Signs and symptoms
In the majority of patients, CLL is asymptomatic at diagnosis and is discovered on a routine blood examination. When symptoms are present, they are nonspecific and include fatigue, weakness, and malaise and, in fact, may not even be attributable to CLL.
Constitutional B symptoms
Constitutional B symptoms (ie, fever, weight loss, and night sweats) are not common at diagnosis but may signal disease transformation. Patients frequently notice enlarged lymph nodes or abdominal distention related to mesenteric lymphadenopathy and/or splenomegaly.
Patients with CLL have an increased susceptibility to infections, which may be the presenting complaint.
Lymphadenopathy
Lymphadenopathy is common at diagnosis. Lymph nodes are usually symmetric, mobile, and nontender.
Splenomegaly and hepatomegaly
The spleen and, less frequently, the liver may be enlarged. Splenomegaly may be massive in advanced cases. Only occasionally is splenomegaly found in the absence of lymphadenopathy, but recognition of such patients may identify a group that may benefit from splenectomy.
Other organs
In advanced disease, other organs may be involved, including the gastrointestinal (GI) mucosa, prostate, lungs, pleura, and bones. Rarely is such involvement clinically important unless (Richter's) transformation has occurred.
Laboratory features
Peripheral blood
The most consistent feature of CLL is lymphocytosis, with median values of 30 to 50 × 109/L. The lymphocytes are small and mature-appearing, with little cytoplasm and clumped chromatin. Smudge cells are frequently seen; when present in a high proportion, they may be predictive of a more indolent course. A few larger nucleolated cells, which represent prolymphocytes, usually constitute < 10% of the total lymphocytes. Diagnostic criteria for CLL defined by the NCI and IWCLL are presented in Table 1.
Diagnostic criteria for CLL according to the National Cancer Institute (NCI) and International Workshop on CLL (IWCLL)
A positive Coombs' test is seen in as many as 30% of patients at some time during the disease course, although it is uncommon (< 5%) during early stages. Autoimmune phenomena are relatively frequent, with hemolytic anemia (lifetime risk, approximately 10%–20%) and thrombocytopenia (lifetime risk, approximately 5% to 10%) occurring most commonly. Autoimmune neutropenia and other autoimmune sequelae are infrequent but more common than in the general population.
Bone marrow
The bone marrow is usually hypercellular but can be normocellular. The most characteristic feature is the presence of at least 30% mature-appearing lymphocytes. The lymphocyte infiltration can be interstitial, nodular, mixed interstitial and nodular, or diffuse. Diffuse lymphocyte infiltration is associated with a poor prognosis.
Other laboratory findings
Progressive hypogammaglobulinemia is seen in > 50% of patients with CLL, usually affecting IgA first, followed by IgM and IgG. However some patients have a polyclonal gammopathy and 5% to 10% of patients may have a small monoclonal peak. Paraproteinemia is more common at disease transformation. Regardless of gammaglobulin levels, essentially all patients have an abnormal repertoire and should be considered immune-deficient.
Elevated serum levels of B2-microglobulin (β2M) have been associated with a poor prognosis. Elevation of serum lactate dehydrogenase (LDH) levels is found in < 10% of patients at diagnosis and may indicate autoimmune hemolytic anemia or (Richter's) transformation to diffuse large B-cell lymphoma (DLBCL).
Immunophenotyping
More than 95% of all cases of CLL have a B-cell phenotype with monoclonality by light chain restriction. In these patients, CD19 and/or CD20 are essentially always coexpressed with CD5, which normally is expressed on T cells and a subset of normal B cells. Other markers, such as CD21 and CD22, may also be expressed. Expression of CD23 helps to differentiate CLL from mantle cell lymphoma, in which cells coexpress CD19 and CD5 but lack CD23. Furthermore, the monoclonal antibody FMC7 (which recognizes an epitope on CD20) rarely reacts with CLL cells but frequently binds the cells of patients with mantle cell lymphoma.
Expression of surface immunoglobulin is usually weak and is lower than in normal B lymphocytes or most other B-cell lymphomas. Expression of CD38 on the surface of CLL cells portends a worse prognosis than that of patients whose cells do not express CD38.
