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 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 percentage 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. 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.

• 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.. Rous noted that one could generate a increase in lymphocyte output via administration of pilocarpine.

• In 1945, the first description of infectious lymphocytosis was reported. 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 leukocyte count of 34000 per microliter with 72% lymphocytes. These observations suggested that high lymphocyte count was associated with infection.

• 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. He noted that mononuclear cells in infectious mononucleosis were usually young or abnormal lymphocytes.

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.
• The genes immunoglobulin variable heavy (IGVH), ZAP-70, CD38, and p53 have been associated with the development of CLL, involving a variety of molecular pathways.
• On gross pathology, there are no specific features of lymphocytosis. However, small lymphocytic lymphoma (which is the solid phase of CLL) is associated with presence of CD5, CD19, and CD23 expression on histology.
• 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).

Clonal processes

Regarding clonal processes that may cause lymphocytosis, two major causes include monoclonal B lymphocytosis and chronic lymphocytic leukemia.

• Monoclonal B lymphocytosis: is defined as the presence of less than 5000 clonal B cells per microliter in the peripheral blood. There are 3 categories of monoclonal B lymphocytosis: these include the CD5(+) subtype, CD5(-) subtype, and CLL-like. CLL-like monoclonal B lymphocytosis includes low-count (<500 B cells per microliter) and high-count (>500 B cells per microliter) subtypes.

• Chronic lymphocytic leukemia is a type of lymphocytosis that is characterized by greater than 5000 clonal B lymphocytes per microliter in the peripheral blood. It is the most common hematologic malignancy in the United States. The lymphocytes in CLL are positive for the cell surface markers CD5, CD19 and CD23. Most patients will have indolent disease (a clinical course that is not aggressive). The presence of chromosome 13q deletion is associated with a favorable outcome, whereas the presence of chromosome 17 deletion (p53 deletion) is associated with a worse prognosis. In some cases, CLL can transform into a clinically aggressive lymphoma, like large cell lymphoma. This is known as Richter transformation.

Advanced stage CLL (presence of anemia and thrombocytopenia or organ involvement) suggests bone marrow replacement by the clonal B lymphocytes.

Causes of relative lymphocytosis include:

• Age less than 2 years
• Acute viral infections
• Connective tissue diseases
• Thyrotoxicosis
• Addison's disease
• 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
• Rickets
• Rubella
• Secondary syphilis
• Syphilis
• Thymoma
• Toxoplasmosis
• Tuberculosis
• Varicella
• Viral pneumonia
• Waldenström macroglobulinaemia

Causes by Organ System

Cardiovascular	No underlying causes
Chemical/Poisoning	Herbal agent adverse reaction , Herbal agent overdose
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Ceftazidime, Drug hypersensitivity, Drug reaction with eosinophilia and systemic symptoms, Epstein-barr virus, Ethotoin, Pergolide, Phenytoin, Rifaximin,
Ear Nose Throat	No underlying causes
Endocrine	Addison's disease, Hyperthyroidism, Thyrotoxicosis
Environmental	No underlying causes
Gastroenterologic	Inflammatory bowel disease, Splenectomy, Splenomegaly
Genetic	X-linked lymphoproliferative disease
Hematologic	Acute lymphoblastic leukemia, Bullis fever syndrome  , Burkitt's lymphoma, Chronic and acute lymphocytic leukemia, Chronic erythroleukemia, Chronic myelogenous leukemia, Follicular lymphoma, Glandular fever, Hairy cell leukemia, Hemophagocytic lymphohistiocytosis  , Large granular lymphocyte leukemia, Lymphosarcoma, Non-hodgkin lymphoma, Polycythemia, Protein deficiency, Splenomegaly, Waldenström macroglobulinaemia,
Iatrogenic	Splenectomy
Infectious Disease	Adenovirus, Brucellosis, Bullis fever syndrome  , Cat scratch disease, Chagas disease, Chicken pox, Coxsackie virus, Cytomegalovirus, Glandular fever, Hepatitis a, Hepatitis b, Herpes virus, Hiv, Human t-lymphotropic virus type i, Infection, Infectious mononucleosis, Influenza, Measles, Mumps, Mycobacterium tuberculosis, Pertussis, Poliovirus, Rickettsia, Rubella, Secondary syphilis, Syphilis, Toxoplasmosis, Tuberculosis, Varicella, Viral pneumonia
Musculoskeletal/Orthopedic	Kashin-bek disease  , Myeloma, Osteomyelofibrosis
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Acute lymphoblastic leukemia, Burkitt's lymphoma, Chronic and acute lymphocytic leukemia, Chronic erythroleukemia, Chronic myelogenous leukemia, Follicular lymphoma, Hairy cell leukemia, Hemophagocytic lymphohistiocytosis  , Immunocytoma, Large granular lymphocyte leukemia, Lymphosarcoma, Myeloma, Non-hodgkin lymphoma, Osteomyelofibrosis, Thymoma, Waldenström macroglobulinaemia
Ophthalmologic	No underlying causes
Overdose/Toxicity	Smoking
Psychiatric	Stress
Pulmonary	Sarcoidosis
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	Sarcoidosis, Serum sickness
Sexual	Hiv, Human t-lymphotropic virus type i, Secondary syphilis, Syphilis
Trauma	Exertion, Stress, Trauma
Urologic	No underlying causes
Miscellaneous	No underlying causes

Causes in Alphabetical Order.

• Acute lymphoblastic leukemia
• Addison's disease
• Adenovirus
• Brucellosis
• Bullis fever syndrome 
• Burkitt's lymphoma
• Cat scratch disease
• Ceftazidime
• Chagas disease
• Chicken pox
• Chronic and acute lymphocytic leukemia
• Chronic erythroleukemia
• Chronic myelogenous leukemia
• Coxsackie virus
• Cytomegalovirus
• Drug hypersensitivity
• Drug reaction with eosinophilia and systemic symptoms
• Epstein-barr virus
• Ethotoin
• Exertion
• Follicular lymphoma
• Glandular fever
• Hairy cell leukemia
• Hemophagocytic lymphohistiocytosis 
• Hepatitis a
• Hepatitis b
• Herbal agent adverse reaction
• Herbal agent overdose
• Herpes virus
• Hiv
• Human t-lymphotropic virus type i
• Hyperthyroidism
• Immunocytoma
• Infection
• Infectious mononucleosis
• Inflammatory bowel disease
• Influenza
• Kashin-bek disease 
• Large granular lymphocyte leukemia
• Lymphosarcoma
• Measles
• Mumps
• Mycobacterium tuberculosis
• Myeloma
• Non-hodgkin lymphoma
• Osteomyelofibrosis
• Pergolide
• Pertussis
• Phenytoin
• Poliovirus
• Polycythemia
• Postoperative
• Protein deficiency
• Rickets
• Rifaximin
• Rubella
• Sarcoidosis
• Secondary syphilis
• Serum sickness
• Smoking
• Splenectomy
• Splenomegaly
• Stress
• Syphilis
• Thymoma
• Thyrotoxicosis
• Toxoplasma
• Toxoplasmosis
• Trauma
• Tuberculosis
• Varicella
• Viral pneumonia
• Waldenström macroglobulinaemia
• Waldenstrom's syndrome
• Whooping cough
• X-linked lymphoproliferative disease

Epidemiology and Demographics

• The prevalence of lymphocytosis depends on the underlying etiology for lymphocytosis.
• In 2015, the incidence of CLL was estimated to be 14000 per year, or 466 cases per 100,000 individuals in the United States. The incidence is 4.1 cases per 100000 persons per year.
• CLL is rare in East Asia.

Age

• Patients of all age groups may develop lymphocytosis.
• Chronic lymphocytic leukemia is more commonly observed among patients of older age. The median age is 65-70.
• Monoclonal B lymphocytosis is more commonly observed among patients of older age, similar to CLL.
• Infectious lymphocytosis does not have an age predilection.

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.
• 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.
• 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).

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:

• Greater than or equal to 5000 B lymphocytes per microliter in the peripheral blood
• The presence of clonal B lymphocytes
• The expression of characteristic B cell marker by flow cytometry, including CD5 and CD23

• 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.
• 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. Other lab findings in hemolytic anemia associated with CLL include low haptoglobin, elevated LDH, elevated reticulocyte count, and elevated indirect bilirubin level. A low platelet count can be found in CLL if there is replacement of the bone marrow (stage IV disease) or there is concurrent immune thrombocytopenia purpura (ITP).

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.

• A PET scan is the imaging modality of choice for assessment of CLL.

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. CD38 and ZAP-70 expression are surrogates for IGHV mutational status.

Treatment

Medical Therapy

There are many treatments for lymphocytosis depending on the etiology.

• The mainstay of therapy for chronic lymphocytic leukemia is chemotherapy. Chemotherapy should be administered for persons with CLL who have cytopenias, splenomegaly, bulky or progressive lymphadenopathy, or significant symptoms. Symptoms that warrant treatment include severe fatigue, bleeding, or infection, as these are signs of bone marrow replacement by CLL cells. Typical chemotherapy regimens include fludarabine, cyclophosphamide, and rituximab (FCR) for persons who can tolerate intensive chemotherapy, or rituximab/bendamustine for those who cannot tolerate intensive chemotherapy. Alternative options include ibrutinib and idelalisib, which can be used for patients with loss of the tumor suppressor p53 (chromosome 17p). Venetoclax, which is a Bcl-2 inhibitor, can be used for patients who have relapsed or refractory disease with 17p deletion.
• Chemotherapy acts by damaging the DNA of the cancer cells (for fludarabine and cyclophoshamide).
• Response to chemotherapy can be monitored with routine blood tests, which include complete blood count with differential every 3-6 months. A rise in the absolute lymphocyte count suggests that there is recurrence of disease. A decrease in absolute lymphocyte count suggests that chemotherapy is working.

Treatment of lymphocytosis due to infection involves treatment of the underlying etiology. Typically, this involves antibiotics or anti-viral agents if an infectious etiology is identified.

Surgery

There is no role for surgery for treatment of lymphocytosis, regardless of the etiology. If lymphocytosis is due to an underlying lymphoma, however, an excisional biopsy may be performed.

Prevention

• There are no primary preventive measures available for lymphocytosis.

• Once diagnosed and successfully treated, patients with chronic lymphocytic leukemia are followed-up every 3 months with routine labs. Follow-up testing includes complete blood count (CBC) with differential, and complete metabolic panel (CMP).

References

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