As in any clinical disorder, a careful history is critical to defining the origin of lymphocytosis. Inherited causes of lymphocytosis are rare. One recently identified inherited lymphocytosis is BENTA disease (B-cell expansion with nuclear factor kappa-B [NF-κB] and T-cell anergy). Germline gain-of-function mutations in caspase-activating recruitment domain 11 (CARD11) drive this disorder, which is characterized by polyclonal lymphocytosis and splenomegaly beginning in infancy. However, in most cases of lymphocytosis, the issue is to deter mine whether a lymphocyte disorder is clonal/malignant or benign and related to infection, drugs, or physiologic stress. Rarely, neither a malignancy nor an underlying condition can be identified, in which case the lymphocytosis is termed persistent polyclonal B-cell lymphocytosis (PPBL). When an excess of B cells exists, clonality can usually be defined by examining cell surface expression of κ- and λ-light chains using antibody techniques; with T-cell proliferation, it may be important to define clonality by examining T-cell receptor gene rearrangement using molecular procedures. In the case of NK cell disorders, clonality can be difficult to determine and often only provided by analysis of chromosomal abnormalities of restriction fragment length polymorphisms of X-linked genes. In general, a restricted flow cytometry pattern of killer immunoglobulin-like receptor (KIR) expression on NK cells is accepted as a surrogate marker of clonality.
Clonal Disorders
Malignant causes of peripheral blood lymphocytosis are covered in Chapters 75, 76, 81, 82, 85, and 88 and include chronic lymphocytic leukemia (CLL), hairy cell leukemia, splenic marginal zone lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mantle cell lymphoma, adult T-cell leukemia or lymphoma, and Sézary syndrome. Occasionally, precursor T-cell or precursor B-cell leukemia presents with circulating small cells, which morphologically appear more similar to mature lymphocytes than blasts.
A recently identified clonal disorder causing lymphocytosis is mono clonal B-cell lymphocytosis (MBL), an accumulation of clonal B lymphocytes in the blood that does not meet the criteria for CLL (greater than 5000 clonal B cells/μL) but is nevertheless defined by the presence of a clonal population of B cells. Data demonstrate that up to 10% to 15% of patients with lymphocytosis have MBL. Three major subtypes of MBL exist: the CLL immunophenotype (CD5+, CD23+), which is by far the most common; the atypical CLL type (CD5+, CD20+, CD23+/−); and non-CLL lymphoproliferative disorder (CD5−). In a systematic study of blood donors more than 45 years of age, 7.1% had detectable MBL. Of these, the majority had the CLL immunophenotype and more than 93% were low-count MBL (B-cell clonal count less than 500 cells/μL). Similar to the relationship between monoclonal gammopathy of uncertain significance and multiple myeloma, only a small proportion of patients with CLL-type MBL (1% to 4% per year) go on to develop progressive disease requiring treatment. Epidemiologic studies of MBL patients have demonstrated strong familial risk for CLL, and the first reports of MBL came from studies of “unaffected” CLL family members. Studies of CLL families suggest that there is an inherited abnormality that increases the risk of developing CLL, and some families exhibit anticipation, with the disease occurring earlier in successive generations. The supposition that MBL is a progenitor lesion for CLL is strengthened by the observation that both low-count and high count MBL carry the same cytogenetic aberrations observed in good prognosis CLL. MBL mutations including SF3B1, BIRC3, DDX3X, CHD2, or NOTCH1 had shorter time-to-treatment and expression of CD38, ZAP-70, and CD49d increased the risk of progression. Only del17p and trisomy 12 were independent predictors of need for treatment. MBL has been identified in up to 30% of individuals infected with hepatitis C virus (HCV), and up to 50% of the HCV-associated cases demonstrate the atypical CLL immunophenotype. The presence of MBL correlates with more advanced liver disease, suggesting that the persistence of viral infection is crucial to development of the B-cell clone. Follow-up for MBL patients is not clearly defined, although it is probably reasonable to have all but low-count CLL-type MBL patients seen by a hematologist at yearly intervals. For high-count CLL-type MBL, CLL-related risk factors including CD38 and CD49D expression, CLL fluorescence in situ hybridization (FISH) markers, and immunoglobulin heavy chain variable region (IGHV) mutation should be evaluated. Cyclin D1 overexpression or t(11;14) should be examined in atypical CLL type MBL. Conventional karyotyping should be considered in both atypical CLL type MBL and non-CLL type MBL. In addition to standard labs, immunoglobulin titers should be followed in all MBL patients, and live vaccinations should be avoided.
Infectious Causes
The most common infections causing lymphocytosis are Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In young children, EBV infection frequently presents as an upper respiratory infection, but in adolescents and young adults, it can result in acute glandular fever with pharyngitis, splenomegaly, lymphadenitis, and profound reactive lymphocytosis. Lymphocytosis is less prominent in older adults. Although the B cells are targeted by EBV, the lymphocytosis consists of CD8+ lymphocytes reacting to neoantigens expressed on the surface of infected B cells. The massive T-cell response usually clears the infection in a matter of days to 1 week, and the lymphocytosis resolves. CMV infection can produce a similar lymphocytosis. However, in the case of CMV, the macrophages are the target of infection, and the T-cell lymphocytosis results from a response to the macrophage neoantigen. CMV infection and lymphocytosis are more common in older adults. In both viral infections, lymphocytosis can be profound, with 50% or more of the circulating white blood cells (WBCs) identified as lymphocytes. Examination of the peripheral smear reveals that up to 10% of the circulating lymphocytes are atypical and larger than normal lymphocytes with open chromatin and increased cytoplasm. It is particularly important to recognize lymphocytosis caused by these two viruses in pregnant women because congenital infection can cause fetal death and birth defects. In addition to EBV and CMV, primary infection with human immunodeficiency virus (HIV) can cause lymphocytosis and should be suspected in the presence of a viral syndrome in the appropriate clinical circumstance. In children, infection with Coxsackie A and B6 viruses, echovirus, and adenovirus can cause a brief but profound lymphocytosis. Infections with other viruses, including human herpes virus 6 (HHV-6) and HHV-8 as well as rubella virus, varicella, human T-lymphotropic virus type 1 (HTLV-1), and hepatitis viruses, can cause a lymphocytosis, although much less frequently than CMV and EBV.
Important nonviral infections causing lymphocytosis include Toxoplasma gondii and Bordetella pertussis. In an immune-competent host, Toxoplasma infection is often asymptomatic, but patients can have fever, chills, and lymphadenopathy. Mild lymphocytosis with atypical lymphocytes can be observed. As in the case of EBV and CMV, infections during pregnancy can lead to adverse effects on the fetus. In children and adults, infection with B. pertussis can lead to lymphocytosis, with the absolute lymphocyte count frequently greater than 10,000/μL. In more severe cases, lymphocytosis is more pronounced. Unlike viral infections and Toxoplasma infection, the lymphocytosis observed in B. pertussis infection is caused by increases in all lymphocyte subsets, and it appears that the pertussis toxin blocks migration of the lymphocytes from the bloodstream into lymph nodes. Tuberculosis, rickettsial infection, brucellosis, and shigellosis may also cause lymphocytosis.
Physiologic Stress
Lymphocytosis related to physiologic stress is a poorly studied phenomenon. After strenuous physical exercise, subjects develop lymphocytosis, which returns to preexercise levels within 15 minutes to 1 hour of ceasing the activity. The exercise-induced rise is thought to be attributable to catecholamine and steroid hormones and their effect on expression of cell adhesion molecules and on cardiac output and shear stress. Exposure to catecholamines increases the expression of β2-adrenergic receptors on lymphocytes influencing cell trafficking. Reports suggest that a number of other physiologic stresses, including surgery, trauma, cardiac conditions, sickle cell crises, abdominal pain, and obstetric emergencies, increase lymphocyte counts. In these cases, all lymphocyte subsets appear to increase, but the increase is most profound for CD4 and CD8 memory T cells. Neutrophil counts also rise in these patients, but in most cases, the lymphocytosis resolves before the peak of the neutrophil count.
Drug Reactions
Drug-induced lymphocytosis can occur as part of a hypersensitivity syndrome. In these cases, the lymphocytosis is usually part of a systemic condition that includes a fever, rash, and lymphadenopathy (drug reaction with eosinophilia and systemic symptoms [DRESS]). Elevation in other WBC counts, including eosinophils and monocytes, is common, and atypical lymphocytes are seen. The period between drug introduction and the syndrome is usually approximately 3 weeks, with the most common implicated drugs being aromatic anticonvulsants and sulfonamides.7 Some studies differentiate this syndrome from drug-induced cutaneous pseudolymphomas in which collections of nonclonal lymphocytes appear in the skin after longer periods of drug exposure, but there is no peripheral lymphocytosis.
Polyclonal B-Cell Lymphocytosis
A final entity causing lymphocytosis is PPBL. This rare disorder is seen primarily in young to middle-aged women who smoke and results in mild polyclonal lymphocytosis. The lymphocytes are medium sized with abundant cytoplasm and a variable proportion is is also observed, and there is an association with the human leukocyte antigen (HLA) antigen D-related 7 (DR7) phenotype. Examination of the B cells reveals that most are CD19+, CD5−, and CD23−, with a normal kappa-to-lambda ratio and a variety of heavy chain rearrangements. Adenopathy, hepatomegaly, or splenomegaly has been observed in some, but not all, patients. Genetic analysis has demonstrated the presence of isochromosome 3q in a proportion of B cells, as well as the presence of multiple B-cell lymphoma immunoglobulin (BCL2-Ig) gene rearrangements. Similar gene rearrangements have been identified in family members of PPBL patients, along with increases in serum IgM, suggesting that there may be an underlying genetic defect. In vitro studies have shown that PPBL cells proliferate in a CD40-CD154 culture system and secrete both IgM and IgG (isotype switching). This suggests that PPBL may arise from deregulation of the microenvironment or from a defect in a different B-cell activation pathway resulting in extensive proliferation. Overall, the clinical course of this disorder is benign, and the lymphocytosis is not usually progressive; however, clonal B-cell disorders have been seen in a few patients with the disorder, suggesting that it may represent a preneoplastic state.
