Lymphocytosis, defined by an increase in absolute lymphocyte count (ALC) to more than 4000 lymphocytes/microL in adult patients, is a common hematologic abnormality. ALC calculates as the total white blood cell count (WBC) multiplied by the percentage of lymphocytes in the peripheral blood. Different lymphocyte subsets (T cells, B cells, or NK cells) may be increased depending on the particular etiology. Lymphocytes represent around 20 to 40% of WBC. The definition of relative lymphocytosis is an increase in WBC of more than 40% in the presence of a normal absolute white cell count. In this review, we present the most common causes in adult patients, in addition to a general approach to diagnosis and management of frequently encountered etiologies.
Distinguishing reactive from malignant lymphocytosis can be challenging and may vary depending on age and other demographics. The following is a list of the most common etiologies.
The epidemiology of lymphocytosis varies by age and particular etiologies. Below is some demographic data for the most common causes.
The pathophysiology of lymphocytosis varies by etiology. Increased lymphocyte production may be either due to a clonal process or a reactive process. Also, redistribution of lymphoid cells may be the primary etiology in some patients presenting with lymphocytosis. The mechanism of some of the most common causes follows:
History and physical (H&P) is an essential part of the evaluation as it might reveal the underlying etiology, or may help to point out the need for an expedited evaluation. Some of the critical points in H&P include:
The evaluation of lymphocytosis begins with a detailed history and physical examination. The complete blood count (CBC) and review of the peripheral blood smear (PBS) are essential to start an appropriate workup.
The management of lymphocytosis depends on the underlying etiology. While some causes reflect only a reactive or physiologic process that does not need any intervention (e.g., stress or asplenia), others indicate a malignant or clonal process that might require intervention.
The differential diagnosis of lymphocytosis is broad and was discussed above in the etiology section.
Keys points pertinent to malignant causes of lymphocytosis were discussed in the above sections.
The prognosis of a patient with lymphocytosis depends on the underlying etiology. Examples of specific disease prognosis are as follows:
The complications from lymphocytosis coincide with the underlying etiology where leukemia is the most common underlying disease.
Appropriate consultation between primary care physicians (PCP) and hematologists is paramount. While some causes of lymphocytosis will resolve with observation or supportive management alone, others may need more prompt evaluation. The presence of highly elevated counts (ALC greater than 30000 cells/microL) or rapidly increasing ones should alert PCP to consult hematology specialists. Likewise, hematology consultants should direct management in cases needing intervention and provide guidance when clinical monitoring is appropriate.
Lymphocytosis by itself is often a sign of an underlying disorder. Recognition of its presence, as defined by an ALC over 4000 cells/microL, is the first step. A second important issue is the recognition of the urgency or lack of it in referral to hematology. A detailed history, coupled with a complete physical examination and review of complete blood counts, provides a preliminary idea regarding the underlying etiology. Patients with no alarming features and typical history for a reactive cause of lymphocytosis can be reassured and monitored clinically. Patients with infectious mononucleosis should be instructed to refrain from contact sports during the acute phase of their illness that fatigue may continue after the resolution of other symptoms.
Any alarming features, like significant weight loss, anorexia, excessive night sweats, or an abnormal physical exam (lymphadenopathy or hepato-splenomegaly), should trigger a hematology referral and workup. Patients with suspicion or confirmation of leukemia should receive a prompt referral to academic centers specializing in the treatment of leukemia.
Lymphocytosis is often incidental and detected on routine peripheral blood count. It is essential to keep a thorough and systematic approach to diagnose the underlying etiology appropriately. A comprehensive history and a detailed physical examination are critical as they provide important clues towards the etiology of lymphocytosis. An Interprofessional team, including primary care physicians (PCP), internists, pathologists, and hematologists, is essential for establishing an accurate diagnosis and initiating appropriate management. This team will also include nursing and pharmacy personnel, depending on the significance of the findings and ultimate diagnosis. Often a pharmacist specializing in oncology will be required to assist with medication selection, management, and family education. An oncology nurse may be required to help with the coordination of care. The family clinician is often the first point of contact. They should familiarize themselves with common causes of lymphocytosis and also recognize alarming features that would prompt additional investigations. All hematologists should review the peripheral blood smear and obtain a peripheral blood flow cytometry if needed. However, if the smear detects an alarming finding, then a trained heme-pathologist must be consulted for confirmation. When clinical observation is appropriate, then communication between the hematologist and the PCP/internist as well as pharmacist and nursing staff should be clear and unambiguous to reassure the patient.
Lymphocytosis has many underlying causes with different approaches to diagnosis and management. The management of lymphocytosis, which occurs secondary to an underlying malignancy like lymphoma or leukemia, is directed towards the underlying cause and is supported by level I evidence.
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