymphoma usually affects older adults. Patients with blastic NK-cell lymphoma have skin lesions that are similar to those associated with leukemia, other cutaneous lymphomas, and other skin diseases. It can only be diagnosed by specific laboratory tests. This disease is hard to treat. The best results have been obtained using a combination of chemotherapy and radiation therapy, followed by bone marrow transplantation. Learning the Basics 14

Why do some people develop non-hodgkin lymphoma? The reasons why some people develop NHL are not well understood. However, scientists have found that people with certain characteristics have a higher risk of developing NHL compared with people who do not have these characteristics. The characteristics that make a person possibly more susceptible to developing any type of disease are called risk factors. Having 1 or more of these risk factors does not mean a person will develop NHL. In fact, most people with risk factors never develop the disease and many people diagnosed with NHL have never been exposed to any clearly identifiable risk factors. Known risk factors for NHL include: n A weakened immune system caused by an inherited immune disorder (for example, hypogammaglobulinemia, Wiskott-Aldrich syndrome), an autoimmune disease (for example, Crohn s disease, rheumatoid arthritis, psoriasis), or treatment with certain drugs used after an organ transplant. n Infections with certain viruses, such as human immunodeficiency virus (HIV which is the virus that causes AIDS), Epstein-Barr virus (EBV), human T-cell leukemia/lymphoma virus (HTLV-1), hepatitis C virus. n Infection with the bacteria Helicobacter pylori (which may cause stomach ulcers and may increase the risk of developing lymphoma in the stomach lining). n Older age NHL may develop in children and adults of all ages but, like most cancers, it is much more common in people older than 60 years of age. n Sex NHL is more common in men compared with women. n Being exposed to certain chemicals such as benzene, certain herbicides and pesticides, and some chemotherapy drugs used to treat other cancers or autoimmune disease. 15 Understanding Non-Hodgkin Lymphoma

n Treatment with radiation therapy for some other cancers, including NHL. n Previous treatment for NHL. NHL cannot be caused by injury or by catching it from someone who has the disease. The children and siblings of patients with NHL have a slightly increased risk of developing this disease compared to the general population. However, there are no clearly identified genetic or hereditary factors to predict this slightly increased risk, and routine screening for NHL is not recommended. Part 1 Learning the Basics 16

Part 1 Learning the Basics Chapter 2: Seeking Medical Help This chapter explains the signs and symptoms of NHL and discusses how a doctor determines whether or not a person has the disease. A symptom is anything unusual in a normal body function, appearance, or sensation that a patient experiences. During a visit with a healthcare practitioner, patients should report all of their symptoms to their doctor or nurse. Symptoms may indicate the presence of lymphoma or another disease. Signs are anything unusual that doctors or nurses notice when they examine their patients. What are the signs and symptoms of non-hodgkin lymphoma? Some patients with NHL do not experience any symptoms. Their disease may be detected initially by their doctor during a routine physical examination or only after the tumor becomes large enough to cause symptoms. General symptoms of NHL can include: n Unexplained weight loss. n Fever for no known reason. n Drenching night sweats that soak clothing and sheets. n Severe or frequent infections. n Easy bruising or bleeding. n Numbness or tingling in feet and/or hands. n Headaches and/or blurry vision. n Fatigue. 17 Understanding Non-Hodgkin Lymphoma

Having one or more of these symptoms does not mean that a person has NHL. These symptoms may be caused by an infection or other conditions (including other cancers). NHL may cause different signs and symptoms depending on the location of the tumor in the body. This table gives some examples of signs and symptoms that may indicate the presence of a lymphoma in a specific part of the body. Be aware that none of these signs and symptoms are specific to NHL exclusively, and may be due to a variety of other conditions. Part 1 Signs and Symptoms Lumps under the skin on the sides of the neck, in the groin or underarms, or above the collar bone Swollen, tender abdomen (belly) Abdominal pain, nausea, or vomiting Stomach pain, nausea, and decreased appetite Coughing, trouble breathing, chest pain, or pressure Headache, trouble thinking, weakness in certain parts of the body, personality changes, and sometimes seizures Double vision, facial numbness, trouble speaking Itchy, red, or purple lumps or nodules under the skin Possible Reason This may be caused by swollen lymph nodes which is a common symptom of lymphoma Enlarged lymph nodes in the abdomen Accumulation of large amounts of liquid in the abdomen Enlarged spleen pressing on the stomach (making a person feel full after eating only a small amount of food) Lymphoma in the intestine or causing swelling near the intestine, possibly blocking bowel movements Lymphoma of the stomach Lymphoma in the chest which may press on the windpipe (trachea) Lymphoma of the brain Lymphoma originating in other parts of the body before spreading to the brain and spinal cord Lymphoma of the skin Learning the Basics 18

When should a patient seek medical attention? Anyone who has persistent symptoms should see a doctor to make sure that lymphoma or another serious condition is not present. A good rule of thumb is to seek medical attention if any of the previously mentioned symptoms last longer than 2 weeks or sooner depending on their severity and impact on a person s daily life. Many of these symptoms can arise from different causes and need not be cancer. There are no specific tests that doctors can use to routinely screen patients to see if they have NHL. During the visit with the doctor, patients should describe all of their symptoms. The doctor will ask detailed questions about medical history and perform a complete physical examination. During the physical examination, the doctor will: n Check for swollen lymph nodes under the chin, in the neck and tonsil area, above the shoulders, on the elbows, in the armpits, and in the groin and upper legs. n Examine other parts of the body to see if there is swelling or fluid in the chest or abdomen that may be caused by swollen lymph nodes. n Examine the abdomen to see whether any internal organs are enlarged. n Ask about any pain experienced. n Look for any weakness or paralysis that may be caused by an enlarged lymph node pressing against nerves or the spinal cord. If doctors suspect lymphoma after reviewing the symptoms reported and signs they have uncovered during the examination, they will order other tests to confirm the diagnosis. These tests should include a biopsy and may also include blood tests, chest x-rays and other imaging tests, scans, and a bone marrow evaluation. Depending on the type and location of the NHL, other tests may be required. These tests and procedures are discussed in more detail in the next chapter. 19 Understanding Non-Hodgkin Lymphoma

Part 1 Learning the Basics Chapter 3: Getting a Diagnosis Doctors need the results of different diagnostic tests to accurately determine whether or not a patient has NHL. This chapter explains the purpose of these different tests and describes what to expect during and after these procedures. Part 1 Cautions About Interpreting Diagnostic Reports n Only a biopsy is definitive. n Tests can be reported as normal even though lymphoma may be present. n Tests may be reported as abnormal even though lymphoma is not present. n Other conditions may mimic NHL. n The interpretation of tests, such as imaging studies and scans, can be difficult in some situations and needs to be made in the context of the disease and the patient. n Often, follow-up tests are needed to determine the true significance of previous results; additional biopsies may be needed to clarify the results. n Some patients like to review their written scan reports; when doing so, it is important to carefully review the findings with their doctor. Learning the Basics 20

How is non-hodgkin lymphoma diagnosed? The only way to be absolutely sure of a diagnosis of NHL (or any cancer) is for a doctor to perform an excisional biopsy to remove an entire lymph node or an incisional biopsy to remove a portion of the diseased tissue (see below, What is a biopsy? ). A pathologist will examine a portion of this biopsy sample under a microscope to see if it contains any lymphoma cells and, if possible, to identify the specific type of lymphoma. A surgical pathologist is a doctor who specializes in the diagnosis of diseases by studying the cells from a patient s blood, body fluids, and tissue samples. A hematopathologist specializes in the pathology of blood cells, and a lymphoma pathologist specializes in the diagnosis and classification of NHLs and HLs. These doctors are trained to recognize different cell types by looking at the shape and size of cells and how they are grouped inside a tissue. In addition to routine pathology analyses, portions of biopsy samples will be used for other tests to confirm the diagnosis and to more exactly identify the specific subtype of lymphoma. This chapter explains how these tests work and what kind of information they provide. What is a biopsy? A biopsy is a procedure in which a piece of tissue from an area of suspected disease is removed from the body and examined under a microscope. The information provided by this tissue sample is crucial to correctly diagnose the disease and decide on the best course of treatment. 21 Understanding Non-Hodgkin Lymphoma

The following are the 2 main types of biopsies doctors use for the initial diagnosis of patients with a lymphoma: Excisional or Incisional Biopsy Core Needle Biopsy n This type of biopsy is the best to establish an initial diagnosis of lymphoma because it allows for the removal of bigger samples than other biopsy procedures. The larger the sample, the more tissue the pathologist can examine, which improves the accuracy of diagnosis. n In this procedure, a surgeon cuts through the skin to remove an entire lymph node (excisional biopsy) or a large portion of tissue (incisional biopsy). n If the lymph node is close to the skin surface, the procedure can be done under local anesthesia to numb the area. If the lymph node is in the chest or abdomen, the patient is sedated and the surgeon removes the tissue either laparoscopically (through a tube inserted in the abdomen) or by performing abdominal surgery. n This procedure is used when the lymph nodes are deep in the chest or abdomen or in other locations that are difficult to reach with excisional biopsy, or when there are medical reasons for avoiding an excisional or incisional biopsy. n In this procedure, a large needle is inserted into a lymph node suspected to be cancerous and a small tissue sample is withdrawn. n A needle biopsy can be done under local anesthesia and stitches are usually not required. n Sometimes the material collected may not be adequate for diagnosis and a subsequent excisional or incisional biopsy may be necessary. Part 1 A fine needle aspirate (FNA) biopsy is, as the name implies, a type of biopsy performed with a very thin needle (smaller than that used for a core needle biopsy). Because of the small needle size, the sample will only contain scattered cells without preserving how the cells are actually arranged in the lymph node. This limited information is not enough for a precise diagnosis. An FNA biopsy is most often used to check for return of the disease (relapse) and is virtually never used for the initial diagnosis. Learning the Basics 22

After a biopsy sample has been removed, it is examined by a pathologist who develops a report. An oncologist then uses this report along with results of other diagnostic tests to confirm a diagnosis. A pathologic diagnosis and accurate classification of specific lymphoma types can sometimes be difficult to make; if the pathologist s interpretation of the biopsy is uncertain, the results should be reviewed by a hematopathologist or a lymphoma pathologist. Second opinions can be helpful, because an accurate diagnosis is crucial in planning the most appropriate treatment plan. What are a bone marrow biopsy and a bone marrow aspiration? Bone marrow is a wet, spongy tissue inside bones where blood cells are generated. A bone marrow biopsy involves removing a small amount of bone marrow from inside a bone. The bone marrow is then examined for the presence of lymphoma cells. A bone marrow aspiration is similar to a bone marrow biopsy except it involves removing only the liquid portion of the marrow, using a fine needle inserted into a bone. A bone marrow biopsy or aspiration is not used for initial diagnosis but is commonly used to see if the NHL has spread, or to collect bone marrow for medical procedures such as stem cell transplant or chromosomal analysis (see page 34, Why might a patient need to have another type of biopsy? ). What questions should a patient ask the doctor before having a biopsy or other diagnostic procedure? Patients diagnosed with a complicated disease will be asked to undergo a variety of procedures for the initial diagnosis and work-up before treatment begins, during the course of treatment, and during the follow-up period. Before patients agree to a procedure, they should make sure that they understand the reasons for the procedure and what will be involved. Here is a list of questions patients may want to ask their doctor. n Why is this procedure necessary? n What will the procedure tell us about my condition? 23 Understanding Non-Hodgkin Lymphoma

n Can the same information be obtained in another way? n What is involved in doing this procedure? n What are the possible risks, complications, and side effects? n Where will I have the procedure done? n Will I have to do anything to prepare for the procedure? Part 1 n How long will the procedure take? Will I be awake? Will I feel pain? n How long will it take for me to recover from the procedure? n Should anyone else be present when I have the procedure? n Will I need someone to take me home afterward? n When will I know the results? n When will we talk about the results? n What will be my out-of-pocket costs? What is immunophenotyping? Immunophenotyping is a process used during evaluation of biopsy material to distinguish between different types of cells (for example, between normal lymphocytes and lymphoma cells), by detecting specific molecules (cell markers or antigens ) found on the cell surface. These cell markers are detected using special antibodies grown and chemically modified in the laboratory so that they will change color when they stick to their corresponding markers. Learning the Basics 24

IMMUNOPHENOTYPING Antibodies change color upon binding to specific cell markers. Antibody Antigen This color change is studied under a microscope using immunohistochemistry (IHC) analysis or sorted and counted using a process called flow cytometry. Sometimes, both IHC and flow cytometry are necessary for accurate immunophenotyping. 25 Understanding Non-Hodgkin Lymphoma

Immunohistochemistry (IHC) n In this test, thin slices of the biopsy sample (or thin layers of fluid or blood) are placed on slides and treated with sets of antibodies that recognize different markers found in different types of lymphoma cells and normal lymphocytes. n The pathologist examines the slides under a microscope to look for the visible color change that happens when the antibody sticks to the marker. n The pathologist identifies and counts the number of cells that change color (meaning that they are positive for the marker) with each of the different antibodies and uses that information to identify the specific type of lymphoma. Part 1 Flow Cytometry n In this test, cells from the biopsy sample are placed in a liquid solution and treated with sets of antibodies that recognize different markers found in different types of lymphoma cells. n The cell-antibody mixture is injected into an instrument called a flow cytometer. This machine uses laser beams to sense the different colors the cells emit because of the different antibodies attached to them. This information is measured and analyzed by a computer. n The results from the flow cytometry analysis will distinguish between different types of lymphoma, other cancers, or some other disease. Learning the Basics 26

What is cytogenetic analysis? Chromosomes are long strands of DNA, the genetic material of a cell. Healthy human cells have 23 pairs of chromosomes. Some lymphomas and other types of cancer have too few or too many chromosomes, or have abnormal chromosome structures. In cytogenetic analysis, chromosomes from a patient s lymphoma cells are examined under a microscope to check for changes in their number (too few or too many) or the presence of other abnormalities. One type of chromosomal abnormality that can be seen through a microscope is called a translocation which happens when part of a chromosome breaks off from its normal location and becomes attached to another chromosome. The results of the cytogenetic analysis can help distinguish between different types of NHL. CHROMOSOME TRANSLOCATION Two different chromosomes exchange portions of their genetic material. Chromosome 14 Chromosome 18 Bcl2 Bcl2 Translocation It usually takes 1 to 2 weeks to get the results from cytogenetic testing because a sufficient number of patient s lymphoma cells must be grown in the laboratory to get enough genetic material for the analysis. 27 Understanding Non-Hodgkin Lymphoma

Part 1 Learning the Basics Chapter 4: Work-up Before Treatment Can Begin After the initial diagnosis of NHL, the doctor may order other tests such as blood tests, molecular genetics tests, imaging studies, heart and lung function tests, and, less frequently, additional biopsies. This process is often called the work-up. Some of these work-up studies are needed to see if and how much the disease has spread to other parts of the body. Doctors will use these test results to determine the stage of a patient s disease. Other tests will check how the disease has affected a patient s overall health and major organ functions. Part 1 Together all of these tests will provide the information needed to help patients and their doctors decide on the course of treatment that will give patients the best chance for curing the disease or putting it into a lasting remission. This chapter will help you understand how NHL is staged, the reason for the various tests, how these tests work, and what to expect. How is non-hodgkin lymphoma staged? Staging is used to describe how widely the lymphoma has spread in adult patients with NHL. As shown in the following figure, there are 4 main stages of lymphoma, designated by the Roman numerals I through IV. This staging system divides the body in half using the diaphragm, the muscle that divides the chest cavity from the abdominal cavity. Learning the Basics 28

STAGING OF NON-HODGKIN LYMPHOMA Stage I: Localized disease Single lymph h node region Single organ outside lymph ph nodes Stage II: Two or more lymph node regions near each other One or more lymph nodes and one organ near each other Stage III: Two or more lymph node regions in different parts of the body with or withoutt involvement of a nearby organ or the spleen Stage IV: Widespread W disease dis d Multiple organs M With W or without lymph lyym node involvement inv Your doctor may also add any of the following single letters to the stage. n n n A if patients have not experienced symptoms such as significant weight loss (more than 10% in 6 months), drenching night sweats, or fevers. B if patients have lost weight (more than 10% in 6 months) and have experienced drenching night sweats or fevers. X if patients have a lymphoma that is greater than 10 cm (4 inches) wide. This is also called bulky disease. Being diagnosed with stage III or IV NHL is common. Keep in mind that these advanced stages can be successfully treated. 29 Understanding Non-Hodgkin Lymphoma

What is the purpose of blood tests? Doctors will test a patient s blood to measure the quantity of the different types of cells (red blood cells, white blood cells, and platelets). This information can help determine how advanced the lymphoma is. These blood tests will most likely include: a complete blood count (CBC), differential (to measure the relative amounts of different types of white blood cells), platelets, and serum lactate dehydrogenase (LDH). Fast-growing lymphoma can cause very high blood levels of LDH. Part 1 Doctors will also most likely order a comprehensive metabolic panel to measure the amount of different chemicals in your blood, which will show whether the lymphoma is affecting the main body organs. The comprehensive metabolic panel usually includes 14 specific tests that measure the function of the kidneys and liver, electrolyte balance, acid/base balance, blood sugar, and different blood proteins. Calcium, magnesium, potassium, and sodium are some of the electrolytes found in your body; abnormal levels of electrolytes can make you sick. Depending on the type of lymphoma, the blood may also be tested for signs of infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). A serum immunoglobulin test (immunoelectrophoresis) may also be performed to test for the presence of certain immunoglobulins (a type of protien) that are sometimes found with certain NHL types. The results from these tests will help patients and their doctors decide between different types of treatments. Many of these blood tests will be repeated during the course of treatment to check how the treatment is affecting the patient s body functions. What is the purpose of molecular genetic tests? Doctors may order molecular genetic tests to confirm the cytogenetic tests and find out more detailed information about the types of damage to the genetic information of the lymphoma cells in the patient s body. Learning the Basics 30

The 2 main types of molecular genetic tests used are: Fluorescent In Situ Hybridization (FISH) n FISH uses fluorescent chemicals to specifically attach to certain parts of chromosomes to show the presence of translocations and other large abnormalities. n FISH can be done on blood or bone marrow samples and the test results are usually available within a few days (quicker than cytogenetic testing). Polymerase Chain Reaction (PCR) n PCR is a test that can detect changes in DNA that are too small to be seen under a microscope, or using cytogenetic analyses or FISH. n PCR tests can be done on a very small quantity of lymphoma cells; using this technique, abnormal areas of DNA reproduce in an exponential fashion until they are large enough to be detectable. What types of imaging tests may be used? A patient s doctor will most likely order imaging tests to help find areas of the body where there may be cancer, to learn how far the cancer has spread, and later on to check how well the treatment is working. Most of these tests are painless and no anesthetic is required. Several types of the following imaging procedures may be needed to thoroughly evaluate the extent of your disease. 31 Understanding Non-Hodgkin Lymphoma

X-ray Computer Tomography (CT) Scan Magnetic Resonance Imaging (MRI) n X-rays use radiation to take pictures of areas inside the body. The amount of radiation used in most diagnostic tests is so small that it poses little risk to the patient. n Findings on a chest x-ray may indicate whether the disease is bulky. n A CT scan takes x-rays from many different angles around the body. A computer combines the pictures obtained from these different angles to give a detailed image of organs inside the body. n Patients with NHL often have CT scans of the neck, chest, abdomen, and pelvis to find out how many lymph nodes are involved, how large they are, and whether internal organs are affected by the disease. n The amount of radiation exposure during a CT scan varies depending on the area scanned. Most CT scans confer little risk to the patient, although CT scans of the abdomen and pelvis do add a moderate amount of risk (1 in 500-1,000) to the general lifetime risk of cancer. n Before a CT scan, the patient may be asked to drink a contrast liquid and/or get an intravenous injection of a contrast dye that will more clearly outline abnormal areas that may be present in the body. n Like a CT scan, an MRI takes images from different angles around the body, but an MRI does not use x-rays like a CT scan; instead it uses magnets and radiofrequency waves. Therefore, an MRI confers no risk of radiation-induced cancer. n An MRI can provide important information about tissues and organs, particularly the nervous system, that is not available from other imaging techniques. n Because this testing technique works well to get clear images of the bones, brain, and spinal cord, an MRI may be ordered if a doctor wants to see whether the lymphoma has spread in these areas. Part 1 Learning the Basics 32

Positron Emission Tomography (PET) Scan n This test evaluates NHL activity in all parts of the body. n To perform the test, radioactive fluorodeoxyglucose (a type of sugar) is first injected into the body. A positron camera is then used to detect the radioactivity and produce cross-sectional images of the body. The amount of radiation used for a PET scan is low and poses little risk to a patient. n PET scans help determine how much disease is present (staging) and how well it is responding to treatment. n While CT scans show the size of a lymph node, PET scans show if the lymph node is active (still has disease). CT and PET scans are now combined into 1 test (PET/CT). What is a MUGA scan? A MUGA scan (multi-gated acquisition scan) is an imaging test that looks at how well the heart muscle is working. A MUGA scan is done to make sure that the patient s body can withstand treatment with certain lymphoma drugs that may damage the heart in rare cases. MUGA scans may be done when patients are resting or exercising, depending on what their doctor wants to assess. A doctor will most likely order a MUGA scan if he or she is considering treating a patient with the drug doxorubicin (Adriamycin). This test is needed to make sure that the heart is functioning normally because doxorubicin may be associated with cardiac toxicity. A 2-dimensional echocardiogram (ECHO) is sometimes used instead of the MUGA scan to test heart function. 33 Understanding Non-Hodgkin Lymphoma

Why might a patient need to have a lung function test? Lung function tests are done to make sure that the body can withstand treatment with certain lymphoma drugs that may stress a patient s lung function (e.g., bleomycin, cyclosphophamide). A doctor may order breathing tests before beginning treatment and at other times during treatment to make sure that a patient s lungs are still working properly. Part 1 Why might a patient need to have another type of biopsy? Once the diagnosis of NHL is made, the doctor may order other types of biopsies for additional pathology studies and other tests to see if and how the disease has spread to other parts of the body. With this information, the doctor can properly stage the disease. Bone Marrow Aspiration and Biopsy n This procedure may be done to determine if the lymphoma has spread to the bone marrow. n The bone marrow is the spongy, soft material found inside our bones where normal blood cells are generated. NHL can spread to the bone marrow or start in the bone marrow. n For the aspiration part of this procedure, the doctor cleans and numbs the skin over the hip and inserts a thin hollow needle into the bone. The doctor uses a syringe to remove a small amount of liquid from the bone marrow. Even with the numbing local anesthetic, this procedure can be painful for a few seconds while the marrow is withdrawn. n For the biopsy part of this procedure (which is usually done right after the aspiration), the doctor inserts a slightly larger needle to take out a small piece of bone and marrow. This procedure may also cause mild pain or a pressure sensation. The procedure does not require any stitches. n Patients who are anxious about the test should talk with their doctor and nurse to see whether taking a calming medication before the procedure would be helpful. Learning the Basics 34