Approach to lymphocytosis

What every physician needs to know about lymphocytosis:

Lymphocytes are white blood cells that serve primarily as the body’s adaptive immune system, and provide humoral or cell-mediated immunity against a variety of bacterial, viral, or other pathogens. They are comprised mainly of T, B, and natural killer (NK) cells, and the body typically maintains the absolute lymphocyte count (ALC) in a range of less than 4,000 lymphocytes per uL. Elevation of the lymphocyte count above this level is most commonly due to a reactive lymphocytosis, the body’s normal response to an acute infection or inflammatory condition.

The mechanisms leading to an increased number of circulating lymphocytes include increased lymphocyte production, release of already formed lymphocytes into the blood, or decreased clearance of lymphocytes from the blood. A less common etiology of an elevated lymphocyte count is malignant lymphocytosis, where the lymphocyte count becomes elevated due to either an acute or chronic lymphoproliferative disorder.

An elevated lymphocyte count alone is unlikely to cause harm. Therefore, taking time to identify the underlying cause is essential, as treatment will differ substantially between reactive and malignant causes. For example, reactive lymphocytosis due to a viral infection, such as in infectious mononucleosis, requires no specific treatment other than supportive care. In contrast, acute lymphoblastic leukemia (ALL) may present with an elevated lymphoblast count which can easily be mistaken as a lymphocytosis. Recognizing an elevated white blood cell count that is due to ALL is important, as this disease requires expedient treatment with intensive chemotherapy.

Other causes of malignant lymphocytosis, such as chronic lymphocytic leukemia (CLL), exhibit a wide range of clinical behavior, and may or may not require expedient treatment depending on a variety of clinical and laboratory factors. Most often, however, chronic lymphoproliferative disorders do not require urgent therapy.

What features of the presentation will guide me toward possible causes and next treatment steps:

Even with highly elevated lymphocyte counts, it is unusual for patients to develop leukostasis or other signs and symptoms directly attributable to lymphocytosis. However, signs and symptoms resulting from the condition responsible for the elevated lymphocyte count may be important clues to help identify the underlying etiology. For example, a young patient with lymphocytosis in the setting of fever, pharyngitis, fatigue, and splenomegaly would raise concern for infectious mononucleosis. In contrast, an older patient with lymphocytosis in the setting of lymphadenopathy, anemia, and thrombocytopenia would cause suspicion for CLL.

The time course of lymphocytosis can be a key discriminating factor between different etiologies. In general, lymphocytosis due to an infectious etiology such as mononucleosis will increase rapidly, and peak in the second or third week of illness. Although it may persist for up to 2 months, reactive lymphocytosis is generally self-limited. Malignant lymphocytosis may develop acutely or more gradually, and although it can wax and wane, it does not tend to resolve without specific treatment. The rate of change of the lymphocyte count can influence treatment decisions. For example, a lymphocyte doubling time of less than 6 months is an important consideration in deciding when to initiate treatment of CLL.

Lymphocyte morphology, as evaluated on the peripheral blood smear, can also be an important clue as to the possible cause of the lymphocytosis. For example, atypical lymphocytes with generous cytoplasm and eccentric nuclei are often seen in infectious mononucleosis. Small, mature-appearing lymphocytes with sparse cytoplasm accompanied by damaged lymphocytes (“smudge cells”) are seen in CLL. An elevated white blood cell count due to ALL may exhibit heterogeneity in the size of the malignant cells, with smaller cells being easily mistaken for lymphocytes. The presence of large lymphoblasts with prominent nucleoli and pale blue cytoplasm suggests ALL and not true lymphocytosis.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

A complete blood count with manual differential should be ordered to accurately quantify the total white blood cell (WBC) and absolute lymphocyte count (ALC). The ALC is calculated by multiplying the total WBC by the percentage of lymphocytes and dividing by 100 (ALC = WBC [cells/uL] x [% lymphocytes /100]). With patients in whom a reactive lymphocytosis is suspected, a thorough infectious work-up should be performed. This may include the heterophile antibody (or monospot) test, viral direct fluorescent antibody testing for influenza, RSV (respiratory syncytial virus), and other common viruses, HIV testing, and blood and throat cultures.

In immunocompromised patients, peripheral blood can be sent for viral PCR (polymerase chain reaction) tests to rule out EBV (Epstein-Barr virus), CMV (Cytomegalovirus), HSV (herpes simplex virus), HHV (human herpesvirus)-8, and adenovirus. If this work-up is negative, or if a malignant etiology is suspected, peripheral blood flow cytometry should be performed to rule out a lymphoproliferative disorder. Generally, flow cytometry is definitive for the detection of blasts or B-cell disorders, though it should be noted that T-cell disorders can sometimes be difficult to characterize by flow cytometry. If the diagnosis remains in question, determining the clonality of the lymphocytes may be helpful. For example, identification of clonal rearrangement of the immunoglobulin genes, as seen in B-cell leukemias/lymphomas, or clonal T-cell receptor rearrangement in T-cell leukemia/lymphomas can help solidify a diagnosis.

Serum free light chains, if elevated and skewed toward kappa or lambda, may also provide evidence for lymphocyte clonality. In addition, FISH (florescent in-situ hybridization) cytogenetics can be performed on the peripheral blood to evaluate for markers typical of a lymphoproliferative disorder. For example, a case with flow cytometry results that are atypical but consistent with CLL may show del 13q14, which would further support the CLL diagnosis. If the above studies remain inconclusive, a bone marrow aspirate and core biopsy may be indicated to more definitively rule out a malignant etiology of the lymphocytosis.

What conditions can underlie lymphocytosis:

Reactive lymphocytosis

Infectious

– Infectious mononucleosis (most commonly due to EBV, less commonly CMV, primary HIV-1 infection, adenovirus, or HHV-6).

– Infectious lymphocytosis (usually in children, can be extreme, with WBC counts occasionally greater than 100,000, thought to be due to enteroviruses, also associated with mild eosinophilia).

– Other viral illnesses (measles, mumps, rubella, hepatitis, influenza, varicella, HTLV-1 [Human T-cell Lymphotropic Virus]).

– Bacterial infection (well-described with Bordetella pertussis, Bartonella henselae [“cat scratch disease”], tuberculosis).

– Parasitic diseases (babesiosis usually causes atypical lymphocytes with normal WBC count, toxoplasmosis can cause atypical lymphocytes with elevated lymphocyte count).

Non-infectious

– Stress-induced lymphocytosis (seen in trauma, where it may confer a poor prognosis, also seen after seizure, cardiac emergencies, sickle crisis).

– Persistent polyclonal B cell lymphocytosis (generally middle-aged female smokers, associated with HLA-DR7).

– Hypersensitivity reactions (for example, drug-related such as with phenytoin, serum sickness).

– Chronic NK cell lymphocytosis (may be associated with anemia and neutropenia).

– Post-splenectomy (morphology tends to be large granular lymphocytes, typically persists for years).

– Miscellaneous (inflammatory bowel disease, vasculitis, thyrotoxicosis, Addison’s disease).

Malignant lymphocytosis

Chronic lymphocytic leukemia (CLL)

– The most common leukemia among adults in Western countries, absolute B cell count must be greater than 5,000 per uL, and typically has a phenotype that is positive for CD19, CD5, CD23, CD20 (dim), and either kappa or lambda (dim).

Prolymphocytic leukemia (PLL)

– May be B or T cell-derived. B-PLL may evolve from CLL or present de novo. T-PLL carries a particularly poor prognosis.

Monoclonal B cell lymphocytosis (MBL)

– A premalignant condition with a phenotype identical to CLL and similar chromosomal abnormalities but less than 5,000 B cells per uL. About 1% of patients per year develop progression to CLL that requires treatment.

Lymphoproliferative disease of large granular lymphocytes (LGL)

– Varied clinical behavior, usually indolent but can develop other cytopenias and systemic symptoms.

Mycosis fungoides

– Sezary syndrome, lymphocytes typically with “cerebriform” nuclei.

Hairy cell leukemia

– Characteristic hair-like projections, positive for CD25, CD11c, CD103.

Non-Hodgkin lymphoma (NHL)with marrow involvement

– Leukemic phase seen more commonly in follicular, mantle-cell, marginal zone, and Burkitt lymphoma, but can occur with almost any NHL subtype.

When do you need to get more aggressive tests:

Any patient presenting with lymphoctyosis should have an aggressive work-up to rule out a malignant etiology. Patients who should generate particular concern include those with a markedly elevated lymphocyte count (for example, above 20,000 per uL), those with malignant-appearing lymphocytes, and/or persistent lymphocytosis of greater than 3 weeks.

If the initial work-up is unrevealing for a reactive cause, or if a malignant etiology is highly suspected, the following additional tests should be pursued:

Peripheral blood flow cytometry
Peripheral blood cytogenetics

– With interphase FISH for common cytogenetic abnormalities, including del 17p, del 11q, del 13q14, and trisomy 12 seen in CLL, and t[11;14] seen in mantle cell NHL).

Immunoglobulin or T cell receptor gene rearrangement studies
Bone marrow biopsy and aspirate
Lymph node biopsy may also be indicated in select cases

What imaging studies (if any) will be helpful?

Imaging is rarely required in the evaluation and management of lymphocytosis. Exceptions include patients whose lymphocytosis is thought to be most likely due to non-Hodgkin lymphoma, patients with palpable lymphadenopathy, patients with CLL and unfavorable cytogenetic abnormalities such as del 17p or del 11q who may have bulky intra-abdominal lymphadenopathy not appreciated on physical exam, and patients with a suspicion of T-ALL, to rule out the presence of a mediastinal mass.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

It is unusual for immediate therapy to be required, and time should be taken to establish a definitive diagnosis prior to initiating treatment. One exception is in patients with aggressive lymphomas with circulating disease, such as Burkitt lymphoma, who may undergo spontaneous tumor lysis syndrome. In patients with these metabolic derangements, aggressive electrolyte management, early administration of intravenous fluids, allopurinol, and, when required, rasburicase, are all important interventions to stabilize the patient while they are being worked up.

What other therapies are helpful for reducing complications?

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What should you tell the patient and the family about prognosis?

The prognosis of patients with lymphocytosis depends on the etiology of the condition, and discussions about prognosis with the patient and family should be postponed until a definitive diagnosis is established.

“What if” scenarios.

If an identifiable cause of reactive lymphocytosis such as infectious mononucleosis is found, supportive care with observation is appropriate. However, should the lymphocytosis persist longterm (for example, greater than 2 months), a re-evaluation must be performed, with a low threshold for pursuing studies to rule out an underlying malignant lymphocytosis.

If lymphocytosis is found to be intermittent, it should not be ignored, and further evaluation may be necessary. For example, patients with early stage CLL or indolent NHL may have borderline elevations of lymphocyte counts that wax and wane, and although these patients may not require immediate treatment, monitoring and definitive diagnostic evaluation should be performed.

Pathophysiology

The pathophysiology of lymphoctyosis varies widely, and depends on the underlying etiology driving the condition, as described in more detail in the topics covering these conditions. In both reactive and malignant lymphocytosis, the mechanisms leading to an increased number of circulating lymphocytes may include increased lymphocyte production, release of already formed lymphocytes into the blood, or decreased clearance of lymphocytes by the reticulo-endothelial system.

What other clinical manifestations may help me to diagnose lymphocytosis

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What other laboratory studies may be ordered?

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