Differential Diagnosis

Absolute lymphocytosis is an increase in the lymphocyte count in the peripheral blood. Relative lymphocytosis is an increase of lymphocyte percentage. Absolute lymphocytosis can be divided into two main categories: secondary (reactive) and primary (clonal).

Secondary lymphocytosis is frequently accompanied by neutropenia and is usually associated with viral infections, including Epstein-Barr virus (EBV), acute infectious lymphocytosis, hepatitis, and numerous others. Lymphocytosis in children and young adults is usually of viral origin, while chronic lymphocytosis in middle-aged and older adults is often due to CLL or other lymphoproliferative disorders.

Infectious mononucleosis due to EBV infection is frequent in adolescents and young adults, but can also be observed in older adults. It usually presents with sore throat, malaise, lymphadenopathy and hepatosplenomegaly. Typical peripheral blood findings include increased WBC, ranging within 12-25 x 103/mL, and absolute lymphocytosis with numerous large, transformed lymphocytes with immature nuclear chromatin and increase in the amount of basophilic cytoplasm or "monocytoid" lymphocytes. These changes are not pathognomonic for EBV, and can be seen in other infections, such as cytomegalovirus, toxoplasmosis, and infectious hepatitis. EBV virus attaches to C3d complement receptor (CD21) on B lymphocytes and stimulates proliferation and production of polyclonal immunoglobulin. The cellular immune response consists of activation and proliferation of T lymphocytes, usually during the second week of illness, and occurs as a reaction to B-cell activation. These actually represent the atypical lymphocytes present in the blood. Diagnosis is based on detection of a specific humoral immune response (increase in titer of IgG and IgM viral capsid antibodies), or of heterophil antibodies that bind to the red cells of other species, such as horse or sheep. Cytomegalovirus infection is a syndrome similar to infectious mononucleosis. There is no rise in heterophil antibody, and diagnosis is made by CMV culture or serology. Persistent polyclonal B-cell lymphocytosis is a rare condition in adults, predominantly female smokers, and in the postsplenectomy state. It is a benign polyclonal B-cell proliferation of clefted or lobated lymphocytes with increased polyclonal serum IgM.

Pertussis (whooping cough) previously was the frequent cause of lymphocytosis in children but has now been reduced by routine immunization. The lymphocytes are small mature T cells. It can occur in adults whose immunity has waned since childhood immunization, and also in unimmunized children. There is a significant lymphocytosis with WBC usually >30 x 103/mL accompanied by characteristic clinical symptoms (paroxysm of coughing with thick sputum production). The lymphocyte count is highest during the first 3 weeks of illness and then decreases. Human T-lymphotropic virus type 1 (HTLV-1) can present as transient T-cell lymphocytosis with 10-40% of the lymphocytes consisting of atypical and immature forms. Some HTLV-1 carriers can eventually develop adult T-cell leukemia/lymphoma.

Primary lymphocytosis is typically due to mature B-cell neoplasms. Numerous lympho-proliferative disorders other than CLL can present as lymphocytosis, with or without lymph node, bone marrow, or splenic involvement. The differential diagnosis includes, in addition to chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/'Waldenstrom's macroglobulinemia, hairy cell leukemia, splenic marginal zone lymphoma, and plasma cell myeloma. In general, disseminated B-cell neoplasms are relatively indolent. Rarely, a leukemic phase of mantle cell lymphoma or follicular lymphoma can occur. Distinction is made on the basis of morphology, immunophenotype, and molecular characteristics (Table 52.1).

B-Cell prolymphocytic leukemia (mentioned previously) is a malignancy of B prolymphocytes (medium-sized round lymphoid cells with prominent nucleoli). Prolymphocytes must exceed 55% of lymphoid cells in the blood. They strongly express surface IgM/IgD as well as CD19, CD20, CD22, and FMC7. CD5 is present in one-third of cases, and CD23 is typically absent.

Lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells, usually lacking CD5, and secreting a serum monoclonal protein (IgM) that may cause symptomatic

Table 52.1 Immunophenotype of Mature B-Cell Neoplasms: Surface Immunoglobin (SIg)

Neoplasm

SIg

CD5

CD23 CD103 Cyclin D1

CD10

B-CLL/SLL

dim +

+

+ - -

-

B-Prolymphocytic leukemia

+ +

-/+

- - -

-

Lymphoplasmacytic lymphoma

+ +

-

- - -

-

Splenic marginal zone B-cell

+

-

- - -

-

lymphoma

Hairy cell leukemia

+

-

- ++ +/ -

-

Plasma cell myeloma

-

-

- - -/+

-/+

Mantle cell lymphoma

+ +

+

- - +

-

Follicular lymphoma

+

-

- - -

+

hyperviscosity or cryoglobulinemia. Translocation t(9;14)(p13;q32) and rearrangement of the PAX-5 gene is reported in up to 50% of cases.

Splenic marginal zone lymphoma is a B-cell malignancy consisting of small lymphocytes of the marginal zone in the splenic germinal centers of white pulp. Lymphoma cells can be found in the peripheral blood as villous lymphocytes (presence of short polar villi). Tumor cells are positive for CD20 and CD79a; they are negative for CD23, CD5, CD10, CD43, and CD103. Allelic loss of chromosome 7q21-32 is present in up to 40% of the cases. Dysregulation of CDK6 gene located at 7q21 has also been reported.

Hairy cell leukemia is a tumor of small B-lymphoid cells with oval nuclei and abundant cytoplasm with "hairy" projections, strongly expressing CD103, CD22, and CD11c. CD5, CD10, and CD23 are negative. Most patients present with splenomegaly and peripheral cytopenias.

Plasma cell neoplasms are disorders of terminally differentiated B cells. They usually involve bone marrow or extramedullary masses (plasmacytomas); significant peripheral involvement is rare (2%). Plasma cell leukemia is defined as greater than 20% or >2 x 103/mL plasma cells in blood. The prognosis is considerably worse when multiple myeloma presents with plasma cell leukemia.

Mantle cell lymphoma is a neoplasm composed of monomorphous small to medium-sized lymphocytes with slightly irregular nuclei. Proliferation centers are absent. They are monoclonal B cells with moderate to strong surface IgM expression, and are typically CD5-positive, FMC7-positive and CD23- and CD10-negative. All cases are bcl-2 protein-positive, and almost all cases express cyclin D1. Bcl-2 is a member of a large family of proteins involved in regulation of apoptosis (programmed cell death). Expression of bcl-2 protects lymphocytes from apoptosis and leads to reduced cell death and steady accumulation. Cyclin D1 belongs to group of proteins involved in regulating the cell cycle. Dysregulation of the activity of cyclins favors cell proliferation Seventy to seventy-five percent of cases demonstrate t(11;14)(q13;q32) translocation.

Follicular lymphoma is a nodal lymphoma composed of follicle center B cells (centro-cytes—small cleaved cells, and centroblasts—large noncleaved cells), which has a predominantly follicular pattern. It can also involve blood, spleen, bone marrow, and extranodal sites. The tumor cells are surface Ig-positive, CD10-positive, and CD5-negative and express B-cell-associated antigens (CD19, CD20, CD22). Tight meshworks of CD21 and CD23 follicular dendritic cells are present in follicular areas. Of all cases reported, 70-90% have t(14; 18), involving rearrangement of the bcl-2 gene.

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