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.
[1] | Brigden ML,Au S,Thompson S,Brigden S,Doyle P,Tsaparas Y, Infectious mononucleosis in an outpatient population: diagnostic utility of 2 automated hematology analyzers and the sensitivity and specificity of Hoagland's criteria in heterophile-positive patients. Archives of pathology [PubMed PMID: 10506437] |
[2] | Rosenberg ES,Caliendo AM,Walker BD, Acute HIV infection among patients tested for mononucleosis. The New England journal of medicine. 1999 Mar 25; [PubMed PMID: 10094651] |
[3] | Fiala M,Heiner DC,Turner JA,Rosenbloom B,Guze LB, Infectious mononucleosis and mononucleosis syndromes. The Western journal of medicine. 1977 Jun; [PubMed PMID: 195404] |
[4] | Arber DA,George TI, Bone marrow biopsy involvement by non-Hodgkin's lymphoma: frequency of lymphoma types, patterns, blood involvement, and discordance with other sites in 450 specimens. The American journal of surgical pathology. 2005 Dec; [PubMed PMID: 16327427] |
[5] | George TI, Malignant or benign leukocytosis. Hematology. American Society of Hematology. Education Program. 2012; [PubMed PMID: 23233622] |
[6] | Matutes E,Parry-Jones N,Brito-Babapulle V,Wotherspoon A,Morilla R,Atkinson S,Elnenaei MO,Jain P,Giustolisi GM,A'Hern RP,Catovsky D, The leukemic presentation of mantle-cell lymphoma: disease features and prognostic factors in 58 patients. Leukemia [PubMed PMID: 15370245] |
[7] | Woyach JA,Smucker K,Smith LL,Lozanski A,Zhong Y,Ruppert AS,Lucas D,Williams K,Zhao W,Rassenti L,Ghia E,Kipps TJ,Mantel R,Jones J,Flynn J,Maddocks K,O'Brien S,Furman RR,James DF,Clow F,Lozanski G,Johnson AJ,Byrd JC, Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014 Mar 20; [PubMed PMID: 24415539] |
[8] | Snow AL,Xiao W,Stinson JR,Lu W,Chaigne-Delalande B,Zheng L,Pittaluga S,Matthews HF,Schmitz R,Jhavar S,Kuchen S,Kardava L,Wang W,Lamborn IT,Jing H,Raffeld M,Moir S,Fleisher TA,Staudt LM,Su HC,Lenardo MJ, Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. The Journal of experimental medicine. 2012 Nov 19; [PubMed PMID: 23129749] |
[9] | Troussard X,Cornet E,Lesesve JF,Kourel C,Mossafa H, Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL). OncoTargets and therapy. 2008 Oct 1; [PubMed PMID: 21127753] |
[10] | Teggatz JR,Parkin J,Peterson L, Transient atypical lymphocytosis in patients with emergency medical conditions. Archives of pathology [PubMed PMID: 3632284] |
[11] | Heath CW Jr,Brodsky AL,Potolsky AI, Infectious mononucleosis in a general population. American journal of epidemiology. 1972 Jan; [PubMed PMID: 5007364] |
[12] | Nye FJ, Social class and infectious mononucleosis. The Journal of hygiene. 1973 Mar; [PubMed PMID: 4348454] |
[13] | Skoff TH,Hadler S,Hariri S, The Epidemiology of Nationally Reported Pertussis in the United States, 2000-2016. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019 May 2; [PubMed PMID: 30169627] |
[14] | Rawstron AC,Green MJ,Kuzmicki A,Kennedy B,Fenton JA,Evans PA,O'Connor SJ,Richards SJ,Morgan GJ,Jack AS,Hillmen P, Monoclonal B lymphocytes with the characteristics of [PubMed PMID: 12091358] |
[15] | Thorley-Lawson DA,Gross A, Persistence of the Epstein-Barr virus and the origins of associated lymphomas. The New England journal of medicine. 2004 Mar 25; [PubMed PMID: 15044644] |
[16] | Kubic VL,Kubic PT,Brunning RD, The morphologic and immunophenotypic assessment of the lymphocytosis accompanying Bordetella pertussis infection. American journal of clinical pathology. 1991 Jun; [PubMed PMID: 2042590] |
[17] | Rezk E,Nofal YH,Hamzeh A,Aboujaib MF,AlKheder MA,Al Hammad MF, Steroids for symptom control in infectious mononucleosis. The Cochrane database of systematic reviews. 2015 Nov 8; [PubMed PMID: 26558642] |
[18] | Shanafelt TD,Wang XV,Kay NE,Hanson CA,O'Brien S,Barrientos J,Jelinek DF,Braggio E,Leis JF,Zhang CC,Coutre SE,Barr PM,Cashen AF,Mato AR,Singh AK,Mullane MP,Little RF,Erba H,Stone RM,Litzow M,Tallman M, Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. The New England journal of medicine. 2019 Aug 1 [PubMed PMID: 31365801] |
[19] | Buchwald DS,Rea TD,Katon WJ,Russo JE,Ashley RL, Acute infectious mononucleosis: characteristics of patients who report failure to recover. The American journal of medicine. 2000 Nov; [PubMed PMID: 11063953] |
[20] | Teepe J,Broekhuizen BD,Ieven M,Loens K,Huygen K,Kretzschmar M,de Melker H,Butler CC,Little P,Stuart B,Coenen S,Goossens H,Verheij TJ, Prevalence, diagnosis, and disease course of pertussis in adults with acute cough: a prospective, observational study in primary care. The British journal of general practice : the journal of the Royal College of General Practitioners. 2015 Oct; [PubMed PMID: 26412843] |
[21] | Cacoub P,Musette P,Descamps V,Meyer O,Speirs C,Finzi L,Roujeau JC, The DRESS syndrome: a literature review. The American journal of medicine. 2011 Jul; [PubMed PMID: 21592453] |
[22] | Röllig C,Ehninger G, How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015 May 21 [PubMed PMID: 25778528] |
[23] | Neparidze N,Lacy J, Malignancies associated with epstein-barr virus: pathobiology, clinical features, and evolving treatments. Clinical advances in hematology & oncology : H&O. 2014 Jun [PubMed PMID: 25003566] |
[24] | Tsimberidou AM,Wen S,McLaughlin P,O'Brien S,Wierda WG,Lerner S,Strom S,Freireich EJ,Medeiros LJ,Kantarjian HM,Keating MJ, Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Feb 20 [PubMed PMID: 19114699] |