Lymphoid leukemia

# Overview
Lymphoid leukemia is a monoclonal disorder which is a result of clonal proliferation and progressive accumulation of functionally incompetent lymphocytes in circulation, bone marrow, spleen, lymphoid tissues. Lymphocytic leukemia is more frequent than non-lymphocytic and other myeloproliferative diseases. The chronic form (CLL) affects older adult, onset is insidious. Acute lymphoblastic leukemia (ALL) is more common in children, peak incidence around 2 to 3 years of age. The identification of cytogenetic abnormalities is highly relevant for the prognosis of ALL. Patients may have findings associated with anemia, neutropenia, and/or thrombocytopenia due to bone marrow involvement. The white blood cell count may be decreased, normal, or markedly elevated. Symptoms can include fatigue, infections, or easy/spontaneous bruising or bleeding. Arthralgias and constitutional symptoms (eg, fever, night sweats, unintentional weight loss) are often present but are generally mild. Hepatomegaly, splenomegaly, and/or lymphadenopathy can be seen as well. Central nervous system (CNS) involvement may present as cranial neuropathies or meningeal symptoms. Lymphoblasts can have different surface molecules called cluster of differentiation (CD) which can be detected by flow cytometry.

# Classification

## ALL classification
There are two types of classifications for acute lymphoblastic leukemia : 
World Health Organization (WHO) and French-American-British (FAB)
WHO classification of acute lymphoblastic leukemia
- B lymphoblastic leukemia/lymphoma:
B lymphoblastic leukemia/lymphoma, Not otherwise specified
B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities:
B lymphoblastic leukemia/lymphoma with t(9;22),BCR-ABL
B lymphoblastic leukemia/lymphoma t(11q23); MLL rearrangement
B lymphoblastic leukemia/lymphoma with t(12;21)
B lymphoblastic leukemia/lymphoma with hyperdiploidy
B lymphoblastic leukemia/lymphoma with hypodiploidy
B lymphoblastic leukemia/lymphoma t(5;14)
B lymphoblastic leukemia/lymphoma t(1;19)
- B lymphoblastic leukemia/lymphoma, Not otherwise specified
- B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities:
- B lymphoblastic leukemia/lymphoma with t(9;22),BCR-ABL
- B lymphoblastic leukemia/lymphoma t(11q23); MLL rearrangement
- B lymphoblastic leukemia/lymphoma with t(12;21)
- B lymphoblastic leukemia/lymphoma with hyperdiploidy
- B lymphoblastic leukemia/lymphoma with hypodiploidy
- B lymphoblastic leukemia/lymphoma t(5;14)
- B lymphoblastic leukemia/lymphoma t(1;19)
- T lymphoblastic leukemia/lymphoma:
FAB classification of acute lymphoblastic leukemia (for historical purposes):
- ALL-L1: Small cells with homogeneous nuclear chromatin, a regular nuclear shape, small or no nucleoli, scanty cytoplasm, and mild to moderate basophilia
- ALL-L2: Large, heterogeneous cells with variable nuclear chromatin, an irregular nuclear shape, one or more nucleoli, a variable amount of cytoplasm, and  basophilia
- ALL-L3: Large, homogeneous cells with fine, stippled chromatin; regular nuclei; prominent nucleoli; and abundant, deeply basophilic cytoplasm. The most distinguishing feature is prominent cytoplasmic vacuolation.

## CLL classification
- There are two staging systems in order to classify CLL:
Rai staging system (this is used more often in the United States, it is based on lymphocytosis)
Stage	Characteristics:
Low Risk (Stage 0): Abnormal increase in the number of lymphocytes in the blood and marrow.
Intermediate Risk (Stages I & II): Abnormal increase in the number of lymphocytes in the blood and the marrow, enlarged lymph nodes or abnormal increase in the number of lymphocytes in the circulating blood and the marrow, enlarged spleen and/or liver.
High Risk (Stages III & IV): Abnormal increase in the number of lymphocytes in the circulating blood and the marrow, anemia (hemoglobin <11g/dL) or abnormal increase in the number of lymphocytes in the circulating blood and the marrow thrombocytopenia (platelets counts <100,000/uL).
Binet staging system (this is more often used in Europe) 
In the Binet staging system, CLL is classified by the number of affected lymphoid tissue groups (neck lymph nodes, groin lymph nodes, underarm lymph nodes, spleen, and liver) and by whether or not the patient has anemia (too few red blood cells) or thrombocytopenia (too few blood platelets).
Binet stage A: Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage B: 3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage C: Anemia and/or thrombocytopenia are present. Any number of lymphoid tissue areas may be enlarged.
- Rai staging system (this is used more often in the United States, it is based on lymphocytosis)
- Stage	Characteristics:
Low Risk (Stage 0): Abnormal increase in the number of lymphocytes in the blood and marrow.
Intermediate Risk (Stages I & II): Abnormal increase in the number of lymphocytes in the blood and the marrow, enlarged lymph nodes or abnormal increase in the number of lymphocytes in the circulating blood and the marrow, enlarged spleen and/or liver.
High Risk (Stages III & IV): Abnormal increase in the number of lymphocytes in the circulating blood and the marrow, anemia (hemoglobin <11g/dL) or abnormal increase in the number of lymphocytes in the circulating blood and the marrow thrombocytopenia (platelets counts <100,000/uL).
- Low Risk (Stage 0): Abnormal increase in the number of lymphocytes in the blood and marrow.
- Intermediate Risk (Stages I & II): Abnormal increase in the number of lymphocytes in the blood and the marrow, enlarged lymph nodes or abnormal increase in the number of lymphocytes in the circulating blood and the marrow, enlarged spleen and/or liver.
- High Risk (Stages III & IV): Abnormal increase in the number of lymphocytes in the circulating blood and the marrow, anemia (hemoglobin <11g/dL) or abnormal increase in the number of lymphocytes in the circulating blood and the marrow thrombocytopenia (platelets counts <100,000/uL).
- Binet staging system (this is more often used in Europe) 
In the Binet staging system, CLL is classified by the number of affected lymphoid tissue groups (neck lymph nodes, groin lymph nodes, underarm lymph nodes, spleen, and liver) and by whether or not the patient has anemia (too few red blood cells) or thrombocytopenia (too few blood platelets).
Binet stage A: Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage B: 3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage C: Anemia and/or thrombocytopenia are present. Any number of lymphoid tissue areas may be enlarged.
- In the Binet staging system, CLL is classified by the number of affected lymphoid tissue groups (neck lymph nodes, groin lymph nodes, underarm lymph nodes, spleen, and liver) and by whether or not the patient has anemia (too few red blood cells) or thrombocytopenia (too few blood platelets).
Binet stage A: Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage B: 3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
Binet stage C: Anemia and/or thrombocytopenia are present. Any number of lymphoid tissue areas may be enlarged.
- Binet stage A: Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
- Binet stage B: 3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia.
- Binet stage C: Anemia and/or thrombocytopenia are present. Any number of lymphoid tissue areas may be enlarged.

# Pathophysiology

## Physiology
- All lymphocytes have a common lymphoid progenitor cell origin known as a lymphoblast, the formation of lymphocytes is known as lymphopoiesis.
- B cells mature into B lymphocytes in the bone marrow, while T cells migrate to and mature in the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs, where they survey for invading pathogens and cancer cells.
- The lymphocytes involved in adaptive immunity (B and T cells) differentiate further after exposure to an antigen, which occurs in the lymph nodes during antigen presentation from the dendritic cells.
- The fully differentiated B and T cells are specific to the presented antigen and work to defend the body against pathogens associated with that antigen.
- Lymphoid tissues are subdivided into primary and secondary lymphoid organs:
The primary lymphoid tissues responsible for the initial generation of B and T lymphocytes are the bone marrow and thymus, respectively.
Secondary lymphoid tissues include lymph nodes, spleen, tonsils, gut-associated lymphoid tissue (GALT), bronchus-associated lymphoid tissue ( BALT).
Within these lymphoid organs, B and T lymphocytes tend to home to different domains, leading to the segregation of B and T cells.
Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicular areas.
Non-lymphoid cells (eg, dendritic cells, monocytes/macrophages, endothelial cells, and follicular dendritic cells) contribute to the formation of these distinct microenvironments, within which specific cell-cell interactions occur that are required for the generation of cellular and humoral immune responses.
- The primary lymphoid tissues responsible for the initial generation of B and T lymphocytes are the bone marrow and thymus, respectively.
- Secondary lymphoid tissues include lymph nodes, spleen, tonsils, gut-associated lymphoid tissue (GALT), bronchus-associated lymphoid tissue ( BALT).
Within these lymphoid organs, B and T lymphocytes tend to home to different domains, leading to the segregation of B and T cells.
Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicular areas.
Non-lymphoid cells (eg, dendritic cells, monocytes/macrophages, endothelial cells, and follicular dendritic cells) contribute to the formation of these distinct microenvironments, within which specific cell-cell interactions occur that are required for the generation of cellular and humoral immune responses.
- Within these lymphoid organs, B and T lymphocytes tend to home to different domains, leading to the segregation of B and T cells.
- Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicular areas.
- Non-lymphoid cells (eg, dendritic cells, monocytes/macrophages, endothelial cells, and follicular dendritic cells) contribute to the formation of these distinct microenvironments, within which specific cell-cell interactions occur that are required for the generation of cellular and humoral immune responses.

## Pathogenesis
- It is understood that lymphoid leukemia is a result of overproduction of cells which is caused by either activation or inactivation of genes.
- Several factors, such as chromosomal translocations as well as genetic or epigenetic alterations, are involved in leukemogenesis.
- Abnormal methylation of DNA and histone modifications are important mechanisms in tumor suppressor silencing, contributing to leukemogenesis along with genetic alterations.
- The activation of oncogenes involves genetic changes to cellular proto-oncogenes.
- Three genetic mechanisms activate oncogenes in human neoplasms, these mechanisms result in either an alteration of proto-oncogene structure or an increase in proto-oncogene expression:
Mutation
Gene amplification
Chromosome rearrangements
- Mutation
- Gene amplification
- Chromosome rearrangements

## Genetics
- Activation or/and inactivation of genes plays an important role in the pathogenesis and prognosis of lymphoid leukemia.
- Epigenetic and genetic alterations are two mechanisms in leukemia.
- Abnormal methylation of DNA and histone modifications are important mechanisms in tumor suppressor silencing, contributing to leukemogenesis along with genetic alterations.
- Epigenetic mechanisms are the most prevalent inactivation ones in lymphoid leukemia and involve the genes implicated in several cellular mechanisms, including gene expression and transcription, cell-cycle regulation and apoptosis.

## Associated Conditions
Conditions associated with lymphoid leukemia include:
- Anemia
- Other cancers such as melanoma
- Lymph node enlargement
- Low grade fever
- Unexplained weight loss
- Night sweats
- Enlarged spleen or liver
- Infections of the skin, lungs, kidneys or other sites, as result of low immunoglobulin levels and decreased neutrophil counts.
- Fatigue
- Shortness of breath during normal physical activity

# Differentiating Lymphoid Leukemia