- ACRONYMS
- ANC - Absolute neutrophil count
- CBC - Complete blood count
- CD - Cluster differentiation
- EBV - Epstein-Barr virus
- ESR - Erythrocyte sedimentation rate
- G-CSF - Granulocyte colony-stimulating factor
- GM-CSF - Granulocyte-monocyte colony-stimulating factor
- HTLV-1 - Human T-cell lymphotropic virus I
- IG - Immunoglobulin
- IL - Interleukin
- MALT - Mucosa-associated lymphoid tissue
- MDS - Myelodysplastic syndromes
- MGUS - Monoclonal gammopathy of undetermined significance
- MHC - Major histocompatibility complex
- NCCN - National Comprehensive Cancer Network
- NCI - National Cancer Institute
- NK - Natural killer
- RA - Rheumatoid arthritis
- TNF - Tumor necrosis factor
- WBC - White blood cell
- DEFINITIONS
- Adaptive immune system - the adaptive immune system (also called "acquired immunity") is the part of the immune system that forms a customized attack against foreign organisms based on antigens present on the pathogen. After an antigen-presenting cell (e.g. macrophage, dendritic cell, B cell) phagocytizes an invading organism, it takes antigens from it and presents them to T cells. This stimulates a tailored attack against the organism made up of activated lymphocytes and antibodies from B cells. In some cases, foreign organisms reside inside host cells (e.g. viruses, parasites, certain bacteria) and are hidden from phagocytic cells. When this occurs, infected host cells can take antigens from the organism and act as antigen-presenting cells. When presented with a new antigen, the adaptive immune response can take days to weeks to become effective; however, during the initial response, memory cells are formed that provide a fast and robust response upon re-exposure to the same antigen. The adaptive immune response differs from the innate immune response in the following ways: (1) the adaptive immune response must be primed, (2) the adaptive immune response is specific, (3) the adaptive immune response has memory. [1,2,5]
- Agranulocyte - agranulocyte is a collective term for B-cells, T-cells, and monocytes. It is derived from the fact that, unlike granulocytes, these cells lack granules in their cytoplasm. [1,2]
- Antigen - an antigen is a molecule that stimulates an immune response when it is bound by leukocyte receptors. Each T and B lymphocyte is programmed to recognize a specific antigen, and since there are millions of these cells, the number of potential antigens is vast. Antigens are typically part of a pathogen, but they can also come from other sources (e.g. foods, pesticides, cosmetics, fumes, animals). Large proteins are the best antigens for stimulating an immune response, and because of this, they are often used as conjugates in vaccines. Many autoimmune diseases occur when the body incorrectly recognizes an innate or "self-antigen" as a foreign antigen. [1,2,5]
- Apoptosis - apoptosis is the process by which cells intentionally destroy themselves. During apoptosis, cells die without leaking cytokines, and an immune response is not elicited. This is in contrast to cell necrosis, where cells are destroyed, and they leak immune-stimulating chemicals. [1,2]
- Auer rods - Auer rods are cytoplasmic inclusion bodies that form from the abnormal fusion of cytoplasmic granules. Auer rods are found in myeloid blast cells, and they are most commonly seen in acute myeloid leukemia. They are an important finding because they do not occur in lymphoblasts, and therefore, they help distinguish myeloid from lymphocytic leukemia. The rods look like needles and are named after one of the physicians who first described them. [Auer rods image]
- Cell-mediated immunity - cell-mediated immunity is the part of the immune response that involves T cells, macrophages, and inflammatory cytokines. This is in contrast to humoral immunity, which relies on antibodies.
- Clonal - clonal means that the cells being described are genetically identical and, therefore, originated from the same source. For example, a clonal monocytosis means that the increase in monocytes is due to the proliferation of a single, genetically identical line of monocytes. When an increase in a particular type of immune cell is observed, it is sometimes important to determine if the cells are clonal because neoplasms will produce clonal cells, whereas other conditions often produce polyclonal cells (cells that originate from more than one cell line).
- Complement system - the complement system is comprised of about 20 circulating proteins. When complement proteins are activated, they aid in the destruction of foreign pathogens. The main complement proteins are C1 through C9, B, and D. The complement system can be activated through several mechanisms. In the classical pathway, antigen-antibody complexes activate the system, and in the alternative pathway, activation is initiated by pathogen surface molecules. Activated complement proteins have the following actions: (1) opsonization of bacteria, (2) activation of mast cells and basophils, (3) attraction of leukocytes, (4) direct lysis of invading organisms. Complement protein C3b acts as a major opsonin, and C5b, C6, C7, C8, C9 come together to form the membrane-attack complex that punches a hole in the pathogen and causes it to lyse. [1,2]
- Döhle bodies - Döhle bodies are light blue-gray, oval, or round inclusion bodies seen in the cytoplasm of neutrophils. They are thought to consist of remnants of ribosomes and endoplasmic reticulum. Their presence typically indicates increased granulocyte production, and they may be seen in bacterial infections, burns, pregnancy, inflammation, G-CSF therapy, trauma, and malignancies. They often occur with toxic granulation. [Döhle bodies image]
- Epitope - an epitope is the part of an antigen that binds to an antibody or leukocyte receptor. Most antigens have several epitopes, and each epitope stimulates a different B cell. This causes multiple antibodies to form against the same organism, strengthening the immune response. Some pathogens have epitopes that are similar in structure to epitopes found on host cells. This can cause antibodies to crossreact with host cell epitopes, leading to autoimmunity. One example of this is rheumatic heart disease which occurs when antibodies to streptococcal proteins crossreact with antigens on heart valve tissue. This phenomenon is not just seen with pathogens; antibodies to certain medications can also crossreact with self-epitopes. [1,2]
- Granulocyte - granulocyte is a term that refers to neutrophils, eosinophils, and basophils. The term comes from the granular appearance of the cell's cytoplasm when viewed under a microscope. The granules contain a mixture of cytotoxic proteins that are used to destroy infectious agents. [1,2]
- Hapten - a hapten is a foreign antigen that must be attached to a carrier molecule, typically a large protein, in order to activate an immune response. A hapten cannot activate an immune response by itself. [1,2]
- Humoral immunity - humoral immunity is immunity conferred by molecules present in body fluids (e.g. plasma, mucus, saliva). Components of the humoral immune system include antibodies, complement proteins, and other antimicrobial peptides. The name "humoral" is derived from the Latin term "humors," which means body fluids. [1,2]
- Immunoglobulins - immunoglobulins are antibodies. "Immuno" is for immune system, and "globulin" is for "globular protein." Immunoglobulins are "gamma globulins," which comes from the name of the band (gamma band) they form on protein electrophoresis. [1,2]
- Karyotype - karyotype is the number and properties of an individual's chromosomes. Under normal conditions, a person has 23 pairs of chromosomes (one from each parent) or 46 total chromosomes. Changes in the number and/or arrangement of chromosomes are associated with certain conditions. For example, patients with Down's syndrome have an extra chromosome 21, and CML is associated with a translocation of DNA between chromosomes 9 and 22. Karyotypes are analyzed by taking chromosomes from a cell, fixing them to a slide, and staining them. Staining the chromosomes creates distinct bands that can be observed under a microscope to assess changes in their number and/or arrangement. This process is called karyotyping.
- Innate immune system - the innate immune system forms a nonspecific, immediate attack against invading organisms. Unlike the adaptive immune system, it does not require any type of priming to become active. It is made up of phagocytic cells that reside in tissues (e.g. monocytes, macrophages, dendritic cells) and granulocytes (e.g. neutrophils, eosinophils) that can quickly deploy to sites of infection. Macrophages and dendritic cells stimulate the adaptive immune system by presenting antigens from destroyed organisms to T cells and B cells. The natural killer lymphocyte is also part of the innate immune system. It is a specialized lymphocyte that can recognize foreign cells and destroy them directly without priming. [1,2]
- Left shift - "left shift" is a term used to describe an increase in immature neutrophils in the blood. A left shift usually occurs when an infection stimulates neutrophil production in the bone marrow, and immature neutrophils spill over into the blood. Band neutrophils are the most common type of immature form, but other types (e.g. juvenile neutrophils) may be seen. Under normal conditions, bands make up less than 5% of circulating neutrophils, and juvenile neutrophils make up less than 1%.
- Leukocyte - the term leukocyte, also called white blood cell, refers to the mobile cells that make up the immune system. Leukocytes include granulocytes, monocytes, lymphocytes, and derivatives of these cells (e.g. macrophages, dendritic cells, plasma cells). Leukocytes are formed in the bone marrow and lymph tissue, and they travel through the blood to different parts of the body in response to infections and inflammation. Under normal conditions, the number of leukocytes found in the blood is 4000 - 11,000 cells/μl. [1,2]
- Lymphocyte - lymphocyte is a collective term for B cells, T cells, and natural killer lymphocytes. These are the primary cells found in lymph fluid, hence the name "lymphocyte." [1,2]
- Lymphokines - lymphokines are substances secreted by lymphocytes that help to initiate and/or promote an immune response. Examples of lymphokines include interleukins, interferons, and GM-CSF. [1,2]
- Lymph nodes - lymph nodes are small encapsulated organs located throughout the body that are designed to enhance the interaction between antigen-presenting cells and T and B lymphocytes. Lymph nodes are connected through a network of lymph vessels that drain fluid from the interstitium and carry it to lymph nodes. The fluid is eventually returned to the venous circulation through the thoracic duct and the right lymph duct. The movement of lymph through lymph nodes and lymph vessels is supported by skeletal muscle contraction but is otherwise passive. During infections, lymph node swelling (lymphadenopathy) occurs when stimulated lymphocytes start to divide and proliferate. [1,2,5]
- Major histocompatibility complex (MHC) proteins / Human leukocyte antigen (HLA) complexes - MHC proteins are also referred to as human leukocyte antigen (HLA) complexes, and the two terms are used interchangeably. MHC is a gene region found in cells that codes for proteins that bind antigens from degraded organisms. The MHC protein-antigen complex is used to present antigens to T cells. MHC type I proteins present antigens to cytotoxic T cells, and almost every cell in the body can present antigens in this manner. MHC type II proteins present antigens to T-helper cells, and this type of presentation is specific to macrophages, dendritic cells, and B lymphocytes. [1,2]
- Mononucleosis - mononucleosis is a term used to describe an infectious syndrome that includes fever, lymphadenopathy, pharyngitis, splenomegaly, and lymphocytosis. Mononucleosis is typically caused by Epstein-Barr virus, but it may also be seen with cytomegalovirus, HIV (acute infection), adenovirus, and Toxoplasma gondii. A common finding in mononucleosis is the presence of atypical lymphocytes on a blood smear. These cells resemble monocytes and are the reason the term "mononucleosis" was coined. See mononucleosis for more.
- Myelocyte - myelocytes are precursor cells to granulocytes. Under normal conditions, they are only found in the bone marrow. Their presence in the blood is a sign of infection, inflammation, or a leukocyte disorder (e.g. leukemia, dysplasia). [1,2]
- Opsonins - opsonins are immune particles that coat pathogens and make them more attractive to phagocytes. Examples of opsonins are IgG antibodies and the C3b molecule of the complement system. Opsonization is the process where opsonins on the surface of an organism promote its destruction by phagocytosis, cytotoxicity, or the complement system. [1,2]
- Opsonization - opsonization is the process where opsonins (e.g. antibodies, complement proteins) on the surface of an organism promote its destruction by phagocytosis, cytotoxicity, or the complement system.
- Phagocytosis - phagocytosis is a process where immune cells engulf an organism and destroy it. The primary phagocytic cells of the immune system are neutrophils, macrophages, and dendritic cells. A neutrophil can phagocytize 3 - 20 bacteria before it becomes inactive and dies. A macrophage can phagocytize up to 100 bacteria, and it can extrude remnants of destruction, which allows it to live for many months. After an organism is phagocytized, granules in the phagocyte's cytoplasm dump proteolytic enzymes into the engulfed vesicle, and the organism is destroyed. Macrophages and dendritic cells can take antigens from the phagocytized organism and present them to T cells. [1,2]
- Polymorphonuclear - polymorphonuclear is a term used to describe the lobular appearance of the nuclei seen in neutrophils, basophils, and eosinophils [1,2]
- Primary lymphoid organs - the thymus and bone marrow are sometimes referred to as primary lymphoid organs. Primary lymphoid organs are where lymphocytes mature. [1,2]
- Reticuloendothelial system - the reticuloendothelial system is a term used to describe the phagocytic immune system present in body tissues. The reticuloendothelial system is vital in tissues that are constantly exposed to foreign organisms and toxins that must be destroyed (e.g. liver). It is composed of monocytes, mobile macrophages, fixed macrophages, and a few specialized cells in the bone marrow, spleen, and lymph nodes. Most of the cells in the reticuloendothelial system originate from monocyte stem cells, which is why it is sometimes referred to as the monocyte-macrophage system. [1,2]
- Secondary lymphoid organs - secondary lymphoid organs include the lymph nodes, tonsils, spleen, and lymphoid tissue associated with the gut, lungs, and urogenital tract. Secondary lymphoid tissue is where mature immune cells perform their designated functions. [1,2]
- Toll-like receptors - toll-like receptors are receptors on phagocytic cells (e.g. macrophages, dendritic cells) that recognize molecules on the surfaces of invading pathogens [1,2]
- Toxic granulation - toxic granulation is a term used to describe dark coarse granules that can occur in the cytoplasm of neutrophils. Toxic granules are normally present in immature neutrophils, and their presence on a peripheral smear is an indicator of increased neutrophil production. Causes of toxic granulation include infections, chemotherapy, G-CSF therapy, and other inflammatory states. They are often accompanied by Döhle bodies. [Toxic granulation image]
- LEUKOCYTES
- Antigen-presenting cells (APCs) - antigen-presenting cells are cells that degrade and process antigens from other organisms so that they can present them to T cells, and in some cases, B cells (see leukocyte illustration below). The antigen may be obtained after the organism is phagocytized (e.g. macrophages, dendritic cells), or it may come from an organism that invaded the cell and was broken down (e.g. viruses). Processed antigens are coupled with MHC proteins and presented to T cells. Almost all cells in the body can present antigens in some way, but the main antigen-presenting cells of the immune system are B cells, dendritic cells, and macrophages. Because of their importance, these 3 cell types are sometimes referred to as "professional antigen-presenting cells." [1,2,5]
- B lymphocytes (B cells) - B lymphocytes originate and mature in the bone marrow (see leukocyte illustration below). They then leave the bone marrow and migrate to lymph tissue, where they take up residence. B lymphocytes circulate continuously in the body through the following cycle: (1) release from lymphogenous tissue into lymph vessels, (2) lymph vessels empty lymph fluid into the subclavian vein, (3) lymphocytes circulate in the blood for a few hours before passing into tissues, (4) lymph drainage from tissues returns lymphocytes to the lymph vessels. A typical cycle lasts 12 - 24 hours, and a lymphocyte can recirculate like this for months to years. Under normal conditions, B lymphocytes account for 5 - 20% of circulating lymphocytes. When a B lymphocyte comes in contact with a foreign antigen it has been programmed to recognize, it stops circulating and starts to divide. Most of the clones it forms will become antibody-secreting plasma cells, but a small number will distribute themselves throughout the body and become memory cells. Memory cells do not participate in the initial immune response, and instead, they lie in wait for a second exposure to the same antigen. Upon re-exposure, memory cells produce a much faster and larger antibody response than the original one. This effect of memory cells is why many vaccines are given as several doses separated by weeks to months. B cells also process and present antigens to T-helper cells so that they can modulate the immune response. [1,2,5]
- Basophils - basophils are one of the three granulocytes formed in the bone marrow (see leukocyte illustration below). Under normal conditions, basophils make up about 0 - 2% of circulating leukocytes. Basophils are related to mast cells in that they release substances like histamine, bradykinin, and chemotactic factors when activated. These inflammatory mediators cause the following actions: (1) increased blood flow and capillary permeability in the surrounding tissue, (2) attraction of eosinophils and neutrophils to the affected site. Basophils also play an important role in allergic reactions. Immunoglobulins of the IgE class can attach themselves to basophils, and when they are bound by an antigen, they cause basophils to rupture and release their inflammatory cytokines. Basophils also release heparin into the circulation on a regular basis. Heparin is important in preventing blood clots and containing coagulation. [1,2]
- Cytotoxic T cells - cytotoxic T cells (also called CD8+ cells) are formed when a T cell is activated by an antigen-presenting cell (see leukocyte illustration below). Cytotoxic T cells look for the antigen they are programmed to find on organisms and cells. When they find the appropriate antigen, they bind to it and secrete perforins that punch holes in the organism's membrane. Fluid then rushes into the organism, causing it to swell and disintegrate. Cytotoxic T cells can also secrete toxins directly into a cell. Besides destroying bacteria, cytotoxic T cells play an important role in destroying virus-infected tissue, cancer cells, and the foreign cells of organ transplants. Cytotoxic T cells differ from natural killer lymphocytes in that they require priming before they can destroy an organism, where natural killer cells do not. Cytotoxic T cells are also involved in "delayed hypersensitivity allergic reactions." These reactions occur when T-helper cells and cytotoxic T cells are primed by an allergy-producing antigen such as the poison ivy toxin. Upon re-exposure to poison ivy, the antigen causes primed T cells to diffuse into the affected tissue and elicit an immune response. This typically takes about a day to occur and differs from IgE-mediated allergic reactions, which occur immediately. [1,2,5]
- Dendritic cells - dendritic cells are antigen-presenting cells that reside in tissues that come in contact with the external environment (e.g. skin, lung epithelium, GI tract). Dendritic cells are derived from monocytes, and their primary function is to process and present foreign antigens to T cells (see leukocyte illustration below). The cells are named for the characteristic dendrites (short extensions) that extrude from their surfaces. [1,2,5]
- Eosinophils - eosinophils are one of the three granulocytes formed in the bone marrow (see leukocyte illustration below). Eosinophils reside in the gut, mammary gland, uterus, thymus, bone marrow, and fat tissue. Under normal conditions, eosinophils make up about 1 - 3% of the circulating WBCs. Eosinophils are released in response to parasitic and worm infections; they secrete factors that punch holes in these organisms and cause them to die. They are also attracted to sites of allergic reactions where it is believed that they play a role in neutralizing inflammatory mediators released by basophils and mast cells and phagocytizing allergen-antibody complexes. Abnormally high eosinophil concentrations can be seen in the lungs of some asthmatics and in the skin after allergic reactions. [1,2,6]
- Histiocyte - histiocyte is a morphological term used to describe tissue-resident macrophages and dendritic cells. "Histio" means tissue, and "cyte" means cell. Histiocytosis is a condition where histiocytes migrate into tissues where they are not normally found and cause damage. [1,2]
- Kupffer cells - Kupffer cells are the name given to macrophages that reside in the liver. Kupffer cells line the liver sinusoids, where they engulf and destroy the large number of bacteria that come from the gastrointestinal tract through the portal circulation. [1,2]
- Langerhan cells - Langerhan cells, named after the German physician who discovered them, are dendritic cells that reside in the epidermis and mucosa of the respiratory, digestive, and urogenital tracts. Langerhan cells process antigens and present them to resident lymphocytes. They can also migrate to nearby lymph nodes and present them there. [1,2]
- Macrophages - macrophages are formed when monocytes pass into tissues and swell to a much larger size (see leukocyte illustration below). Macrophages phagocytize and destroy invading organisms. A macrophage can phagocytize up to 100 bacteria, and it can extrude the remnants of destruction, which allows it to live for many months. Macrophages can also phagocytize organisms that are larger than bacteria, where neutrophils cannot. After an organism is phagocytized, granules in the macrophage cytoplasm dump proteolytic enzymes into the engulfed vesicle, and the organism is destroyed. Macrophages are concentrated in tissues that are frequently exposed to invading organisms, and they can be mobile or fixed. In lymph nodes, macrophages line sinuses, where they destroy organisms that have made it into the lymphatic fluid. In the lungs, macrophages in the alveolar walls phagocytize inhaled organisms. They also engulf inhaled particles like silica, asbestos, and tuberculosis bacilli that they are incapable of destroying. These macrophage-particle complexes can form "giant cell" capsules that persist forever. In the liver, macrophages (also called Kupffer cells) line the sinusoids, where they engulf and destroy the large number of bacteria that come from the gastrointestinal tract through the portal circulation. Organisms that gain access to the blood are destroyed by macrophages in the spleen and bone marrow. Macrophages also work with the adaptive immune system by presenting antigens to B and T cells. [1,2,5]
- Mast cells - mast cells share many of the same functions as basophils, and it was initially thought that they shared a common lineage; however, recent research has shown that mast cells are derived from their own bone marrow progenitor cells (see leukocyte illustration below). Mast cells are located in tissues surrounding capillaries throughout the body. When activated, mast cells release substances like histamine, bradykinin, and chemotactic factors. These inflammatory mediators cause the following actions: (1) increased blood flow and capillary permeability in the surrounding tissue, (2) attraction of eosinophils and neutrophils to the affected site. Mast cells also play an important role in allergic reactions. Immunoglobulins of the IgE class can attach themselves to mast cells, and when they are exposed to the appropriate allergen, they cause mast cells to rupture and release their cytokines. Depending on the situation, these reactions can range in severity from mild allergic rhinitis to anaphylaxis. Mast cells also release heparin into the circulation on a regular basis. Heparin is important in preventing blood clots and containing coagulation. [1,2,4]
- Megakaryocyte - megakaryocytes are formed in the bone marrow, where they fragment and release platelets into the circulation (see leukocyte illustration below). About 30,000 platelets per microliter of blood are produced each day, and the entire circulating platelet population is replaced every 10 days. [1,2]
- Memory cells - memory cells are B and T lymphocytes formed during the initial exposure to an antigen (see leukocyte illustration below). Unlike other lymphocyte clones (e.g. plasma cells, cytotoxic T cells), memory cells do not participate in the initial immune response. Instead, they distribute themselves throughout the body and wait for re-exposure to the same antigen. Upon re-exposure, they produce a much larger and faster response than the initial response. This effect of memory cells is why many vaccines are given as several doses separated by weeks to months. [1,2,5]
- Microglial cells - microglial cells are macrophages that reside in the brain. Microglial cells perform a broad range of functions, including removing damaged neurons and plaques and forming the first line of defense against invading organisms. [1,2]
- Monocytes - monocytes are formed in the bone marrow (see leukocyte illustration below). Once they leave the bone marrow, they migrate into tissues where they can become macrophages, dendritic cells, or remain as monocytes. Under normal conditions, monocytes make up about 5.3% of circulating leukocytes. Monocytes that reside in tissues can phagocytize organisms and present antigens to lymphocytes. They can also transform into macrophages with the appropriate stimulus. [1,2,5]
- Natural killer (NK) lymphocytes - natural killer lymphocytes are specialized lymphocytes that can recognize and destroy tumor cells, foreign cells, and infected cells (see leukocyte illustration below). Unlike other lymphocytes that have to be primed before they attack an organism, natural killer lymphocytes attack organisms directly, making them part of the innate immune system. NK cells originate in the bone marrow from the common lymphoid progenitor cell. Some NK cells mature in the bone marrow while others mature in secondary lymphoid tissue. NK cells represent about 5 - 20% of circulating lymphocytes. NK cells are best known for their ability to kill virus-infected cells and developing tumor cells. This latter effect makes them a popular target for cancer immunotherapy. NK cells destroy their targets by releasing cytotoxic granules that cause the cells to lyse. In the presence of lymphokines, NK cells become even more potent at killing, and this is why they are sometimes called lymphokine-activated killer cells. [1,2,3]
- Neutrophils - neutrophils are one of the three granulocytes formed in the bone marrow (see leukocyte illustration below). Mature neutrophils continually circulate, and under normal conditions, they are the most abundant leukocyte, accounting for 62% of circulating WBCs. When a neutrophil is released from the bone marrow, it remains in the bloodstream for 4 - 8 hours before passing into tissue. In infected tissues, neutrophils phagocytize invading organisms and destroy them by dumping proteolytic enzymes into the surrounding vesicle. A neutrophil can phagocytize 3 - 20 bacteria before it becomes inactive and dies. This usually takes about 4 - 5 days, but serious infections can cause the entire process to speed up, in which case, the neutrophil lifespan outside of the bone marrow may only be a few hours. Neutrophils cannot phagocytize organisms that are larger than bacteria, but macrophages can. [1,2]
- Plasma cells - when B cells are activated by an antigen, they divide and form plasma cells. Plasma cells secrete antibodies against the antigen that activated the B cell (see leukocyte illustration below). Initially, plasma cells secrete IgM, but they switch to IgG after 1 - 2 weeks. Depending on the situation, they can also produce IgA, IgD, and IgE. [1,2,5]
- Regulatory T cells - regulatory T cells (also called suppressor T cells, Tregs, and CD4+CD25+ cells) are T lymphocytes that regulate or suppress the immune response. Regulatory T cells play an important role in preventing autoimmunity and in containing the immune response so that it does not harm healthy host tissue. The full actions of regulatory T cells have not been completely defined, but they appear to suppress T-helper cells, cytotoxic T cells, antigen-presenting cells, and most likely, B cells.
- T-helper cells - T-helper cells (also called CD4+ cells) are the most abundant type of T cell, accounting for more than 75% of all T cells (see leukocyte illustration below). When activated, T-helper cells secrete interleukins, interferon, and GM-CSF. These lymphokines have a number of stimulatory effects on the immune system that include the following: (1) stimulation of B cell growth, plasma cell formation, and antibody production, (2) growth and proliferation of cytotoxic and suppressor T cells, (3) macrophage attraction and stimulation (4) activation of more T-helper cells. T-helper cells are essential to forming a successful immune response, and without them, a person becomes susceptible to many different types of infections. Such is the case with the human immunodeficiency virus (HIV), which selectively destroys T-helper cells.
- T lymphocytes (T cells) - T lymphocytes originate in the bone marrow before migrating to the thymus gland, where they divide rapidly (see leukocyte illustration below). In the thymus, thousands of T lymphocytes are formed that have reactivity against thousands of different antigens. To prevent autoimmunity, T lymphocytes are tested to see if they react with self-antigens, and the ones that do are destroyed. Processed T lymphocytes then leave the thymus and take up residence in different lymphoid tissues throughout the body. Lymphocytes circulate continuously in the body through the following cycle: (1) release from lymphogenous tissue into lymph vessels, (2) lymph vessels empty lymph fluid into the subclavian vein, (3) lymphocytes circulate in the blood for a few hours before passing into tissues, (4) lymph drainage from tissues returns lymphocytes to the lymph vessels. A typical cycle lasts 12 - 24 hours, and a lymphocyte can recirculate like this for months to years. T lymphocytes become activated when they come into contact with a foreign antigen. But unlike B cells that can be activated solely by an antigen, T cells are only activated by antigens that are bound to major histocompatibility complex (MHC) proteins on the surface of antigen-presenting cells (e.g. macrophages, B cells, dendritic cells). When a T cell is activated, it starts to divide and form clones that become T-helper cells, cytotoxic T cells, and memory cells. Memory cells do not participate in the initial immune response, and instead, they distribute themselves throughout the lymph tissue. When they are re-exposed to the same antigen, they produce a much faster and larger response than the original one.
- ANTIBODIES
- Overview
- Antibodies are proteins secreted by plasma cells. Antibodies are often referred to as immunoglobulins; "Immuno" is for immune system, and "globulin" is for "globular protein." Immunoglobulins are also called "gamma globulins," which comes from the name of the band (gamma band) they form on protein electrophoresis. Antibodies are composed of light chains and heavy chains, and each antibody is specific for a particular antigen. There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE. Initially, plasma cells secrete IgM, but they switch to IgG after 1 - 2 weeks. Depending on the situation, they can also produce IgA, IgD, and IgE. When antibodies bind to a pathogen, they have the following effects: (1) neutralization of the pathogen so that it cannot penetrate host cells, (2) precipitation of the pathogen, which makes it an easy target for phagocytosis, (3) tagging the pathogen so that phagocytes and cytotoxic cells know to attack it, (4) fixing complement to the pathogen which promotes opsonization and can lead to complement-mediated cell lysis. Today, many of the medications used to treat a range of conditions are actually antibodies that are engineered in a lab. These medications are part of a drug class called biologicals, and they are typically antibodies directed against immune-modulating lymphokines and their receptors. Once they are injected or infused, they can circulate for 2 - 3 weeks before they are broken down.
- Immunoglobulin G (IgG)
- IgG is the most abundant type of immunoglobulin, accounting for 75% of all antibodies (see antibody illustration). IgG has four subtypes - IgG1, IgG2, IgG3, and IgG4. When plasma cells are exposed to an antigen, they initially secrete IgM. They then switch to IgG around 1 - 2 weeks later (see antibody response below). IgG has a half-life of 23 days, and detectable levels of IgG can persist for a lifetime with some infections. Upon re-exposure to an antigen, IgG levels rise rapidly because it is the primary antibody secreted by memory B cells. When IgG is bound to a pathogen, it promotes its agglutination. It can also fix complement for opsonization. IgG is the only antibody that crosses the placenta. [1,2]
- Immunoglobulin M (IgM)
- IgM consists of 5 antibody subunits bound together, making it the largest antibody (see antibody illustration). IgM accounts for about 8% of circulating antibodies, and it has an average half-life of 5 days. IgM is the first antibody secreted by activated plasma cells upon exposure to a new antigen, and it takes about 5 - 7 days for IgM levels to become detectable in plasma. IgM levels increase for several weeks before declining and giving way to IgG (see antibody response below). Depending on the infection, IgM can remain detectable in plasma for 1 - 4 months. Because of its multiple antigen-binding sites, IgM is excellent at agglutinating foreign pathogens. It is also able to fix complement for opsonization. [1,2]
- Immunoglobulin A (IgA)
- Most forms of IgA consist of 2 antibody subunits bound together (see antibody illustration). IgA has 2 subtypes, IgA1 and IgA2. IgA1 is produced in the bone marrow and released into the circulation, where it accounts for about 15% of circulating antibodies. IgA2 is found in tears, saliva, and the mucosal surfaces of the gastrointestinal, respiratory, and urogenital tracts. IgA binds and neutralizes pathogens, inhibiting their adhesion to epithelial cells. This makes it one of the first lines of defense against infection. [1,2]
- Immunoglobulin E (IgE)
- IgE antibodies represent less than 1% of circulating antibodies (see antibody illustration). IgE antibodies are involved in antiparasitic immunity (e.g. helminths, protozoa), but they are mostly known for their role in allergic reactions. IgE antibodies have a propensity to attach themselves to mast cells and basophils. When bound by an allergen, they cause basophils and mast cells to release histamine and other leukotrienes. These substances promote vasodilation, capillary permeability, contraction of smooth muscle, and attraction of eosinophils and neutrophils. IgE-mediated allergic reactions are called "immediate hypersensitivity reactions" because they occur immediately upon exposure. This is in contrast to the "delayed hypersensitivity reactions" caused by cytotoxic T cells, which typically take a day or so to form. Immediate hypersensitivity reactions are responsible for a range of conditions, including urticaria (hives), allergic asthma, allergic rhinitis, and anaphylaxis. [1,2]
- Immunoglobulin D (IgD)
- IgD antibodies represent about 1% of circulating antibodies (see antibody illustration). They are also found on the surface of naïve B cells. The exact function of IgD antibodies is unknown, but it has been theorized that they play a role in immune tolerance and/or basophil and mast cell activation. [1,2]
- CYTOKINES
- Overview
- Cytokines are substances (e.g. interleukins, interferon, tumor necrosis factor) secreted by cells that affect the activity of other cells. Most cytokines are secreted by cells of the immune system, but many other types of cells can also secrete cytokines. Depending on the situation, cytokines have both pro-inflammatory and immunosuppressive effects on their target cells. Many of the biologics that are used to treat a range of conditions today are antibodies directed against cytokines and their receptors. Some of the more clinically relevant cytokines are reviewed below. [1,2,7]
- Interleukin-1
- Cells that secrete: monocytes, macrophages, dendritic cells, lymphocytes, endothelial cells, fibroblasts, microglia
- Target: B cells, macrophages, endothelial cells, tissue cells
- Main actions: (1) lymphocyte activation, (2) macrophage stimulation, (3) increased leukocyte adhesion factor on endothelial cells, (4) fever induction through hypothalamus stimulation, (5) release of acute phase reactants from liver, (6) stimulation of hematopoiesis [1,2,7]
- Related medications:
- Anakinra (Kineret®) - recombinant form of interleukin-1 receptor antagonist
- Corticosteroids - corticosteroids inhibit the effects of IL-1
- Interleukin-2
- Cells that secrete: T-helper cells and cytotoxic T cells
- Target: T cells
- Main actions: (1) activates more T-helper cells, (2) promotes the growth and proliferation of cytotoxic and suppressor T cells (3) stimulates B-cell differentiation and antibody production, (4) under certain conditions it is also immunosuppressive [1,2,7]
- Related medications:
- Aldesleukin (Proleukin®) - recombinant interleukin-2. [Proleukin PI]
- Interleukin-4
- Cells that secrete: T-helper cells, mast cells, eosinophils, basophils
- Target: B cells and T cells
- Main actions: (1) promotes B-cell growth and proliferation, the formation of plasma cells, and antibody secretion, (2) promotes antibody class switching to IgE, (3) involved in allergic reactions, (4) closely related to IL-13
- Related medications:
- Dupilumab (Dupixent®) - monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding to the IL-4 receptors
- Interleukin-5
- Cells that secrete: T-helper cells and mast cells
- Target: B cells and eosinophils
- Main actions: (1) promotes B-cell growth and proliferation, the formation of plasma cells, and antibody secretion, (2) promotes antibody class switching to IgA, (3) promotes eosinophil growth, differentiation, recruitment, and activation [1,2,7]
- Related medications:
- Benralizumab (Fasenra®) - monoclonal antibody that blocks IL-5 receptors
- Mepolizumab (Nucala®) - monoclonal antibody that binds IL-5
- Reslizumab (Cinqair®) - monoclonal antibody that binds IL-5
- Interleukin-6
- Cells that secrete: T and B lymphocytes, fibroblasts, monocytes, macrophages, endothelial cells
- Target: B cells, T cells, hepatocytes,
- Main actions: (1) promotes B-cell growth and proliferation, the formation of plasma cells, and antibody secretion, (2) stimulates release of acute phase reactants from liver (3) stimulates hematopoiesis (4) causes T cell activation, (5) causes fever [1,2,7]
- Related medications:
- Sarilumab (Kevzara®) - monoclonal antibody that binds IL-6 receptors
- Tocilizumab (Actemra®) - monoclonal antibody that binds IL-6 receptors
- Interleukin-12
- Cells that secrete: monocytes, macrophages, dendritic cells
- Target: natural killer cells, T-helper cells
- Main actions: (1) activates natural killer cells and T-helper cells, (2) induces interferon gamma production (3) closely related to IL-23, (4) overproduction can lead to allergic disorders
- Related medications:
- Ustekinumab (Stelara®) - monoclonal antibody that binds IL-12 and IL-23 p40 protein subunit
- Corticosteroids - corticosteroids inhibit the effects of IL-12
- Interleukin-13
- Cells that secrete: T-helper cells, natural killer cells, mast cells
- Target: monocytes, fibroblasts, epithelial cells, B cells
- Main actions: (1) stimulates B cell growth and differentiation, (2) promotes antibody class switching to IgE, (3) increases mucus production by epithelial cells, (4) increases collagen synthesis by fibroblasts, (5) works with IL-4 to promote allergic reactions and antiparasitic activity [1,2,7]
- Related medications:
- Dupilumab (Dupixent®) - monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding to the IL-4 receptor alpha subunit that is shared by the IL-4 and IL-13 receptors
- Interleukin-17
- Cells that secrete: T-helper cells
- Target: epithelial cells, endothelial cells, keratinocytes, macrophages
- Main actions: (1) stimulates release and production of IL-6 and other cytokines (2) enhances activity of antigen-presenting cells [1,2,7]
- Related medications:
- Brodalumab (Siliq®) - monoclonal antibody that binds IL-17
- Ixekizumab (Taltz®) - monoclonal antibody that binds IL-17
- Secukinumab (Cosentyx®) - monoclonal antibody that binds IL-17
- Interleukin-23
- Cells that secrete: macrophages, dendritic cells
- Target: T-helper cells
- Main actions: (1) maintenance and expansion of IL-17 production by T-helper cells
- Related medications:
- Guselkumab (Tremfya®) - monoclonal antibody that binds IL-23
- Risankizumab (Skyrizi®) - monoclonal antibody that binds IL-23
- Tildrakizumab (Ilumya™) - monoclonal antibody that binds IL-23
- Ustekinumab (Stelara®) - monoclonal antibody that binds IL-12 and IL-23 p40 protein subunit
- Tumor necrosis factor (TNF)
- Cells that secrete: T-helper cells, macrophages, mast cells, endothelial cells
- Target: macrophages, lymphocytes, endothelial cells
- Main actions: (1) stimulates release of pro-inflammatory cytokines, (2) attracts neutrophils, (3) causes fever, (4) stimulates angiogenesis, (5) stimulates release of acute phase reactants from the liver [1,2,7]
- Related medications:
- Adalimumab (Humira®) - monoclonal antibody specific for human tumor necrosis factor alpha
- Certolizumab (Cimzia®) - antibody specific for human tumor necrosis factor alpha
- Etanercept (Enbrel®) - dimeric soluble form of TNF receptor that can bind TNF molecules
- Golimumab (Simponi®) - human IgG1 monoclonal antibody specific for human tumor necrosis factor alpha
- Infliximab (Remicade®) - chimeric IgG1 monoclonal antibody specific for human tumor necrosis factor alpha
- Corticosteroids - corticosteroids inhibit the production of TNF
- NEUTROPHIL DISORDERS
| Neutrophil levels in adults | ||
|---|---|---|
| Range | Absolute neutrophil count (cells/μl) |
|
| High | > 7500 | May occur from an overall increase in neutrophils or a shift from bone marrow to the circulation |
| Normal | 2500 - 6000 | Neutrophils typically account for 40 - 60% of total WBCs |
| Mild neutropenia | 1000 - 1500 | Not associated with an increased risk of infection |
| Moderate neutropenia | 500 - 999 | Slight increased risk of infection in some patients |
| Severe neutropenia | < 500 | Increased risk of infection in most patients |
| Band neutrophils | ||
| Normal | 0 - 500 | Neutrophil bands typically account for 0 - 5% of total WBCs |
| Left shift | > 500 | Typically a sign of bacterial infection |
- NEUTROPENIA
- Overview
- Neutropenia is defined as an absolute neutrophil count < 1500 cells/μl (see neutrophil levels above). In the U.S., the prevalence of neutropenia varies by race and sex with black females having the highest rate (10.5% in some studies) and Caucasians and Hispanics having the lowest (< 1%). Neutropenia may be congenital or acquired, and the table below lists different causes for each type. [13]
| Causes of neutropenia |
|---|
| Congenital neutropenia |
Benign ethnic neutropenia (BEN)
|
Benign familial neutropenia
|
Cyclic neutropenia
|
Severe congenital neutropenia (SCN)
|
| Acquired causes |
Infections
|
Drug-induced neutropenia
Drugs that are known to cause neutropenia
Drugs that have been associated with neutropenia
|
Autoimmune neutropenia
|
Hematologic disorders
|
Nutritional disorders
|
- Evaluating neutropenia
- When evaluating neutropenia, it's important to take a thorough medical history because neutropenia is often a secondary effect of another condition as opposed to a primary neutrophil disorder. The steps below can help to identify the etiology of neutropenia, but the medical history should be first and foremost when considering a workup.
| Steps to evaluating neutropenia |
|---|
|
Step 1 - Assess the degree of neutropenia
|
|
Step 2 - Order labs and determine if the neutropenia is chronic or new onset
|
|
Step 3 - Based on findings, consider the following
|
- NEUTROPHILIA
- Overview
- Neutrophilia is defined as an ANC > 7500 cells/μl on a CBC (see neutrophil levels above). Neutrophilia may occur from an increase in the total number of neutrophils, a shift of neutrophils from the bone marrow to the circulation, or a combination of the two. The table below lists different causes of neutrophilia. Neutrophilia is almost always a secondary effect of another process, and the diagnosis and treatment lies in addressing the underlying disorder.
- LYMPHOCYTE DISORDERS
| Lymphocyte levels in adults | |
|---|---|
| Range | Absolute lymphocyte count (cells/μl) |
| Lymphocytosis | > 4000 |
| Normal | 1000 - 4000 (20 - 40% of WBCs) |
| Mild to moderate lymphopenia | 500 - 1000 |
| Severe lymphopenia | < 500 |
|
|
- LYMPHOPENIA
- Overview
- Lymphopenia, also called lymphocytopenia, is typically defined as an absolute lymphocyte count of < 1000 cells/μl (see lymphocyte levels above). Under normal conditions, T lymphocytes make up 60 - 80% of circulating lymphocytes, and B lymphocytes and natural killer lymphocytes each represent about half of the remaining 20 - 40%. Most cases of lymphopenia are from a reduction in circulating T cells.
- Lymphopenia may be primary or secondary. Primary lymphopenia occurs from inherited disorders of the immune system, and these syndromes are rare. Secondary lymphopenia or "acquired lymphopenia" is the result of other conditions that affect lymphocytes, and most cases of lymphopenia are of this type.
| Causes of lymphopenia |
|---|
Advanced age
|
Primary immune disorders
|
Infections
|
Medications
|
Autoimmune diseases
|
Other
|
- Evaluating lymphopenia
- The steps below provide some guidance in evaluating lymphopenia. They are adapted from review articles and the U.K.'s National Health Service recommendations for evaluating lymphopenia in primary care. In most cases, the medical history will be the most important tool in narrowing the differential.
| Steps in evaluating lymphopenia |
|---|
Step 1 - order HIV, peripheral smear, and assess the following:
|
|
Step 2 - further testing
|
- LYMPHOCYTOSIS
- Overview
- Lymphocytosis in adults is defined as an absolute lymphocyte count > 4000 cells/μl (see lymphocyte levels above). Circulating lymphocytes as seen on a CBC consist of T lymphocytes (60 - 80%), B lymphocytes (5 - 20%), and natural killer lymphocytes (5 - 20%). Lymphocyte types can be identified with flow cytometry but not with a CBC or peripheral smear. Lymphocytosis may be either reactive (e.g. infections, hypersensitivity reactions) or secondary to lymphoproliferative disorders (e.g. leukemia, lymphoma). The table below lists different causes of lymphocytosis.
| Causes of lymphocytosis |
|---|
| Infections |
Viral Infections
|
Bacterial infections
|
|
Protozoan infections
|
Mycobacterium infections
|
| Hematologic disorders |
|
| Medications |
|
| Other |
|
- Evaluating lymphocytosis
- The medical history typically narrows the differential in lymphocytosis. In many cases, the etiology will be obvious (e.g. recent viral syndrome), and at other times, additional lab work will be required to pinpoint the cause. The labs listed below may be helpful depending on the situation.
| Diagnostic testing in lymphocytosis |
|---|
|
- EOSINOPHIL DISORDERS
| Eosinophil levels in adults | |
|---|---|
| Range | Absolute eosinophil count (cells/μl) |
| Severe eosinophilia | > 5000 |
| Moderate eosinophilia | 1500 - 5000 |
| Mild eosinophilia | 500 - 1500 |
| Normal | 50 - 500 (1 - 3% of WBCs) |
| Eosinopenia | < 50 |
- EOSINOPHILIA
- Overview
- Eosinophilia is defined as an absolute eosinophil count > 500 cells/μl (see eosinophil levels above). A registry study that reviewed CBCs ordered by general practitioners from 359,950 individuals found a eosinophilia prevalence of 4%. Causes of eosinophilia can be divided into three different categories - primary, secondary, and idiopathic. Most cases of eosinophilia are secondary or "reactive"; primary and idiopathic eosinophilia are rare. Causes of eosinophilia divided into these main categories are presented in the table below. [26,27]
| Causes of eosinophilia |
|---|
| Primary eosinophilia |
|
| Idiopathic eosinophilia |
|
| Secondary eosinophilia |
Allergic conditions
|
Autoimmune diseases
|
Fungal infections
|
Gastrointestinal disorders
|
Medications
|
Malignancies
|
Parasitic infections
|
Vasculitis
|
Other
|
- Evaluating eosinophilia
- The differential in eosinophilia is broad, and there is no one-size-fits-all diagnostic approach that can be applied to every patient. As usual, the medical history plays an important role in narrowing the search for a cause. The recommendations below are from the British Society of Hematology. They are somewhat broad and rely heavily on patient findings.
| Steps in evaluating eosinophilia |
|---|
Step 1 - check the following labs in all patients
|
|
Step 2 - consider the following based on patient history
|
| Step 3 - if testing and/or history is not revealing, refer to heme/onc for hematologic malignancy and HES testing |
- Eosinopenia
- Eosinopenia is defined as an absolute eosinophil count of < 50 cells/μl (see eosinophil levels above). Eosinopenia has primarily been studied as a prognostic indicator of worse outcomes and mortality in a number of conditions including COVID-19, myocardial infarction, stroke, and sepsis to name a few. It has also been looked at as a diagnostic tool in differentiating bacterial sepsis from other inflammatory conditions. As a primary condition, it has not been evaluated extensively, and there is no meaningful information on it in the medical literature.
- BASOPHIL DISORDERS
- Basophilia
- Basophilia is defined as an absolute basophil count > 100 cells/μl. It is a rare finding, occurring in < 0.1% of CBCs ordered in general practice. Given its limited prevalence, it has not been studied extensively, and there is little information in the medical literature about it. Basophilia may be either reactive or associated with hematologic disorders, most commonly chronic myeloid leukemia. Causes of basophilia are listed in the table below, but it's important to keep in mind that many of the proposed associations are based on weak or anecdotal evidence. [31,32]
- Evaluating basophilia
- Basophilia on a CBC should first be confirmed with a peripheral smear or flow cytometry. If the basophilia is determined to be real, signs and symptoms of a reactive basophilia should be investigated (see reactive basophilia above). Based on these findings, consider the following:
- Isolated basophilia, no signs of a reactive basophilia, or basophil count > 1000 cells/μl
- Refer to heme/onc to evaluate for CML, myelodysplasia, acute myeloid leukemia, and other myeloproliferative disorders
- Symptoms suggestive of a reactive basophilia
- Repeat basophil count with an accurate method in 2 - 3 weeks. If basophilia persists, refer to heme/onc to evaluate for CML, myelodysplasia, acute myeloid leukemia, and other myeloproliferative disorders [31]
- Basopenia
- Under normal conditions, basophils may not be present on a CBC, so basopenia is not a condition that receives a lot of attention. There are no guidelines or review articles from professional journals that give recommendations on evaluating basopenia. Some conditions that have been associated with basopenia are listed below.
- Conditions associated with basopenia:
- Anxiety / Stress
- Autoimmune diseases
- Chronic urticaria
- Cushing disease
- Glucocorticoid therapy
- Immediate hypersensitivity reactions
- Infectious diseases
- Neoplasms [31]
- MONOCYTE DISORDERS
- Monocytosis
- Monocytosis is defined as an absolute monocyte count > 1000 cells/μl. Monocytosis may be either reactive or primary. Reactive monocytosis occurs secondary to another process (e.g. infection), and primary monocytosis occurs from myelodysplastic or myeloproliferative disorders. The table below lists different causes of monocytosis. [33]
| Causes of monocytosis |
|---|
|
Reactive monocytosis
|
Primary monocytosis
|
- Evaluating monocytosis
- There are no guidelines from professional organizations that give recommendations on evaluating monocytosis. Some general points about monocytosis are given below. Almost all patients with persistent monocytosis should be referred to heme/onc for further evaluation.
- Monocytosis on a CBC should be confirmed with a peripheral smear
- Monocytosis in the presence of neutropenia suggests a reactive etiology
- An absolute monocyte count > 1000 cells/μl is suggestive of a neoplasm
- A persistent, unexplained monocytosis in the elderly is consistent with chronic myelomonocytic leukemia [33]
- Monocytopenia
- Monocytopenia is defined as an absolute monocyte count < 200 cells/μl. There are no guidelines or review articles from professional journals that give recommendations on evaluating monocytopenia. Most published information on monocytopenia relates to its association with other primary disorders. A group of genetic disorders that affect the GATA2 gene may present as severe monocytopenia. Conditions that have been associated with monocytopenia are listed below.
- Conditions associated with monocytopenia
- Acetaminophen overdose
- Acute lymphoblastic leukemia
- Adenovirus infection
- Aplastic anemia
- Chemotherapeutic agents
- Corticosteroids
- Cyclic neutropenia - may cause an intermittent monocytopenia
- Epstein-Barr virus infection
- GATA2 gene mutation - GATA2 is a transcription protein critical for the formation of blood cells and lymphatic vessels. GATA2 deficiency may cause lymphedema, myeloid neoplasms, and blood dyscrasias, including severe monocytopenia.
- Hairy cell leukemia
- Hemodialysis - the monocyte count drops during the first 30 minutes then returns to normal
- HIV infection
- Hodgkin lymphoma
- IVIG therapy
- Severe burns
- Tuberculosis [34,43]
- LEUKEMIA
- Overview
- Leukemia is a cancer of blood cells that starts in the bone marrow. This is in contrast to lymphomas which originate in lymph nodes. Leukemia occurs when there is uncontrolled proliferation of hematopoietic stem cells in the lineage of a blood cell, most often leukocytes. Leukemias are divided into two major groups - lymphocytic and myeloid. Lymphocytic leukemias originate in the cell lines of B and T lymphocytes, and myeloid leukemias develop in the cell lines of granulocytes, monocytes, megakaryocytes, and erythrocytes (see blood cell development illustration). Leukemias are further divided into acute and chronic subtypes. Acute leukemias develop quickly and can be fatal within months if untreated. Chronic leukemias develop slowly and can go years without being symptomatic.
- Leukemia is a relatively common cancer; in the general U.S. population, the lifetime risk of developing leukemia is 1.5%. Males are affected more than females, and Whites have the highest risk while Asians have the lowest. [35,36,37]
- Symptoms
- Acute leukemia symptoms are often nonspecific and can overlap with other common conditions like viral syndromes. When these symptoms persist beyond a normal amount of time or if more concerning features are present (e.g. easy bruising), acute leukemia should be considered, and a CBC should be ordered.
- Chronic leukemias are less likely to cause symptoms and are often found incidentally on routine blood work
- Symptoms of leukemia
- Weight loss
- Fatigue
- Fever
- Night sweats
- Loss of appetite
- Bone and joint pain
- Splenomegaly
- Hepatomegaly
- Lymphadenopathy (more common with lymphoblastic leukemia)
- Shortness of breath (if anemia is present)
- Excessive bruising or bleeding (if thrombocytopenia is present)
- Recurrent infections (if neutropenia is present)
- Coughing and trouble breathing (if thymus is enlarged)
- Stroke-like syndromes (rare but may be seen with very high blast counts)
- Superior vena cava (SVC) syndrome - may be seen in T-cell ALL that causes the thymus to swell and press on the superior vena cava. SVC syndrome causes swelling of the neck, arms, and face, along with headaches, dizziness, and mental status changes. [35,36,37]
- Diagnosis
- A CBC and peripheral smear are the initial labs for diagnosing leukemia. Leukocytosis (WBCs > 20,000 cells/μl) is almost always present in chronic leukemia, and it may or may not be present in acute leukemia. Blast cells on the peripheral smear are a common finding, and other hematologic abnormalities (e.g. anemia, thrombocytopenia) are often present. Patients with abnormal findings should be referred to heme/onc for further testing which often includes the tests listed below.
- Bone marrow biopsy/aspiration - bone marrow samples may be obtained through biopsy or aspiration. Bone marrow aspiration is a procedure where a small needle is used to remove a liquid sample of marrow from the bone. In a bone marrow biopsy, a larger needle is used to remove a piece of bone with marrow in it. Normal bone marrow has a blast count of ≤ 5%. In acute leukemia, the blast count is ≥ 20% in most cases. The presence of Auer rods in blast cells is highly suggestive of AML.
- Cytogenetic analysis (karyotyping) - cytogenetic analysis is a procedure where WBCs from a blood or bone marrow sample are grown in a culture. The chromosomes from the cells are then fixed and stained. Staining allows distinct bands on the chromosomes to be observed under a microscope. The bands are used to determine chromosome structure so that any changes in size, shape, or arrangement of the chromosomes can be observed. Certain chromosomal changes are associated with certain leukemias. For example, a translocation of DNA between chromosome 9 and 22 is called the Philadelphia translocation, and it is associated with CML and a subtype of ALL.
- Fluorescence in situ hybridization (FISH) - FISH is a technique where fluorescent probes that attach to specific DNA sequences are used to detect certain genes in a sample of cells. FISH can detect DNA changes that are too small to be seen on cytogenetic analysis.
- Polymerase chain reaction (PCR) - In PCR, a probe that looks for a specific sequence of DNA or RNA is added to a sample. If the probe finds its target, it creates copies of the target over and over again so that it is easier to detect. PCR is very powerful as it is able to detect a single leukemia cell among a million normal cells.
- Flow cytometry - flow cytometry is a process where cells are passed individually in front of a laser. Light scattered from the laser is measured and used to tell different characteristics about the cell. Fluorescent reagents (e.g. conjugated antibodies, DNA binding dyes) that target specific cell components can also be added to the cells and measured during flow cytometry. Flow cytometry detects surface proteins that identify what type of cells are present in a sample. In leukemia, it is used to determine cellular maturity and to distinguish B cells from T cells.
- Direct DNA sequencing - direct DNA sequencing is a process where the nucleic acid sequence of DNA is read directly. There are a handful of techniques that can do this. Direct DNA sequencing is often used to look for a mutation in the immunoglobulin heavy chain variable (IGHV) region that is a prognostic indicator in CLL. [35,36,37]
- Acute lymphocytic leukemia (ALL)
- Epidemiology: The lifetime risk of developing ALL in an average-risk person is 0.1%. The risk is highest among children < 5 years of age. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including ALL. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: ALL develops in the bone marrow from immature B and T cells (see blood cell development illustration). B cell precursors are the most common type of lymphocyte affected, accounting for the vast majority of cases in children and 75% of cases in adults. When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause leukemia or turn off genes that suppress it. For example, the most common cause of ALL in adults is from a translocation of DNA between chromosome 9 and 22 which is called the Philadelphia translocation. Chromosomal changes are detected using the diagnostic tests mentioned above (see diagnosis). They also help to determine prognosis and guide treatment regimens.
- Known risk factors
- Age - ALL risk is highest in children < 5 years old. The risk then gradually decreases until the mid-20s, stabilizes, and starts to rise again after the age of 50.
- Radiation exposure (environmental and iatrogenic)
- Previous chemotherapy
- Benzene
- Certain viral infections (HTLV-1, EBV)
- Genetic syndromes (e.g. Down syndrome, Klinefelter, Neurofibromatosis)
- Race (Whites > Blacks)
- Sex (Male > Female)
- Family history
- Possible risk factors
- Electromagnetic fields (such as living near power lines or using cell phones)
- Workplace exposure to diesel, gasoline, pesticides, and certain other chemicals
- Smoking
- Hair dyes
- Staging - ALL does not form solid tumors, and leukemia cells have easy access to the circulation which allows them to spread across the entire body. Because of this, ALL is not staged like other cancers. ALL treatment and prognosis primarily depend upon the subtype of leukemia cells and patient characteristics.
- Treatment The treatment of ALL is complex and constantly evolving. The NCCN publishes up-to-date and widely-recognized treatment guidelines on its website - NCCN guidelines
- Prognosis: The 5-year survival rate for ALL varies greatly with age. Children < 5 years old have a 5-year survival rate of 94%, and the rate drops to < 15% in adults ≥ 65 years old. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including ALL. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Acute myeloid leukemia (AML)
- Epidemiology: The lifetime risk of developing AML is 0.5 - 1%. AML typically occurs in adults and is uncommon in people < 45 years old. The average age at diagnosis is 68 years. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including AML. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: AML develops in the bone marrow from premature granulocytes, erythrocytes, monocytes, and megakaryocytes (see blood cell development illustration). Most cases of AML occur in neutrophil precursors. When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause leukemia or turn off genes that suppress it. Chromosomal changes are detected using the diagnostic tests mentioned above (see diagnosis). They also help to determine prognosis and guide treatment regimens.
- Known risk factors
- Advanced age - AML is uncommon in people < 45 years old
- Sex (Male > Female)
- Smoking
- Benzene
- Previous chemotherapy with alkylating agents (e.g. cyclophosphamide, mechlorethamine, procarbazine, chlorambucil, melphalan, busulfan, carmustine, cisplatin, carboplatin)
- Previous chemotherapy with topoisomerase II inhibitors (e.g. etoposide, teniposide, mitoxantrone, epirubicin, doxorubicin)
- Radiation exposure (environmental and iatrogenic)
- Myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis
- Genetic syndromes (e.g. Down syndrome, Fanconi anemia, Bloom syndrome, Neurofibromatosis)
- Family history
- Possible risk factors
- Formaldehyde
- Electromagnetic fields (such as living near power lines or using cell phones)
- Workplace exposure to diesel, gasoline, pesticides, and certain other chemicals
- Staging - AML does not form solid tumors, and leukemia cells have easy access to the circulation which allows them to spread across the entire body. Because of this, AML is not staged like other cancers. AML treatment and prognosis primarily depend upon the subtype of leukemia cells and patient characteristics.
- Treatment The treatment of AML is complex and constantly evolving. The NCCN publishes up-to-date and widely-recognized treatment guidelines on its website - NCCN guidelines
- Prognosis: The 5-year survival rate for AML varies by age. People under 20 years of age have a 5-year survival around 64%, and the rate drops to < 10% in people > 65 years. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including AML. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Chronic lymphocytic leukemia (CLL)
- Epidemiology: The lifetime risk of developing CLL in an average-risk person is 0.57%. CLL typically affects older adults with an average age at diagnosis of 70 years. It is very rare in people < 40 years old. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including CLL. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: CLL develops in the bone marrow from immature B and T cells (see blood cell development illustration). Most forms of CLL start in B cell precursors, but there are some rare forms that originate in T cells and natural killer cells. When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause leukemia or turn off genes that suppress it. Chromosomal changes are detected using the diagnostic tests mentioned above (see diagnosis). They also help to determine prognosis and guide treatment regimens.
- Known risk factors
- Advanced age - 90% of people with CLL are > 50 years old
- Agent Orange
- Sex (Male > Female)
- Family history
- Race/ethnicity - more common in people of European descent than Asian descent
- Staging - CLL does not form solid tumors, and leukemia cells have easy access to the circulation which allows them to spread across the entire body. Because of this, CLL is not staged like other cancers. A staging system specific for CLL has been developed that uses specific patient findings (lymphadenopathy, splenomegaly, hepatomegaly, anemia, thrombocytopenia) to predict survival and guide treatment decisions. It is called the Rai staging system and an online calculator is available here - Rai staging system calculator
- Treatment CLL is divided into fast-growing and slow-growing types. Slow-growing CLL is often asymptomatic and does not cause significant blood dyscrasias (e.g. anemia, thrombocytopenia). In these cases, immediate treatment is not necessary and the disease can be observed. Fast-growing CLL can cause anemia and thrombocytopenia and requires treatment. There is no cure for CLL, and the disease is managed based on symptoms and blood counts. The NCCN publishes up-to-date and widely-recognized treatment guidelines for treating CLL on their website - NCCN guidelines
- Prognosis: Most CLL patients do well; the 5-year survival rate is close to 80% in patients ≥ 65 years old. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including CLL. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Chronic myeloid leukemia (CML)
- Epidemiology: The lifetime risk of developing CML is about 0.20%. CML typically affects older adults with an average age at diagnosis of 64 years. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including CML. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: CML develops in the bone marrow from premature granulocytes, erythrocytes, monocytes, and megakaryocytes (see blood cell development illustration). Granulocyte precursors are most commonly affected, and CML is sometimes referred to as chronic granulocytic leukemia. When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause leukemia or turn off genes that suppress it. In CML, almost all patients have a translocation between chromosome 9 and 22 that produces a new gene on chromosome 22 called the BCR-ABL gene. The translocated chromosome 22 is called the Philadelphia chromosome. Chromosomal changes are detected using the diagnostic tests mentioned above (see diagnosis). They are also helpful in determining prognosis and guiding treatment regimens.
- Known risk factors
- Advanced age - almost half of cases occur in people ≥ 65 years
- Radiation exposure (environmental and iatrogenic)
- Sex (Male > Female)
- Staging - CML primarily resides in the bone marrow and blood, and it is staged differently that other cancers. CML is classified into three stages - chronic phase, accelerated phase, and blast phase. The phases are based on the number of blast cells that are present in the blood and/or bone marrow. Phases are defined below.
- Chronic phase: < 10% blasts in bone marrow or blood
- Accelerated phase (any of the following present)
- The blood samples have 15% or more, but fewer than 30% blasts
- Basophils make up 20% or more of the blood
- Blasts and promyelocytes combined make up 30% or more of the blood
- Very low platelet counts (< 100,000/μl) that are not caused by treatment
- New chromosome changes in the leukemia cells with the Philadelphia chromosome
- Blast phase: > 20% blasts in bone marrow or blood
- Treatment CML is divided into three phases: chronic phase, accelerated phase, and blast phase. Chronic phase is the most common form, and it is the most amenable to treatment. In the accelerated phase, immature blast cell production increases, and treatment is less effective. Blast phase is the most aggressive phase of the disease, and it behaves similar to acute myeloid leukemia. The BCR-ABL gene mutation in CML produces a protein by the same name that causes uncontrolled cellular division. The BCR-ABL protein is a type of protein known as a tyrosine kinase, and there is a class of drugs that have been developed that inhibit its activity. These drugs are called tyrosine kinase inhibitors (e.g. imatinib, ponatinib, nilotinib), and they have greatly improved outcomes in CML. See the NCCN guidelines for recommendations on treating CML - NCCN guidelines
- Prognosis: The 5-year survival rate among all patients with CML is around 68%. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including CML. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Hairy cell leukemia
- Hair cell leukemia is a rare subtype of CLL that originates in mature B cells. Even though it is called a leukemia, it is sometimes classified as a type of lymphoma. It often presents as an incidental finding of pancytopenia on routine blood tests, and monocytopenia is a sensitive and specific feature. The term "hairy cell" comes from the fact that affected B cells have projections on their membrane that look like short hairs under a microscope. Hairy cell leukemia responds well to treatment; however, up to 58% of patients will experience a relapse. Asymptomatic cases with no significant blood dyscrasias can be followed without treatment. Patients with symptoms or significant cytopenias are treated with the purine analogs cladribine and pentostatin. Complete remission is achieved in 85% of patients and the 5-year survival is 90%. See the NCCN guidelines for recommendations on treating hairy cell leukemia - NCCN guidelines [42]
- Large granular lymphocytic (LGL) leukemia
- LGL leukemia is a rare subtype of CLL that originates in cytotoxic T cells (85%) or natural killer cells (< 10%). Most patients with LGL leukemia have symptoms at the time of diagnosis; however, up to a third of cases may be asymptomatic, and it is discovered incidentally when neutropenia and/or anemia are found on routine blood work. For unknown reasons, patients with autoimmune diseases, particularly RA, are at much greater risk of LGL leukemia; up to 36% of cases of LGL leukemia occur in patients with RA. The description "large granular" comes from the fact that affected lymphocytes are larger than normal and contain granules in their cytoplasm. Asymptomatic cases with no significant blood dyscrasias can be followed without treatment. Patients with significant neutropenia, anemia, or associated RA will require treatment. No standardized treatment guidelines exist, and immunosuppressants like methotrexate, cyclophosphamide, and cyclosporine are often used. The overall 10-year survival rate for LGL leukemia is about 70%, but a small percentage of patients develop aggressive disease that is difficult to treat and often fatal within months. [35,36,38]
- Chronic myelomonocytic leukemia (CMML)
- CMML is a rare subtype of CML that originates in monocyte precursor cells. CMML is uncommon in people < 60 years old. In children, another form of the disease called juvenile myelomonocytic leukemia can occur, but it is very rare. CMML has characteristics of both myelodysplastic and myeloproliferative syndromes so it has been categorized as a myelodysplastic/myeloproliferative neoplasm. CMML presents with monocytosis (≥ 1000 cells/μl) for > 3 months that is often accompanied by thrombocytopenia and anemia. Other more common myeloproliferative disorders must be ruled out, and the blast count in the bone marrow and/or peripheral blood cannot exceed 20%. Treatment involves supportive care for anemia and cytopenias (e.g. blood transfusions, blood cell growth factors), and chemotherapy for progressive disease. Stem cell transplant is the only curative therapy. CMML has a poor prognosis (5-year survival of 25%), and 15 - 30% of affected patients will go on to develop AML.
- LYMPHOMA
- Overview
- Lymphoma is a cancer of B and T lymphocytes that usually starts in a lymph node; in rarer cases, lymphoma may originate in other lymph tissue (e.g. MALT, spleen). This is in contrast to leukemias which originate in the bone marrow. Lymphomas are divided into two major types: Hodgkin lymphoma and non-Hodgkin lymphoma. In Hodgkin lymphoma, the cancer originates in B cells. In non-Hodgkin lymphoma, B cells account for 85 - 90% of cases and T lymphocytes and natural killer cells make up the rest (see blood cell development illustration).
- Non-Hodgkin lymphoma is much more common than Hodgkin lymphoma. In 2018, the incidence of non-Hodgkin lymphoma in the U.S. was 19.4 cases per 100,000 people, and the incidence of Hodgkin lymphoma was 2.6 cases per 100,000. Males are affected more than females, and Whites are affected more than other races. [35,36]
- Symptoms
- The most common presenting symptom in lymphoma is one or more enlarged lymph nodes. The swollen nodes are usually painless and located in the neck, upper chest, armpit, abdomen, and/or groin. Other symptoms of lymphoma are listed below. Some symptoms are designated as "B symptoms," and they are a sign of more advanced disease that might require more aggressive treatment.
- Symptoms of lymphoma
- Enlarged lymph nodes - lymph nodes are usually painless but may hurt after drinking alcohol
- Drenching night sweats (B symptom)
- Weight loss of ≥ 10% over 6 months (B symptom)
- Unexplained fever for ≥ 1 week (B symptom)
- Fatigue
- Persistent cough or shortness of breath (if chest lymph nodes are affected)
- Itchy skin
- Loss of appetite
- Splenomegaly
- Hepatomegaly
- Rash and/or skin nodules (if skin lymph nodes are affected)
- Diagnosis
- Lymphoma is diagnosed by examining tissue from an affected lymph node. If the lymph node is under the skin, it can often be removed with a local anesthetic. If it is located inside the abdomen or chest, general anesthesia is required. Removing the entire lymph node is preferred and this is called an excisional biopsy. If only a portion of the lymph node is removed, it is called an incisional biopsy. Once the tissue is obtained, it is examined under a microscope, and testing, which may include some of the assays discussed below, is performed.
- Blood tests in lymphoma are mostly nonspecific. Lymphocytosis may be observed on a CBC, and if the lymphoma has invaded the bone marrow, other cytopenias (e.g. anemia) may be present.
- Immunohistochemical staining - immunohistochemical staining is a process where antibodies to specific cellular markers (e.g CD proteins) are added to a tissue sample. If the antibodies find their target antigen, they will bind to it and remain in the sample when it is washed. The antibodies are conjugated to markers (e.g. enzymes, fluorescent probes) that allow them to be observed under a microscope. Certain lymphomas express unique proteins that can be identified with a probe. For example, Reed-Sternberg cells in classic Hodgkin lymphoma express CD15 and CD30 on their surface.
- Bone marrow biopsy/aspiration - a bone marrow biopsy or aspiration may be performed to see if the lymphoma has invaded the bone marrow. Bone marrow aspiration is a procedure where a small needle is used to remove a liquid sample of marrow from the bone. In a bone marrow biopsy, a larger needle is used to remove a piece of bone with marrow in it.
- Gene expression microarrays - gene expression microarray analysis is a process that identifies which genes are being expressed in a sample of cells. To perform the analysis, mRNA is extracted from the cells and converted to complementary DNA (cDNA). The cDNA is labeled with a fluorescent probe and then added to a microarray slide that has DNA probes spread out across it. Fluorescent-labeled cDNA will bind to the probes and create a specific pattern across the slide that will reflect which genes are most active in the cells. The pattern of gene expression in the sample can be compared to known standards, and this helps to identify what type of cells are present.
- Cytogenetic analysis (karyotyping) - cytogenetic analysis is a procedure where WBCs from a blood or bone marrow sample are grown in a culture. The chromosomes from the cells are then fixed and stained. Staining allows distinct bands on the chromosomes to be observed under a microscope. The bands are used to determine chromosome structure so that any changes in size, shape, or arrangement of the chromosomes can be observed. Certain chromosomal changes are associated with certain types of lymphoma.
- Fluorescence in situ hybridization (FISH) - FISH is a technique where fluorescent probes that attach to specific DNA sequences are used to detect certain genes in a sample of cells. FISH can detect DNA changes that are too small to be seen on cytogenetic analysis.
- Polymerase chain reaction (PCR) - In PCR, a probe that looks for a specific sequence of DNA or RNA is added to a sample. If the probe finds its target, it creates copies of the target over and over again so that it is easier to detect. PCR is very powerful as it is able to detect a single lymphoma cell among a million normal cells.
- Flow cytometry - flow cytometry is a process where cells are passed individually in front of a laser. Light scattered from the laser is measured and used to tell different characteristics about the cell. Fluorescent reagents (e.g. conjugated antibodies, DNA binding dyes) that target specific cell components can also be added to the cells and measured during flow cytometry. Flow cytometry detects surface proteins that identify what type of cells are present in a sample. In lymphoma, it can be used to distinguish B cells from T cells.
- Direct DNA sequencing - direct DNA sequencing is a process where the nucleic acid sequence of DNA is read directly. There are a handful of techniques that can do this. [35,36]
- Hodgkin lymphoma
- Epidemiology: In 2018, the incidence of Hodgkin lymphoma in the U.S. was 2.6 cases per 100,000 people. Hodgkin lymphoma typically affects adults and is rarely seen before the age of 12. It has a bimodal peak incidence with the first peak occurring between 20 - 30 years of age and the second peak occurring between 50 - 70. The median age of onset is 33 years. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including Hodgkin lymphoma. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: Hodgkin lymphoma originates in B lymphocytes that reside in lymph nodes. It is named after the physician who first described the condition (Thomas Hodgkin) in 1832. When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause lymphoma or turn off genes that suppress it. Hodgkin lymphoma is distinguished from other lymphomas by the presence of Reed-Sternberg cells (named after the scientists who discovered them). Reed-Sternberg cells are larger-than-normal lymphocytes that have two or more nuclei with perinuclear clearing that creates a halo or "owl's eye" effect. Other lymphoma cells in Hodgkin lymphoma are called Hodgkin cells; they are smaller than Reed-Sternberg cells, but still larger than normal lymphocytes.
- Known risk factors
- Epstein-Barr virus (EBV) infection - EBV is found in 25% of Reed-Sternberg cells and Hodgkin cells in the U.S
- Age - risk is highest in twenties and after age 50
- HIV infection - people living with HIV have a higher risk of Hodgkin lymphoma
- Sex (Male > Female)
- Family history
- Immunosuppression - people who take immunosuppressive medications (e.g. organ transplant, autoimmune diseases) are at higher risk for Hodgkin lymphoma
- Staging Hodgkin lymphoma is staged using the Lugano system outlined in the table below. The National Cancer Institute has a web application that provides current survival rates for Hodgkin lymphoma based on sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
| Hodgkin Lymphoma Stages | |
|---|---|
| Stage | Finding |
| I |
One of the following:
|
| II |
One of the following:
|
| III |
One of the following:
|
| IV |
|
Other findings that may be used to further stage Hodgkin lymphoma include:
|
|
- Treatment The treatment of Hodgkin lymphoma is complex and constantly evolving. The NCCN publishes up-to-date and widely-recognized treatment guidelines on its website - NCCN guidelines
- Prognosis: Hodgkin lymphoma is one of the most curable forms of cancer. The 5-year survival for people < 50 years of age is close to 95%. The 5-year survival for people aged 65 - 74 is 67%. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including Hodgkin lymphoma. The information can be filtered by sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
- Non-Hodgkin lymphoma
- Epidemiology: Non-Hodgkin lymphoma is much more common than Hodgkin lymphoma. The lifetime risk of developing non-Hodgkin lymphoma in males is 2.3%, and the lifetime risk in females is 1.9%. Non-Hodgkin lymphoma affects people of all ages, and it is one of the most common cancers in children, teens, and young adults. As people age, the risk gradually increases, and more than half of cases occur in people ≥ 65 years. The National Cancer Institute has a web application that provides current incidence rates for all types of cancer including non-Hodgkin lymphoma. The information can be filtered by sex, age, and race. A link to that application is available here - NCI cancer statistic web application
- Pathology: Non-Hodgkin lymphoma typically originates in B lymphocytes (85 - 90% of cases) that reside in lymph nodes. It may also originate in T lymphocytes and natural killer cells, but this is less common (10 - 15% of cases). When cells divide, they make a copy of their chromosomes, and during this process, errors can occur. DNA may be deleted, added, rearranged (called an inversion), or removed from its original chromosome and placed on another (translocation). These errors can sometimes turn on genes that cause lymphoma or turn off genes that suppress it. There are over 60 subtypes of non-Hodgkin lymphoma. Criteria used to classify non-Hodgkin lymphoma include the following: lymphocyte affected (B cell, T cell, natural killer cell), appearance of cell under microscope, chromosomal changes, cell surface markers, and aggressive vs indolent.
- Known risk factors
- Age - risk gradually increases with age
- Sex (Male > Female)
- Ethnicity (White > Hispanic > Asian and Black)
- Family history in first-degree relative
- Radiation exposure (environmental and iatrogenic)
- Immunosuppression (e.g. organ transplant, ataxia-telangiectasia syndrome, Wiskott-Aldrich syndrome)
- HTLV-1 infection - associated with T-cell lymphoma; mostly seen in Japan and the Caribbean.
- HIV - patients with HIV have a higher risk of primary CNS lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma
- Epstein-Barr infection - associated with Burkitt lymphoma in parts of Africa and in patients with HIV
- Human herpes virus 8 - associated with a rare type of lymphoma called primary effusion lymphoma that mostly occurs in people with HIV
- Helicobacter pylori (H pylori) infection - associated with MALT lymphoma of the stomach
- Chlamydophila psittaci lung infection - associated with MALT lymphoma in the tissues around the eye that is called ocular adnexal marginal zone lymphoma
- Campylobacter jejuni infection - associated with MALT lymphoma called immunoproliferative small intestinal disease; mostly seen in eastern Mediterranean countries
- Breast implants (particularly textured implants) - associated with anaplastic large cell lymphoma of the breast
- Possible risk factors
- Benzene
- Herbicides and insecticides
- Chemotherapy
- Immunosuppressants (e.g. methotrexate, tumor necrosis factor inhibitors)
- Autoimmune diseases (e.g. RA, lupus, celiac disease, Sjogren disease)
- Hepatitis C infection - associated with splenic marginal zone lymphoma
- Obesity
- Staging Non-Hodgkin lymphoma is staged using the Lugano system outlined in the table below. The National Cancer Institute has a web application that provides current survival rates for non-Hodgkin lymphoma based on sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
| Non-Hodgkin Lymphoma Stages | |
|---|---|
| Stage | Finding |
| I |
One of the following:
|
| II |
One of the following:
|
| III |
One of the following:
|
| IV |
|
Stage categories:
|
|
- Treatment The treatment of non-Hodgkin lymphoma is complex and constantly evolving. The NCCN publishes up-to-date and widely-recognized treatment guidelines on its website. Non-hodgkin lymphoma guidelines are divided into B-cell lymphomas, T-cell lymphomas, and other subtypes. See NCCN guidelines for more.
- Prognosis: The prognosis in non-Hodgkin lymphoma is highly dependent upon the subtype, stage, and patient characteristics. The overall 5-year survival rate for patients younger than 50 years is around 82%. For patients 65 years of age and older, the 5-year survival dips to 63%. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including non-Hodgkin lymphoma. The information can be filtered by sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
- Waldenstrom macroglobulinemia (WM) / Lymphoplasmacytic lymphoma
- Waldenstrom macroglobulinemia (also called lymphoplasmacytic lymphoma) is a rare subtype of non-Hodgkin lymphoma that typically originates in the bone marrow. Lymphoma cells in WM are called lymphoplasmacytoid cells because they have characteristics of both B lymphocytes and plasma cells. Lymphoplasmacytoid cells secrete large amounts of monoclonal IgM that can be identified on serum protein electrophoresis (M-spike). High IgM levels may lead to increased blood viscosity, cryoglobulins (proteins that clump together in cool temperatures and can block blood vessels), cold agglutinins (IgM antibodies that bind RBCs), amyloidosis (build up of IgM light chains in organs), and neuropathy (when IgM attacks nerves). See NCCN guidelines for WM treatment recommendations. The overall 5-year survival rate for Waldenstrom macroglobulinemia (based on data from 2001 - 2010) is about 78%.
- MYELOMA
- Epidemiology
- Myeloma is a cancer of plasma cells that typically occurs in the bone marrow. In most cases, it is found at multiple sites and is therefore often referred to as "multiple myeloma." Less often, it is only found in one location in which case it is called a plasmacytoma (see plasmacytoma below for more). Plasmacytomas usually occur in bone, but they may also be found in other tissues.
- In the U.S., the lifetime risk of developing myeloma is 0.76%. Myeloma primarily occurs in older adults with a median age at diagnosis of 70 years. Men are affected more than women, and Blacks are affected more than Whites and Asians. [35,36,40]
- Risk factors
- Known risk factors
- Age - median age of diagnosis is 70 years; less than 1% of cases occur in people < 35 years of age
- Sex (Male > Female)
- Race - in the U.S., Blacks have double the risk of Whites
- Family history - people with a family history have a slightly increased risk
- Obesity
- Monoclonal gammopathy of undetermined significance
- Plasmacytoma
- Possible risk factors
- Radiation exposure
- Pesticides
- Fertilizers
- Agent Orange
- Firefighters [35,36]
- Pathology
- Myeloma is a cancer of plasma cells that typically occurs in the bone marrow. In most cases, it is found at multiple sites and is therefore often referred to as "multiple myeloma." Less often, it is only found in one location in which case it is called a plasmacytoma (see plasmacytoma below for more). Plasmacytomas usually occur in bone, but they may also be found in other tissues. Myeloma cells divide and take over the surrounding marrow. They also secrete a substance that causes osteoclasts to increase bone resorption. This leads to bone weakening, hypercalcemia, and fractures. In the majority of myeloma cases, the affected cells all secrete the same antibody (monoclonal antibody), and the most common subtype is IgG (50% of cases). Antibodies are made of heavy and light chains joined together (see antibody structure). Sometimes myeloma cells are not good at attaching the heavy chains to the light chains. In these cases, none or only a small amount of fully-formed antibody is created, and "free light chains" are secreted instead. Free light chains can build up in the kidneys and other organs (called amyloidosis) and lead to organ failure. When no intact antibody is detected and only free light chains are present, the myeloma is referred to as "nonsecretory myeloma." If a small amount of intact antibody is detected along with light chains, the myeloma is called "oligosecretory myeloma." Light chains have two isotypes, kappa (κ) and lambda (λ). Under normal conditions, the ratio of these two isotypes in serum is close to one. In myeloma, one isotype is typically produced in greater amounts than the other, and the ratio becomes distorted one way or the other. [19,35,36,40]
- Symptoms
- Symptoms of myeloma depend upon how far the disease has progressed. Some patients have no symptoms, and the condition is discovered incidentally on routine blood work. The acronym "CRAB" is sometimes used to describe the main signs of myeloma.
- Calcium elevation - hypercalcemia from accelerated bone resorption is seen in about a third of patients at some point during the disease. Symptoms of hypercalcemia are described with the mnemonic "stones, bones, abdominal moans, and psychic groans." See hypercalcemia for more.
- Renal insufficiency - renal impairment in myeloma is often multifactorial and occurs from the following: light-chain tubular cast nephropathy, amyloidosis, light-chain deposition, dehydration, infections, and nephrotoxic drugs.
- Anemia - marrow destruction from myeloma cells can lead to decreased erythropoiesis and anemia
- Bone abnormalities - bone pain and fractures can occur when myeloma weakens the surrounding bone. Osteolytic bone lesions are found in 80% of myeloma patients at the time of diagnosis or relapse. Common sites for bone lesions are the spine and pelvis.
- Infections - infections may occur if leukopenia is present
- Bleeding - bleeding may occur if thrombocytopenia is present
- Peripheral neuropathy - peripheral neuropathy may occur from myeloma antibodies that target neurons. Amyloidosis can also cause neuropathy.
- Hyperviscosity syndrome - large amounts of antibody can thicken blood and cause headaches, chest pain, shortness of breath, and stroke-like symptoms
- Sequelae of amyloidosis - amyloidosis can affect the heart (hypertrophy and heart failure), liver (hepatomegaly), tongue (swelling and throat obstruction), skin (discoloration and bruising), and nerves (peripheral neuropathy) [35,36,40]
- Diagnosis
- When myeloma is suspected, the tests below are used to make a diagnosis
- Immunoglobulin levels - quantitative levels of antibodies in the serum can be measured directly. In myeloma, levels of one subtype of antibody may be elevated while others may be suppressed.
- Serum protein electrophoresis (SPEP) - SPEP is a procedure where serum proteins are separated out in a gel matrix based on their size and electrical charge. There are 5 basic protein groups (also called zones) that form during SPEP - albumin, alpha1, alpha2, beta, and gamma. Albumin is the main fraction in a normal SPEP. The alpha1 zone of proteins contains alpha-1 antitrypsin, transcortin, and thyroid-binding globulin. Alpha2 is composed of ceruloplasmin, alpha-2 macroglobulin, and haptoglobin. The beta zone contains transferrin, B-lipoprotein and C3 complement, and the gamma zone contains the 5 different types of antibodies (IgG, I gA, IgM, IgD, IgE). A focal spike in the gamma zone (called an M spike) is an indication that a monoclonal antibody may be present. High levels of free light chains sometimes cause a spike on SPEP, but this is not always the case. Light chains are rapidly cleared by the kidneys and are more likely to be found in the urine with UPEP or in the serum with a free light chain assay. The subtype of antibody in an M spike cannot be identified from SPEP alone; immunofixation must be performed on the sample in order to determine this. [19,35,36]
- Urine protein electrophoresis (UPEP) - UPEP is a procedure where urine proteins are separated out in a gel matrix based on their size and electrical charge. There are 5 basic protein groups (also called zones) that are evaluated during UPEP - albumin, alpha1, alpha2, beta, and gamma. The alpha1 zone of proteins contains alpha-1 antitrypsin, transcortin, and thyroid-binding globulin. Alpha2 is composed of ceruloplasmin, alpha-2 macroglobulin, and haptoglobin. The beta zone contains transferrin, B-lipoprotein and C3 complement, and the gamma zone contains the 5 different types of antibodies (IgG, I gA, IgM, IgD, IgE). Under normal conditions, little to no protein is present in the urine and none of the zones have significant readings. If a monoclonal antibody is present, a spike (called an M spike) may be seen in the gamma zone. UPEP is less sensitive than SPEP for detecting intact monoclonal antibodies. However, free light chains are rapidly cleared by the kidneys, and they are sometimes easier to detect with UPEP than SPEP. Free light chains in the urine are sometimes called "Bence Jones proteins" after the doctor who discovered them. The subtype of antibody in an M spike and the isotype of free light chains cannot be identified from UPEP alone; immunofixation must be performed on the sample in order to determine this. [19,35,36]
- Immunofixation - immunofixation is a process where antibodies to immunoglobulin subtypes (IgG, IgA, IgM) and light chain isotypes (kappa, lambda) are applied to an SPEP or UPEP sample. The antibodies bind to the immunoglobulins in the sample and cause them to precipitate. The sample is then treated, and distinctive bands form based on the type of immunoglobulin present. The bands are then used to identify antibody subtypes and light chain isotypes. [19,35,36]
- Serum free light chains - the serum free light chain assay measures the levels of unbound free light chains (kappa and lambda) in the serum. It also provides a ratio of kappa to lambda chains. Elevations in free light chains are seen in oligosecretory and nonsecretory myeloma (see myeloma pathology). The ratio of kappa to lambda isotypes is also useful when evaluating myeloma. Under normal conditions, the ratio is close to one. In myeloma, one isotype is typically produced in greater amounts than the other, and the ratio becomes distorted one way or the other. [19,35,36]
- Bone marrow biopsy/aspiration - bone marrow aspiration is a procedure where a small needle is used to remove a liquid sample of marrow from the bone. In a bone marrow biopsy, a larger needle is used to remove a piece of bone with marrow in it. In myeloma, bone marrow biopsy/aspiration is performed to examine the number of plasma cells present. The percentage of plasma cells in the marrow plays an important role in determining treatment, prognosis, and progression of myeloma syndromes (e.g. MGUS, smoldering multiple myeloma). [35,36]
- Beta-2 microglobulin - Beta-2 microglobulin is the light chain component of class I HLA complex. It is produced by myeloma cells, and serum levels rise with increasing myeloma activity; this makes it useful in myeloma staging and prognosis. A value of < 0.4 mg/L is considered good while a level > 2 mg/L is a sign of more active disease. [19,35,36]
- Staging
- Myeloma is staged using the Revised International Staging System (RISS) outlined in the table below. The National Cancer Institute has a web application that provides current survival rates for myeloma based on sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
| Revised International Staging System (RISS) Stages | |
|---|---|
| Stage | Finding |
| I |
All of the following:
|
| II |
|
| III |
Serum beta-2 microglobulin > 5.5 mg/L and one of the following:
|
- Treatment
- No current therapy can cure myeloma, and myeloma treatment is marked by periods of remission that are inevitably followed by disease recurrence. As time progresses, remissions become shorter and recurrences become harder to treat. That being said, recent advances in myeloma treatment have greatly improved survival times. A large number of drugs including newer biologics are now available to combat the disease. Patients who are healthy enough often receive stem cell transplants, and while these transplants may be curative in other diseases, they only help to prolong remission in myeloma. The NCCN publishes up-to-date and widely-recognized myeloma treatment guidelines on its website. See NCCN guidelines for more.
- Prognosis
- Myeloma is not curable, but therapy advances have greatly improved survival times. The 5-year survival rate for people less than 50 years of age is around 70%, and it drops to around 43% for those 65 years and older. The National Cancer Institute has a web application that provides current survival rates for all types of cancer including myeloma. The information can be filtered by sex, age, race, and cancer stage. A link to that application is available here - NCI cancer statistic web application
- Plasmacytoma
- Most of the time, myeloma is found in multiple locations in the bone marrow. Less often, it is only found in one location in which case it is called a plasmacytoma. A plasmacytoma is a solitary accumulation of myeloma cells that can occur in the bones, skin, muscles, or lungs. When it occurs outside of the bones, it is called an "extramedullary plasmacytoma." Plasmacytomas are treated differently than multiple myelomas so it is important that an extensive search for other foci of myeloma be performed before the diagnosis is made. Radiation therapy is the standard treatment for plasmacytoma, and it is often curative. Patients with a history of plasmacytoma are at increased risk of developing multiple myeloma and must be followed closely. Fifty percent of patients with bone plasmacytoma will develop multiple myeloma within 10 years. For extramedullary plasmacytoma, the risk is around 30%. [35,36,40]
- Monoclonal gammopathy of undetermined significance (MGUS)
- High levels of a monoclonal antibody can occur in other conditions besides myeloma. Waldenstrom macroglobulinemia is one example as are a handful of other lymphomas. Some people with high levels of a monoclonal antibody do not have any identifiable cancer on workup. These patients are said to have monoclonal gammopathy of undetermined significance, or MGUS, for short. Criteria for MGUS include M-protein size < 30 g/L, bone marrow plasma cells < 10%, and no evidence of end-organ damage (hypercalcemia, renal failure, anemia, lytic bone lesions). Patients with MGUS are at increased risk of developing multiple myeloma. The risk depends on a number of factors including M-protein size, monoclonal antibody subtype, and free light chain ratio. A calculator is available that provides a risk estimate based on these values. See MGUS myeloma risk calculator. [35,36,40]
- Smoldering multiple myeloma (SMM)
- Smoldering multiple myeloma is multiple myeloma that is asymptomatic and has not caused any end-organ damage (hypercalcemia, renal failure, anemia, lytic bone lesions, amyloidosis). Criteria for SMM include M-protein size ≥ 30 g/L and/or bone marrow plasma cells of 10% - 60%. Free light chain ratio must be < 100, and there must be ≤ 1 focal lesion on MRI. SMM may go years before it becomes active (symptomatic), so treatment is held until this occurs. The risk of conversion to active myeloma depends upon bone marrow plasma cell percentage and M-protein size. A calculator is available that estimates the 15-year risk based on these values (see smoldering multiple myeloma progression calculator). [35,36,40]
- MYELODYSPLASTIC SYNDROME (MDS)
- Epidemiology
- MDS is primarily seen in older people. In 2018, the overall incidence of myelodysplastic syndrome in the U.S was 3.7 cases per 100,000 people; in people 75 years and older, the rate was 37.5 cases per 100,000. Males are affected almost twice as much as females, and Whites are affected more than Blacks and Asians. [35,41]
- Risk factors
- Age - most important risk factor; MDS is very rare in patients younger than 50 years
- Race (White > Black > Asian)
- Sex (Male > Female)
- Radiation therapy
- Chemotherapy - particularly alkylating agents (e.g. cyclophosphamide) and topoisomerase II inhibitors (e.g. doxorubicin); MDS usually occur 2 - 7 years after exposure [35,41]
- Pathology
- Myelodysplastic syndromes are a group of cancers that start in bone marrow stem cells. They can originate in the lineage of leukocytes, erythrocytes, or thrombocytes, and affected cells are dysplastic, meaning they are abnormal in shape, size, and/or appearance. An abnormal increase in the number of blast cells may also be present. In some cases, dysplastic cells still function normally, and in other cases, they do not. MDS can range in severity from mild forms that do not require any treatment to severe forms that are fatal. In the more severe forms, blast cells can start to take over the bone marrow, and cytopenias (e.g. anemia, thrombocytopenia, neutropenia) can develop. MDS arises when chromosomes are altered during cell division. A number of chromosomal changes that are specific to MDS have been identified, and they are used to guide treatment and prognosis. [35,41]
- Symptoms
- MDS may remain asymptomatic for years and is often discovered incidentally on routine blood work. Anemia is the most common abnormality at presentation, and if clinically significant, patients may complain of fatigue, shortness of breath, and lightheadedness. Thrombocytopenia may result in bleeding and easy bruising, and neutropenia can cause recurrent infections. [35,41]
- Diagnosis
- MDS typically presents as abnormalities on a CBC. Anemia is the most common finding, and it is present in 60 - 80% of patients at the time of diagnosis. A peripheral smear should be performed to look for blast cells and other abnormalities. If anemia is present, a reticulocyte count may be helpful to see if the bone marrow is responding appropriately. Patients with MDS have impaired bone marrow, so they will often have an inappropriately normal or low reticulocyte count. Most patients are referred to hematology for a bone marrow biopsy and other testing. Like blood cell cancers, MDS arises from genetic abnormalities, so the evaluation often includes karyotyping and other DNA tests (see leukemia testing above for a discussion of these techniques). Main diagnostic criteria for MDS are presented below. In 2021, an MDS prediction tool was created that uses age, gender, CBC values, glucose, and creatinine to estimate a patient's probability of having MDS (see MDS online prediction calculator and PMID 34387647 for more).
- MDS is diagnosed when there is ≥ 1 cytopenia (anemia, neutropenia, or thrombocytopenia) and at least one of the following:
- Obvious dysplasia in at least 10% of red blood cells, white blood cells, or platelets
- Bone marrow blasts of 5 - 19%
- MDS-specific chromosomal abnormalities [35,41]
- Treatment
- MDS treatment varies widely, with observation only in mild cases to stem cell transplant in severe disease. Cytopenis are treated supportively with transfusions, colony-stimulating factors, erythropoietin, thrombopoietin, and other agents. A class of chemotherapeutic agents known as hypomethylating agents is available to treat patients with rising blast counts. In some types of MDS, lymphocytes can attack the bone marrow, and immunosuppressants may be used. Stem cell transplantation is reserved for severe disease and is the only potentially curative treatment. The NCCN publishes up-to-date and widely-recognized MDS treatment guidelines on its website. See NCCN guidelines for more. [35,41]
- Prognosis
- The prognosis in MDS depends upon the subtype of disease. A scoring system called the Revised International Prognostic Scoring System (IPSS-R) has been developed that gives an estimated survival based on genetic findings, marrow blast percentage, and number of cytopenias. An online IPSS-R calculator is available here - IPSS-R MDS prognosis calculator.
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