Chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow produces too many lymphocytes, which are a type of white blood cell. B cell lymphocytes can begin to collect in the blood, spleen, lymph nodes, and bone marrow; these cells malfunction and crowd out healthy blood cells. CLL is divided into slow-growing and fast-growing variants.
Most individuals have no symptoms when they are first diagnosed with CLL. Around five to 10% of patients may experience fever, fatigue, unexplained weight loss, loss of appetite, painless swelling of the lymph nodes, enlargement of the spleen, and/or anemia. These symptoms often worsen over time. Patients with CLL also have an increased risk of developing serious infections. The exact cause of CLL is unknown, but risk factors include a family history of CLL, tobacco use, or environmental exposure to Agent Orange, ionizing radiation, certain insecticides. Diagnosis is typically by testing the blood for high numbers of mature lymphocytes and smudge cells.
Asymptomatic patients of CLL are often managed by watchful waiting and monitoring for other infections, and there is currently no evidence that early intervention can alter the course of the disease. Those with significant symptoms are treated with chemotherapy, immunotherapy, or a combination of both, depending on the individual's age, physical condition, and whether they have the del or TP53 mutations.
CLL is the most common type of leukemia in the Western world. It most commonly affects individuals over the age of 65, due to the accumulation of genetic mutations that occur over time. CLL is rarely seen in individuals less than 40 years old. Men are more commonly affected than women, although the average lifetime risk for both genders are similar. It represented less than 1% of deaths from cancer between 1980 and 2015.
Signs and symptoms
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. Most commonly, patients have no symptoms at first. In a small number of cases, patients with CLL may present with enlarged lymph nodes, partially in areas around the neck, armpit, or groin. In rare circumstances, the disease is recognized only after the cancerous cells overwhelm the bone marrow, resulting in low red blood cells, neutrophils, or platelets. This can then result in symptoms such as fever, easy bleeding/bruising, night sweats, weight loss, and increased tiredness. In some instances, the cancerous cells can accumulate in the spleen and result in splenomegaly.Complications
About 25% of patients with CLL have very low levels of antibodies in their bloodstream at diagnosis, with several more patients developing this throughout the course of their disease. This decrease in antibodies increases the patient's risk of recurrent infections and other autoimmune complications, such as autoimmune hemolytic anemia and immune thrombocytopenia. Autoimmune hemolytic anemia occurs in about 5-10% of CLL patients, which is when one's own immune system attacks its own red blood cells.A more serious complication called Richter's transformation occurs in 2-10% of patients with CLL. This is a process in which the original CLL cells convert to a far more aggressive disease that has the biology and histopathology of diffuse large B cell lymphoma or less commonly Hodgkin's lymphoma. These patients typically present with a sudden clinical deterioration that can be characterized by unexplained fevers or weight loss, asymmetric and rapid growth of lymph nodes, and/or a significant drop in the number of white blood cells, red blood cells, or platelets. Treatment for RT typically consists of various chemotherapy/chemo-immunotherapy protocols.
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.
Gastrointestinal involvement can also rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and bleeding. 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.
Causes
The exact cause of CLL is unknown. However, family history has been strongly correlated with the development of disease. Environmental factors may also play a role in the development of CLL. For instance, 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.Mechanism
CLL results from an unusual growth and expansion of white blood cells. This manifestation typically begins with a single hematopoietic stem cell that acquires certain mutations over time that allows it to continue to expand and grow at a faster rate than other cells. Each patient with CLL may be affected by a different set of mutations, making these cells sometimes difficult to target and treat. Some of the most common mutations that have been found in CLL-affected cells include the following: NOTCH1, TP53, ATM, and SF3B1.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, 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.
As CLL cells accumulate, they begin to promote inflammation and an immunosuppressive environment through the release of different chemical signals.
CLL is commonly preceded by a pre-cancerous state known as monoclonal B-cell lymphocytosis. This occurs when there is in an increase in a specific type of white blood cells but the number remains less than 5 billion cells per liter of blood. This subtype, termed chronic lymphocytic leukemia-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 monoclonal, which means they are produced by a single ancestral B-cell. They share some of the same cell marker proteins, chromosome abnormalities, and gene mutations that are found in CLL.
CLL-type MBL can be separated into two groups:
- Low-count MBL has monoclonal B-cell blood counts of <0.5 billion cells/liter
- High-count MBL has blood monoclonal B-cell counts ≥0.5 billion/L but <5 billion/L.
Diagnosis
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 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.Classification
In order to be diagnosed with CLL, the patient must have a white blood cell count greater than 5 billion cells per liter of blood. If CLL-type cells are mainly found in the lymph nodes or lymphoid tissue, a diagnosis of small lymphocytic lymphoma is made. When these cancerous cells appear mostly in the blood, the disease is classified as CLL.Clinical staging
Staging, which helps determine the extent of the disease, is done using one of two systems: the Rai staging system or the Binet classification. These systems are simple, requiring the use of only physical examination and blood test results.Rai staging system
Source:- Low-risk disease ': characterized by lymphocytosis with cancer cells in the blood and/or bone marrow without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia
- Intermediate-risk disease ': characterized by lymphocytosis, swollen lymph nodes, spleen enlargement, and/or liver enlargement
- High-risk disease : characterized by lymphocytosis with associated anemia OR thrombocytopenia with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia
Binet classification
This classification system is based on the number of areas within the body that have been affected and the presence of anemia or thrombocytopenia. Areas of involvement include the head and neck, one or both of the armpits, the groin, the spleen, and the liver. They are considered affected if a lymph node greater than 1 cm in diameter is present and/or the spleen or liver are palpable.
- Clinical stage A: characterized by no anemia or thrombocytopenia and no greater than two areas of lymphoid involvement
- Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement
- Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymph node or organ enlargement