Lymphocytosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2], Luke Rusowicz-Orazem, B.S.
Synonyms and keywords: Lymphocytosis; lymphocyte count raised (peripheral blood)
Overview
Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood, usually detected when a complete blood count is routinely obtained. Lymphocytes are white blood cells that are derived from the common lymphoid progenitor, which arises from the hematopoietic stem cell. Lymphocytes include two broad categories: B cells and T cells. Both of these cell types arise from the bone marrow. B cells mature in the bone marrow, while T cells mature in the thymus. Lymphocytes normally represent 20 to 40% of circulating white blood cells. The absolute lymphocyte count can be directly measured by flow cytometry, or calculated by multiplying the total white blood cell (WBC) count by the percentage of lymphocytes found in the differential count. For example, if the total WBC count is 30,000 per microliter, and the %lymphocytes is 10%, the absolute lymphocyte count is 3,000 per microliter. In absolute lymphocytosis, the total lymphocyte count is elevated. In relative lymphocytosis, there is a higher proportion of lymphocytes amongst the white blood cells compared to other subsets of white blood cells, but a normal absolute number of lymphocytes. In adults, absolute lymphocytosis is present when the absolute lymphocyte count is greater than 4,000 per microliter, while relative lymphocytosis is present if the absolute lymphocyte count is normal but the differential percentage of lymphocytes is higher than 40%. Relative lymphocytosis is normal in children under age 2.
Lymphocytosis can be a feature of infection, particularly in children. In the elderly, lymphoproliferative disorders, including chronic lymphocytic leukemia and lymphomas, often present with lymphadenopathy and a lymphocytosis.
Historical Perspective
- Lymphocytosis was first described prior to the 1900s. Some of the first scientists who studied leukocytosis were Roemer and Gartner.[1] However, there is limited published data from these scientists.
In 1906, lymphocytosis was further explored by W. Henwood Harvey, a British research from the Pharmacologic Laboratory of Cambridge.[1]
In 1908, F.P Rous investigated mechanical factors that contribute to lymphocytosis. He noted that an increase in lymphocytosis could be produced by the flushing effect of lymph flow.[2]. Rous noted that one could generate a increase in lymphocyte output via administration of pilocarpine.[3]
In 1945, the first description of infectious lymphocytosis was reported.[4] Birge and colleagues from the Raymond Blank Memorial Hospital for Children reported the case of a 4-year-od girl with earache who had a leukoocyte count of 34000 per microliter with 72% lymphocytes. These observations suggested that high lymphocyte count was associated with infection.[4]
In 1946, Dr. Leo Meyer from King's County Hospital in Brooklyn, NY noted that the cellular basis for infectious mononucleosis was an increase in lymphocytes.[5] He noted that mononuclear cells in infectious mononucleosis were usually young or abnormal lymphocytes.[5]
Classification
- Lymphocytosis may be classified according to the cell type of origin:
- B cell lymphocytosis
- T cell lymphocytosis
- natural killer cell lymphocytosis
Pathophysiology
- The pathogenesis of lymphocytosis is characterized by either a reactive process (e.g. response to infection) or a primary malignant process (e.g. cancers like chronic lymphocytic leukemia. The underlying etiology include chronic antigen stimulation.[6]
- The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
- On gross pathology, there are no specific features of lymphocytosis.
- On microscopic histopathological analysis, abundance of [lymphocytes] is characteristic findings of [lymphocytosis]. These can be B lymphocytes or T lymphocytes.
Causes
- Lymphocytosis may be caused by either a primary process (e.g. malignant proliferation) or a secondary process (e.g. response to an infection or inflammation).
- Lymphocytosis is not caused by a particular mutation in a gene. However, lymphocytosis due to malignant origin can be associated with a variety of gene mutations.
- There are multiple established causes for Lymphocytosis including infection and malignancy.
Causes of absolute lymphocytosis include: acute viral infections, such as infectious mononucleosis (glandular fever), Epstein-Barr virus infection, and hepatitis; other acute infections such as pertussis and toxoplasmosis; chronic intracellular bacterial infections such as tuberculosis or brucellosis, or malignancy (or pre-malignant conditions).[6]
Regarding clonal processes that cause lymphocytosis, two major causes include monoclonal B lymphocytosis and chronic lymphocytic leukemia.[7]
Monoclonal B lymphocytosis is defined as the presence of less than 5000 clonal B cells per microliter in the peripheral blood.[7] There are 3 categories of monoclonal B lymphocytosis: these include the CD5(+) subtype, CD5(-) subtype, and CLL-like.[8] CLL-like monoclonal B lymphocytosis includes low-count (<500 B cells per microliter) and high-count (>500 B cells per microliter) subtypes.[8]
Causes of relative lymphocytosis include: age less than 2 years; acute viral infections; connective tissue diseases, thyrotoxicosis, Addison's disease, and splenomegaly with splenic sequestration of granulocytes.
Common Causes
- Acute lymphoblastic leukemia
- Adenovirus
- Brucellosis
- Bullis fever syndrome
- Burkitt's lymphoma
- Cat scratch disease
- Chagas disease
- Chicken pox
- Chronic and acute lymphocytic leukemia
- Chronic erythroleukemia
- Chronic myelogenous leukemia
- Coxsackie virus
- Cytomegalovirus
- Follicular lymphoma
- Glandular fever
- Hairy cell leukemia
- Hemophagocytic lymphohistiocytosis
- Hepatitis a
- Hepatitis b
- Herpes virus
- Hiv
- Human t-lymphotropic virus type i
- Immunocytoma
- Infection
- Infectious mononucleosis
- Influenza
- Large granular lymphocyte leukemia
- Lymphosarcoma
- Measles
- Mumps
- Mycobacterium tuberculosis
- Myeloma
- Non-hodgkin lymphoma
- Osteomyelofibrosis
- Pertussis
- Poliovirus
- Rickettsia
- Rubella
- Secondary syphilis
- Syphilis
- Thymoma
- Toxoplasmosis
- Tuberculosis
- Varicella
- Viral pneumonia
- Waldenström macroglobulinaemia
Causes by Organ System
Causes in Alphabetical Order.[9] [10]
Epidemiology and Demographics
- The prevalence of [lymphocytosis] is approximately [number or range] per 100,000 individuals worldwide.
- In [2015], the incidence of [CLL] was estimated to be [14000] per year, or 466 cases per 100,000 individuals in [the United States].[11]
Age
- Patients of all age groups may develop lymphocytosis.
- Chronic lymphocytic leukemia is more commonly observed among patients of older age.
- Monoclonal B lymphocytosis is more commonly observed among patients of older age.
Gender
- Lymphocytosis affects men and women equally.
Race
- There is no racial predilection for lymphocytosis.
Risk Factors
- Common risk factors in the development of CLL are age and monoclonal B lymphocytosis.
Natural History, Complications and Prognosis
- The majority of patients with lymphocytosis remain asymptomatic unless there is significant lymphadenopathy or infection.
- Early clinical features can include, but do not necessarily need to include, fever, fatigue, night sweats, weight loss, and lymphadenopathy.
- If left untreated, 1.1% of patients with [monoclonal B lymphocytosis] may progress to develop [CLL] per year.[11]
- Common complications of CLL include fatigue due to anemia, bleeding due to thrombocytopenia, and infections due to leukopenia. These manifestations occur when the malignant B cells replace the normal cells of the bone marrow.[11]
- Prognosis is generally good if the etiology of lymphocytosis is due to a mild viral infection or if the etiology is due to favorable-risk CLL. Favorable risk [[C}} is characterized by the absence of p53 (17p deletion, and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%].
Diagnosis
Diagnostic Criteria
- The diagnosis of lymphocytosis is made when a complete blood count showed elevated lymphocytes in the peripheral blood.
- The diagnosis of [CLL] is made when the following diagnostic criteria are met:
- The diagnosis of [monoclonal B lymphocytosis] is made when the following diagnostic criteria are met:
- Less than 5000 B lymphocytes per microliter in the peripheral blood
- The absence of lymphadenopathy
Symptoms
- Symptoms of lymphocytosis may include the following:
- weight loss
- fever
- night sweats
- palpable lymphadenopathy
- abdominal pain if splenomegaly is present
- fatigue if marrow replacement occurs affecting normal erythropoiesis
- infection
- bleeding if marrow replacement occurs affecting normal thrombopoiesis
Physical Examination
- Patients with lymphocytosis usually appear asymptomatic but can feel fatigued and ill if the disease affects the other components of the bone marrow and disrupts hematopoiesis.[11]
- Physical examination may be remarkable for:
- fever
- splenomegaly
- lymphadenopathy
- pallor
- petechiae or ecchymoses
Laboratory Findings
- A positive Coomb's test can be associated with CLL if there is accompanying autoimmune hemolytic anemia.
Imaging Findings
- A PET scan can show lymphadenopathy if the etiology of lymphocytosis is small lymphocytic lymphoma or stage 1 or greater CLL.
- A CT scan can show lymphadenopathy also. It can also show splenomegaly. However, a PET scan will show areas of metabolic activity and may be more sensitive for lymphadenopathy.
Other Diagnostic Studies
- A full infectious workup should be completed to determine etiology of lymphocytosis, including blood cultures and other pertinent tests based on focal or localizing symptoms. These tests include, but are not limited to, chest Xray, lumbar puncture with CSF sampling, urinalysis, CT of the abdomen, and PET scan.
- Expression of CD38 ,ZAP-70, and unmutated immunoglobulin heavy variable IGHV chain are associated with a worse prognosis in CLL.[11]
Treatment
Medical Therapy
There are many treatments for lymphocytosis depending on the etiology.
- The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
- [Medical therapy 1] acts by [mechanism of action 1].
- Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].
Surgery
- Surgery is the mainstay of therapy for [disease name].
- [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
- [Surgical procedure] can only be performed for patients with [disease stage] [disease name].
Prevention
- There are no primary preventive measures available for [disease name].
- Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
- Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
References
- ↑ 1.0 1.1 Harvey WH (1906). "Experimental lymphocytosis". J Physiol. 35 (1–2): 115–8. PMC 1465814. PMID 16992864.
- ↑ Rous FP (1908). "AN INQUIRY INTO SOME MECHANICAL FACTORS IN THE PRODUCTION OF LYMPHOCYTOSIS". J Exp Med. 10 (2): 238–70. PMC 2124515. PMID 19867129.
- ↑ Rous FP (1908). "THE EFFECT OF PILOCARPINE ON THE OUTPUT OF LYMPHOCYTES THROUGH THE THORACIC DUCT". J Exp Med. 10 (3): 329–42. PMC 2124525. PMID 19867134.
- ↑ 4.0 4.1 BIRGE RF, HILL LF (1945). "Acute infectious lymphocytosis". Am J Clin Pathol. 15: 508–12. PMID 21010664.
- ↑ 5.0 5.1 MEYER LM (1946). "Acute infectious lymphocytosis". Am J Clin Pathol. 16: 244–56. PMID 20985252.
- ↑ 6.0 6.1 Henriques A, Rodríguez-Caballero A, Criado I, Langerak AW, Nieto WG, Lécrevisse Q; et al. (2014). "Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders". Haematologica. 99 (5): 897–907. doi:10.3324/haematol.2013.098913. PMC 4008118. PMID 24488564.
- ↑ 7.0 7.1 Strati P, Shanafelt TD (2015). "Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification". Blood. 126 (4): 454–62. doi:10.1182/blood-2015-02-585059. PMC 4624440. PMID 26065657.
- ↑ 8.0 8.1 Kalpadakis C, Pangalis GA, Sachanas S, Vassilakopoulos TP, Kyriakaki S, Korkolopoulou P; et al. (2014). "New insights into monoclonal B-cell lymphocytosis". Biomed Res Int. 2014: 258917. doi:10.1155/2014/258917. PMC 4177785. PMID 25295254.
- ↑ Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016
- ↑ Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB; et al. (2015). "Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015". J Natl Compr Canc Netw. 13 (3): 326–62. PMC 4841457. PMID 25736010.