chronic lymphocytic leukemia chronic lymphocytic leukemia chronic lymphocytic leukemia (cll) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). early on, there are typically no symptoms. later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. enlargement of the spleen and low red blood cells (anemia) may also occur. it typically worsens gradually over years. chronic lymphocytic leukemiaother namesb-cell chronic lymphocytic leukemia (b-cll)peripheral blood smear showing cll cellsspecialtyhematology and oncologysymptomsearly: nonelater: non-painful lymph nodes swelling, feeling tired, fever, weight lossusual onsetolder than 50risk factorsfamily history, agent orange, certain insecticidesdiagnostic methodblood testsdifferential diagnosismononucleosis, hairy cell leukemia, acute lymphocytic leukemia, persistent polyclonal b-cell lymphocytosistreatmentwatchful waiting, chemotherapy, immunotherapyprognosisfive-year survival ~88% (us)frequency904,000 (2015)deaths60,700 (2015) risk factors include having a family history of the disease, with 10% of those who develop cll having a family history of the disease. exposure to agent orange, certain insecticides, sun exposure, exposure to hepatitis c virus, and common infections are also considered risk factors. cll results in the buildup of b cell lymphocytes in the bone marrow, lymph nodes, and blood. these cells do not function well and crowd out healthy blood cells. cll is divided into two main types: those with a mutated ighv gene and those without. diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells. early-stage cll in asymptomatic cases responds better to careful observation, as there is no evidence that early intervention treatment can alter the course of the disease. immune defects occur early in the course of cll and these increase the risk of developing serious infection, which should be treated appropriately with antibiotics. in those with significant symptoms, chemotherapy, immunotherapy, or chemoimmunotherapy may be used. depending on the individual's age, physical condition, and whether they have the del(17p) or tp53 mutation, different first line treatments may be offered. as of 2021, btk inhibitors such as ibrutinib and acalabrutinib are often recommended for first line treatment of cll. the medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy. cll affected about 904,000 people globally in 2015 and resulted in 60,700 deaths. in 2021, the estimated incidence of cll in the united states is 21,250 new cases and 4,320 deaths. the disease most commonly occurs in people over the age of 65, due to the accumulation of genetic mutations that occurs over time. men are diagnosed around twice as often as women (6.8 to 3.5 ratio). it is much less common in people from asia. five-year survival following diagnosis is approximately 83% in the united states. it represents less than 1% of deaths from cancer. signs and symptoms a diagram showing the cells affected by cll most people are diagnosed as having cll based on the result of a routine blood test that shows a high white blood cell count, specifically a large increase in the number of circulating lymphocytes. these people generally have no symptoms. less commonly, cll may present with enlarged lymph nodes. if enlarged lymph nodes are caused by infiltrating cll-type cells, a diagnosis of small lymphocytic lymphoma (sll) is made. less commonly, the disease comes to light only after the cancerous cells overwhelm the bone marrow, resulting in low red blood cells, neutrophils, or platelets. or there is fever, night sweats, weight loss, and the person feels tired. cll can be grouped with small lymphocytic lymphoma (sll) as one disease with two clinical presentations. whereas, with cll, diseased cells propagate from within the bone marrow, in sll they propagate from within the lymphatic tissue. clls are, in virtually all cases, preceded by a particular subtype of monoclonal b-cell lymphocytosis (mbl). this subtype, termed chronic lymphocytic leukemia-type mbl (cll-type mbl) is an asymptomatic, indolent, and chronic disorder in which people exhibit a mild increase in the number of circulating b-cell lymphocytes. these b-cells are abnormal: they are monoclonal, i.e. produced by a single ancestral b-cell, and have some of the same cell marker proteins, chromosome abnormalities, and gene mutations found in cll. cll/sll mbl consist of two groups: low-count cll/sll mbl has monoclonal b-cell blood counts of <0.5x9 cells/liter (i.e. 0.5x9/l) while high-count cll/sll mbl has blood monoclonal b-cell counts ≥0.5x9/l but <5x109/l. individuals with blood counts of these monoclonal b-cells >5x9/l are diagnosed as having cll. low-count cll/sll mbl rarely if ever progresses to cll while high-count cll/sll mbl does so at a rate of 1-2% per year. thus, cll may present in individuals with a long history of having high-count cll/sll mbl. there is no established treatment for these individuals except monitoring for development of the disorder's various complications (see treatment of mbl complications) and for their progression to cll. complications complications include a low level of antibodies in the bloodstream (hypogammaglobulinemia), leading to recurrent infection, warm autoimmune hemolytic anemia in 10–15% of patients, and bone marrow failure. chronic lymphocytic leukemia may also develop a richter's transformation i.e. conversion to a far more aggressive form that has the histopathology of diffuse large b cell lymphoma or hodgkin's lymphoma. cll has also been reported to convert into other more aggressive diseases such as lymphoblastic lymphoma, hairy cell leukemia, high grade t cell lymphomas, acute myeloid leukemia, lung cancer, brain cancer, melanoma of the eye or skin, salivary gland tumors, and kaposi's sarcomas. while some of these conversions have been termed rts, the world health organization and most reviews have defined rt as a conversion of cll/sll into a disease with dlbcl or hl histopathology. the incidence of this transformation is estimated to be around 5% in people with cll. gastrointestinal (gi) involvement can rarely occur with chronic lymphocytic leukemia. some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. usually, gi complications with cll occur after richter transformation. two cases to date have been reported of gi involvement in chronic lymphocytic leukemia without richter's transformation. cause cll can also be caused by a number of epigenetic changes, which are adaptations that add a tag to specific dna sequences, rather than altering the sequence itself. in cll, these changes can be classified into the addition of three different methyl subgroups (naïve b-cell-like, memory b-cell-like, and intermediate), which impact how much that dna sequence is transcribed. some relevant genetic mutations may be inherited. since there is no one single mutation that is associated with cll in all cases, an individual’s susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of cll are co-inherited. up until 2020, 45 susceptibility loci have been identified. of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or wnt signaling. exposure to agent orange increases the risk of cll, and exposure to hepatitis c virus may increase the risk. there is no clear association between ionizing radiation exposure and the risk of developing cll. blood transfusions have been ruled out as a risk factor. diagnosis micrograph of a lymph node affected by b-cll showing a characteristic proliferation center (right of image), composed of larger, lighter-staining, cells, h&e stain the diagnosis of cll is based on the demonstration of an abnormal population of b lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. cll is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. this frequently is an incidental finding on a routine physician visit. most often the lymphocyte count is greater than 5000 cells per microliter (µl) of blood but can be much higher. the presence of lymphocytosis in a person who is elderly should raise strong suspicion for cll, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary. molecular examination of peripheral blood and flow cytometry the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of cll. both are easily accomplished on a small amount of blood. a flow cytometer instrument can examine the expression of molecules on individual cells in fluids. this requires the use of specific antibodies to marker molecules, with fluorescent tags recognized by the instrument. in cll, the lymphocytes are all genetically identical since they are derived from the same b cell lineage, expressing common b-cell markers cd19 and cd20, with abnormal expression of surface markers cd5 and cd23. these b cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells and can indicate the presence of the disease. smudge cells are due to cancer cells lacking in vimentin, a type of cytoskeleton proteins which is a structural component in a cell which maintains the cell's internal shape and mechanical resilience).: 1899 smudge cells in peripheral blood surface markers the atypical molecular pattern on the surface of the cell includes the coexpression of cell surface markers clusters of differentiation 5 (cd5) and 23. in addition, all the cll cells within one individual are clonal, that is, genetically identical. in practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal b cells. normal b lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. the lack of the normal distribution of these b cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any b cell malignancy (b cell non-hodgkin lymphoma).the matutes's cll score allows the identification of a homogeneous subgroup of classical cll, that differs from atypical/mixed cll for the five markers' expression (cd5, cd23, fmc7, cd22, and immunoglobulin light chain) matutes's cll scoring system is very helpful for the differential diagnosis between classical cll and the other b cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical cll and mantle cell lymphoma (mcl malignant b cells). discrimination between cll and mcl can be improved by adding non-routine markers such as cd54 and cd200. among routine markers, the most discriminating feature is the cd20/cd23 mean fluorescence intensity ratio. in contrast, fmc7 expression can surprisingly be misleading for borderline cases. clinical staging staging, determining the extent of the disease, is done with the rai staging system or the binet classification (see details) and is based primarily on the presence of a low platelet or red cell count. early-stage disease does not need to be treated. cll and sll are considered the same underlying disease, just with different appearances.: 1441 rai staging system (most commonly used in the united states) stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia stage i: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia stage ii: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy stage iii: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dl) with or without lymphadenopathy, hepatomegaly, or splenomegaly stage iv: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia binet classification (most commonly used in europe) clinical stage a: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (rai stages 0, i, and ii) clinical stage b: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (rai stages i and ii) clinical stage c: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (rai stages iii and iv) array-based karyotyping array-based karyotyping is a cost-effective alternative to fish for detecting chromosomal abnormalities in cll. several clinical validation studies have shown >95% concordance with the standard cll fish panel. related diseases in the past, cases with similar microscopic appearance in the blood but with a t cell phenotype were referred to as t-cell cll. however, these are now recognized as a separate disease group and are currently classified as t-cell prolymphocytic leukemias (t-pll). an accurate diagnosis of t-pll