Hairy Cell Leukemia

Overview

Definition

Hairy cell leukemia (HCL) is a rare, chronic B-cell leukemia characterized by the accumulation of small mature B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions that have hair-like projections visible on microscopy.

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 
  • 3 per 1 million persons per year in the United States
  • Rare: approximately 2% of all leukemia cases
• Median age at diagnosis: approximately 50 years
• Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria: male > female (4:1)
• Race/ethnicity:
  • More common in Caucasians ( incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is 3× higher than in African Americans)
  • Rare in people of African and Japanese descent
• First-degree family members have an 8× higher risk than the general population.

Etiology

Hairy cell leukemia is a clonal B-cell malignancy Malignancy Hemothorax. The exact etiology is unknown, but several environmental exposures appear to increase the risk of developing HCL.

• Exposures as possible causes:
  • Ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Organophosphorus pesticides
  • Farming and agricultural chemicals
  • Wood dust
  • Previous history of infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis
• Familial relationships: due to sharing an HLA haplotype

Pathophysiology

The underlying issue in HCL is that the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis produces far too many B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, which crowd out the other types of blood cells. These abnormal B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions are unable to protect the body from infectious invaders the way normal B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions can.

Pathophysiology

• B-cell lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology with hair-like projections (hairy cells) undergo clonal proliferation
• Hairy cells accumulate in:
  • Peripheral blood
  • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis
  • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy (less common)
  • Lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy (uncommon)
• Infiltration of the reticuloendothelial system:
  • Interferes with bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis function
  • Results in bone marrow failure Bone marrow failure Inherited or acquired diseases characterized by insufficient and/or dysplastic blood cells. Paroxysmal Nocturnal Hemoglobinuria and/or pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia
• Infiltrates the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy: results in organomegaly
• Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease due to disease- and treatment-related immunosuppression:
  • Major cause of death
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease may be bacterial, viral, fungal, or nontuberculous mycobacterial.

Pathogenesis

The pathogenesis is incompletely understood, but most cases appear to arise from late activated memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, which acquire an activating BRAF V600E gene mutation Gene Mutation Myotonic Dystrophies.

• BRAF V600E activating mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (fundamental cause of biologic features of HCL): 
  • Results in constitutive activation of the RAF-MEK-ERK signaling pathway → leads to inhibition of apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage/enhanced cell survival
  • Acts as a molecular trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation and marker
  • Present in nearly 100% of cases
• Hairy cells have the following features:
  • Expression of pan-B-cell surface antigens: CD19, CD20, and CD22
  • Nonexpression of immature B-cell markers CD10 and CD21 CD21 Molecular sites on or in B-lymphocytes, follicular dendritic cells, lymphoid cells, and epithelial cells that recognize and combine with complement C3D. Human complement receptor 2 (CR2) serves as a receptor for both C3dg and the gp350/220 glycoprotein of Human Herpesvirus 4 and binds the monoclonal antibody OKB7, which blocks binding of both ligands to the receptor. Epstein-Barr Virus
  • Expression of surface antigens that are not common on B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, such as:
    • ≥1 Ig Ig X-linked Agammaglobulinemia heavy chains Heavy chains The largest of polypeptide chains comprising immunoglobulins. They contain 450 to 600 amino acid residues per chain, and have molecular weights of 51-72 kda. Immunoglobulins: Types and Functions and monotypic light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions
    • CD11c (typically found in monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation and neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation)
    • CD25 (typically found in activated T cells Activated T cells Adaptive Cell-mediated Immunity)
    • CD103 (typically found in intraepithelial T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions)
• Other mutations that may play a role in the molecular pathogenesis:
  • Overexpression of cyclin D1 Cyclin D1 Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11; 14) translocation, and is implicated in various neoplasms. Non-Hodgkin Lymphomas protein (an important cell-cycle regulator)
  • Mutations in CDKN1B/p27 (a cell-cycle inhibitor)
  • Mutations in KLF2 (a transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription)
• Associated with other systemic immunologic disorders:
  • Scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma
  • Polymyositis Polymyositis Polymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children. Polymyositis
  • Polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides
  • Erythematous maculopapules
  • Pyoderma gangrenosum Pyoderma gangrenosum An idiopathic, rapidly evolving, and severely debilitating disease occurring most commonly in association with chronic ulcerative colitis. It is characterized by the presence of boggy, purplish ulcers with undermined borders, appearing mostly on the legs. The majority of cases are in people between 40 and 60 years old. Its etiology is unknown. Crohn’s Disease

Clinical Presentation

Symptoms related to cytopenias Cytopenias IPEX Syndrome

• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (most common presenting symptoms):
  • Weakness
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
• Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia → bleeding symptoms (⅓ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
  • Ecchymosis Ecchymosis Extravasation of blood into the skin, resulting in a nonelevated, rounded or irregular, blue or purplish patch, larger than a petechia. Orbital Fractures
  • Epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis
  • Gingival bleeding
  • Menorrhagia
• Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (⅓ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever (due to infection)
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Symptoms related to infiltration in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy

• Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly causing abdominal discomfort (classic feature of HCL, seen in 80%–90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
  • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy may be massive: splenic edge extending > 8 cm beyond the left costal margin in 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency and severity of splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly may be decreasing as patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are being diagnosed earlier.
  • Spontaneous splenic rupture Splenic rupture Splenic rupture is a medical emergency that carries a significant risk of hypovolemic shock and death. Injury to the spleen accounts for nearly half of all injuries to intra-abdominal organs. The most common reason for a rupture of the spleen is blunt abdominal trauma, specifically, motor vehicle accidents. Rupture of the Spleen may occur → a medical emergency
• Hepatomegaly and lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy are not major features of HCL:
  • Hepatomegaly present in 20% of HCL patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy present in 10% of HCL patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

Asymptomatic

• Incidental finding during workup for unrelated cause
• ¼ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

Diagnosis

The diagnosis is based on identifying hairy cells on a peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types, immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency, and/or flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia and, potentially, a bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.

Laboratory

Laboratory findings may include:

• Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types: identification Identification Defense Mechanisms of hairy cells
  • Fine, hairlike cytoplasmic projections
  • Large mononuclear cells 
  • Nuclei are most commonly ovoid and eccentrically located.
  • Can be identified with a Romanowsky stain
• CBC/DIFF:
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (normochromic–normocytic): 85% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia: 80%
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia: 80%
  • Monocytopenia: 80%
  • Leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus (> 10,000 cells/µL): 10%–20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Other serologic testing:
  • BUN elevated: 30%
  • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests abnormal: 20%
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C serologies for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship whose planned treatment is with rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
• Flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia of peripheral blood: can confirm immunophenotype of circulating B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

• Difficult or impossible to aspirate (“dry tap”) due to HCL-induced marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
• Requires a trephine bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
• Immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency (IHC) staining:
  • Best method to determine diagnosis and extent of involvement 
  • To distinguish classic HCL from other peripheral small B-cell neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
  • Assess for the BRAF V600E somatic mutation Somatic Mutation Non-Hodgkin Lymphomas: highly sensitive but not specific to HCL (also detected in other entities)
  • Allows for assessment of typical HCL antigens: CD19, CD20, CD22, CD11c, CD25, and CD103

Management

Goals of care

• Improve symptoms.
• Reverse cytopenias Cytopenias IPEX Syndrome.
• Prolong survival to a near-normal lifespan (though the disease is technically not curable)

Asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: observation

Asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be observed rather than treated.

• Can be observed for months or years
• Approximately 10% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship never require therapy.
• No clear advantage to early treatment (risk of therapy may be greater than benefit)
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can be followed with interval histories, exams, and CBC/DIFF approximately every 3 months.

Symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: treatment

Treatment is indicated in the following clinical situations:

• Significant cytopenias Cytopenias IPEX Syndrome: 
  • Absolute neutrophil count Absolute neutrophil count The number of neutrophils (as opposed to the percentage of WBCs) circulating per µL of blood . Neutropenia: < 1000/µL
  • Hemoglobin: < 11 g/dL
  • Platelet count: < 100,000/µL
• Less severe cytopenias Cytopenias IPEX Syndrome with the following:
  • Repeated infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Clinical bleeding
  • Progressive lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis
• Symptomatic splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly (common)
• Symptomatic adenopathy (uncommon)
• Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and/or night sweats Night sweats Tuberculosis (signs of infection), weight loss Weight loss Decrease in existing body weight. Bariatric Surgery

Treatment options

• Purine analogs Purine Analogs Antimetabolite Chemotherapy: cladribine Cladribine An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. Antimetabolite Chemotherapy, pentostatin Pentostatin A potent inhibitor of adenosine deaminase. The drug induces apoptosis of lymphocytes, and is used in the treatment of many lymphoproliferative malignancies, particularly hairy cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity. Antimetabolite Chemotherapy
  • Cytotoxic Cytotoxic Parvovirus B19 effects on both B and T lymphocytes T lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
  • 1st-line treatment for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with normal renal function
  • Complete remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches is achieved in > 90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with progression-free survival (PFS) of 9‒11 years.
  • Induces a profound neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia → risk of infection due to treatment
• Interferon alfa Interferon Alfa Antivirals for Hepatitis C:
  • Inhibits cell growth, interferes with oncogene and surface antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination expression
  • Can be used as an alternative agent in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who would benefit from ↑ blood counts prior to starting purine analog therapy.
  • Indications: 
    • Severe pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia
    • Active infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (though most can just be observed until after delivery)
• Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants:
  • A monoclonal antibody against CD20 (found on B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions)
  • May be added to purine analog therapies to improve response
  • Associated with immunosuppression
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are at risk for reactivation Reactivation Herpes Simplex Virus 1 and 2 and severe hepatitis.
• Splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen:
  • May temporarily improve blood counts
  • Not done routinely, but indications include:
    • Palliative therapy for symptomatic splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly (e.g., pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, severe enlargement)
    • Emergency treatment for splenic rupture Splenic rupture Splenic rupture is a medical emergency that carries a significant risk of hypovolemic shock and death. Injury to the spleen accounts for nearly half of all injuries to intra-abdominal organs. The most common reason for a rupture of the spleen is blunt abdominal trauma, specifically, motor vehicle accidents. Rupture of the Spleen
    • Pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia due to splenic sequestration Splenic sequestration Severe Congenital Neutropenia
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
• Other therapies:
  • Antibiotics to treat infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Vaccines to prevent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
  • Transfusions to treat severe/symptomatic cytopenias Cytopenias IPEX Syndrome ( patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship require irradiated blood products)

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• With treatment, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can achieve long-term remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches.
• 5-year survival rate: 84%–94%
• Long treatment-free periods
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with symptomatic relapses should be given further therapy.

Differential Diagnosis

• Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis: myeloproliferative neoplasm due to mutations in the hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis that is characterized by chronic myeloproliferation with fibroblastic deposition, resulting in bone marrow fibrosis Bone Marrow Fibrosis Primary Myelofibrosis. Symptoms are primarily related to anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types and extramedullary hematopoiesis Extramedullary Hematopoiesis Primary Myelofibrosis and include severe fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Laboratory studies show anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (and other cytopenias Cytopenias IPEX Syndrome), and bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma reveals extensive fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. Management is with hematopoietic cell transplantation (HCT) and symptom-directed interventions.
• CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia: mature B-cell neoplasm characterized by a progressive accumulation of functionally incompetent monoclonal B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions. Most cases of CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia are asymptomatic, with exam findings of painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly. CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia can be differentiated from HCL on the basis of differences in the peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types, bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, and immunophenotype of circulating lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology on flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia. Management is with observation for asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship and chemotherapy Chemotherapy Osteosarcoma in later stages. 
• Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia: rare life-threatening condition characterized by pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia and hypocellularity of the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis, in the absence of any abnormal cells, reflecting damage to the hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis (HSCs). Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia can be acquired or inherited. Multiple causes are known, including autoimmune damage to HSCs, medications, chemicals, whole-body radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma, viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, immune diseases, pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, Fanconi anemia Fanconi anemia Congenital disorder affecting all bone marrow elements, resulting in anemia; leukopenia; and thrombopenia, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous chromosome breakage is a feature of this disease along with predisposition to leukemia. There are at least 7 complementation groups in Fanconi anemia: fanca, fancb, fancc, fancd1, fancd2, fance, fancf, fancg, and fancl. Aplastic Anemia, and Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21).
• Mantle-cell lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum: aggressive, rare form of non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum (NHL) involving mature B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions. Mantle-cell lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum is caused by overexpression of cyclin D2 and tends to occur in older men. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship tend to present with advanced disease and may have symptoms including fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats Night sweats Tuberculosis, and unintentional weight loss Weight loss Decrease in existing body weight. Bariatric Surgery (B-cell symptoms). Diagnosis is by tissue biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma and immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency. Management may include chemotherapy Chemotherapy Osteosarcoma, immunotherapy, and possibly hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation.