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Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic
leukemia

Authors Section Editor Deputy Editor


Kanti R Rai, MD Richard A Larson, MD Rebecca F Connor, MD
Stephan Stilgenbauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2014. | This topic last updated: Jan 21, 2015.

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders
(lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes,
which are usually monoclonal in origin.

CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell
neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. (See "Clinical
manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma".)

The epidemiology, clinical presentation, pathologic features, diagnosis, and differential diagnosis of CLL will be
reviewed here. The pathophysiology, molecular biology, cytogenetic abnormalities, and treatment of CLL are
discussed elsewhere. (See "Pathophysiology and genetic features of chronic lymphocytic leukemia" and "Overview
of the treatment of chronic lymphocytic leukemia".)

EPIDEMIOLOGY — CLL is the most common leukemia in adults in Western countries, accounting for approximately
25 to 30 percent of all leukemias in the United States [1]. The disorder is more common in men, with a male to
female ratio of approximately 1.7:1 [2]. The incidence rates among men and women in the United States are
approximately 6.75 and 3.65 cases per 100,000 population per year, respectively [3]. In Europe, these incidence
rates are 5.87 and 4.01 cases per 100,000 population per year, respectively [4].

CLL is considered to be mainly a disease of older adults, with a median age at diagnosis of 70 years [5]; however, it
is not unusual to make this diagnosis in younger individuals from 30 to 39 years of age [2]. The incidence increases
rapidly with increasing age. It is estimated that 15,720 new cases of CLL will be diagnosed in 2014: 9100 in males
and 6620 in females [6].

The incidence of CLL varies by race and geographic location. In the United States, there is a higher incidence
among Caucasians as compared with African Americans or Asian Pacific Islanders [2,3]. The incidence of CLL is
extremely low in Asian countries such as China and Japan, where it is estimated to occur at a frequency that is
approximately 10 percent of that seen in Western countries [7-10]. The incidence of CLL in Africa is not as low as it
is in Asia [11,12].

Genetic rather than environmental factors are the most likely explanation for these differences. A genetic effect on
incidence was initially suggested by observational studies that have shown that Japanese who settled in Hawaii do
not have a higher incidence of CLL than native Japanese [13,14]. Further support for a genetic effect was provided
by a genotyping study in African Americans that demonstrated that this population had a lower frequency of single
nucleotide polymorphisms associated with an increased incidence of CLL in other populations [15]. Furthermore, the
cytogenetic and molecular genetic characteristics of CLL appear to be similar throughout the world, although one
study suggests that the clinical course may be more aggressive in Japan [16,17].

There are no clearly discernible occupational or environmental risk factors that predispose to CLL [18,19]. Although
there has been an increase in all other types of leukemias among atomic bomb survivors, there has been no
increase in the incidence of CLL [20,21]. In addition, despite a few reports of an excess risk of CLL among farmers
[18,19], those with benzene and heavy solvent exposure [18,19,22,23], rubber manufacturing workers [23,24], or
those with multiple episodes of pneumonia [25], these associations have not been proven [26].

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Family studies — CLL and other lymphoid, hematologic, and solid tumors occur with higher than expected
frequency among first-degree family members of patients with CLL [27-32]. In addition, one study demonstrated that
up to 17 percent of first-degree family members of patients with CLL were found by flow cytometry to have
monoclonal B cell lymphocytosis (MBL) [33]. Of note, while virtually all cases of CLL are preceded by MBL, only a
small percentage of persons with MBL will ultimately develop CLL. (See 'Monoclonal B cell lymphocytosis' below.)

A study of multi-generational familial cases of CLL noted that the median ages at onset in the child (51 years) and
parent generations (72 years) were significantly different (ie, genetic anticipation) [34]. Although there is no available
proof of genetic transmission of this disease, certain genetic polymorphisms may predispose patients to familial
cancer, including CLL [35-38]. DNA analysis in a set of monozygotic twins with CLL suggested that the transforming
events in CLL occur late in life and result, even in monozygotic twins, in genetically distinct malignant cells [39].

A number of candidate chromosomal regions are currently being explored for the presence of susceptibility genes for
familial CLL [31,40,41].

CLINICAL PRESENTATION

Symptoms — Patients with CLL may have a wide range of symptoms and physical and laboratory abnormalities at
the time of diagnosis. Some patients consult a physician because they have noted painless swelling of lymph nodes,
often in the cervical area, which spontaneously wax and wane, but do not altogether disappear.

Most patients feel entirely well with no symptoms when a routine blood count reveals an absolute lymphocytosis,
leading to a diagnosis of CLL. Five to 10 percent of patients present with the typical "B" symptoms of lymphoma
which include one or more of the following [42]:

● Unintentional weight loss ≥10 percent of body weight within the previous six months.

● Fevers of >100.5ºF (>38ºC) for ≥2 weeks without evidence of infection.

● Drenching night sweats without evidence of infection.

● Extreme fatigue (ie, ECOG Performance status 2 or worse; cannot work or unable to perform usual activities)
(table 1).

Occasionally, the presenting features are those of an acquired immunodeficiency disorder, manifested by infections,
autoimmune complications such as hemolytic anemia, thrombocytopenia or pure red cell aplasia, or exaggerated
reactions to insect stings or bites (especially mosquito). (See "Overview of the complications of chronic lymphocytic
leukemia".)

Signs

Lymphadenopathy — The most common abnormal finding on physical examination of the patient with CLL is
lymphadenopathy, present in 50 to 90 percent of patients among various series [43,44]. Lymph node enlargement
may be generalized or localized, and individual lymph nodes can vary greatly in size. The most commonly affected
sites are cervical, supraclavicular, and axillary.

Characteristically, enlarged nodes in CLL are firm, rounded, discrete, nontender, and freely mobile upon palpation.
Exceptions to these generalizations are encountered, particularly when the nodes have grown rapidly. Occasionally,
several enlarged nodes in the same anatomical site (eg, cervical triangle, axilla or femoral-inguinal areas) may
become confluent, forming large spherical lymphoid masses. In addition, new lymph nodes may appear in places
other than the usual lymph node-bearing sites, such as over the sacrum or the thorax.

Splenomegaly — The spleen is the second most frequently enlarged lymphoid organ, being palpably enlarged in
25 to 55 percent of cases [43,44]. As is the case with enlarged lymph nodes, an enlarged spleen in CLL is usually
painless and nontender to palpation, with a sharp edge and a smooth firm surface. Painful and infarcted splenic
enlargement is an unusual presenting feature.

Hepatomegaly — Enlargement of the liver may be noted at the time of initial diagnosis in 15 to 25 percent of

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cases [43,44]. The liver is usually only mildly enlarged, ranging from 2 to 6 cm below the right costal margin, with a
span of dullness to percussion of approximately 10 to 16 cm. Upon palpation, the liver is usually nontender and firm
with a smooth surface.

Skin — Infiltration with CLL cells may occur in any organ, but, at the time of diagnosis, the skin (leukemia cutis)
is the most commonly involved non-lymphoid organ. These lesions most commonly involve the face and can
manifest as macules, papules, plaques, nodules, ulcers, or blisters [45]. Diagnosis is made based upon biopsy of the
involved skin. Leukemia cutis is seen in fewer than 5 percent of cases and may not significantly affect overall
prognosis unless they represent foci of Richter's transformation. (See "Pathobiology and treatment of Richter's
transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Nonspecific secondary cutaneous lesions may be due to infection, bleeding, vasculitis, or paraneoplastic pemphigus
[46]. An exaggerated reaction to insect bites, especially mosquito bites, has been reported, and may alert the
clinician to the diagnosis of CLL [47].

Other organ involvement — Virtually any lymphoid tissue may be enlarged at diagnosis, including Waldeyer's
ring in the pharynx. In contrast to other lymphomas, clinically relevant gastrointestinal mucosal involvement is rarely
seen in CLL. Similarly, meningeal leukemia is unusual at the time of initial presentation.

Membranoproliferative glomerulonephritis (MPGN) has occasionally been described in CLL and appears to be a
paraneoplastic phenomenon mediated by deposition and possibly processing of cryoprecipitating or
noncryoprecipitating M-components [48-50]. (See "Clinical presentation, classification, and causes of
membranoproliferative glomerulonephritis" and "Glomerular diseases due to nonamyloid fibrillar deposits", section
on 'Immunotactoid glomerulopathy'.)

LABORATORY ABNORMALITIES

Lymphocytosis — The most noteworthy laboratory abnormality found in CLL is lymphocytosis in the peripheral
blood and bone marrow. Although the absolute blood lymphocyte threshold for diagnosing CLL has been placed at
>5000/microL [5 x 109/L] B lymphocytes [42], a significant proportion of patients present with counts as high as
100,000/microL [100 x 109/L]. (See "Approach to the patient with lymphocytosis or lymphocytopenia".)

Although very unusual, it should be noted that when blood leukocyte counts are greatly in excess of 400,000/microL
[400 x 109/L], the increased number of cellular elements may result in abnormally high whole blood viscosity. (See
"Hyperleukocytosis and leukostasis".)

Cytopenias — Neutropenia, anemia, and thrombocytopenia may be observed at the time of initial diagnosis, and
are usually not severe. These can be related to autoimmune hemolytic anemia, pure red cell aplasia, autoimmune
thrombocytopenia, or agranulocytosis (see "Overview of the complications of chronic lymphocytic leukemia"):

● Patients with CLL have an increased incidence of autoimmune hemolytic anemia (AIHA). The direct
antiglobulin (Coombs') test (DAT) may be positive at some time during the course of the disease in up to 35
percent of cases; overt AIHA occurs in 11 percent of cases [51]. The positive and negative predictive value of
the DAT was reported as part of a prospective clinical trial in patients with CLL [52]. The DAT status was able to
correctly predict the development of AIHA in 83 percent of cases with a positive predictive value (chance that a
DAT-positive patient will develop AIHA) of 28 percent and a negative predictive value (chance that a
DAT-negative patient will remain free of AIHA) of 93 percent. (See "Pathogenesis of autoimmune hemolytic
anemia: Warm agglutinins and drugs", section on 'Genesis of antibody production' and "Autoimmune
complications following purine analog therapy".)

● Pure red cell aplasia (PRCA) is rare, occurring in approximately 0.5 percent of patients. However, if this
disorder is specifically sought for via bone marrow aspiration and absolute reticulocyte count, PRCA may be
found in up to 6 percent of patients with CLL [51]. Unlike AIHA, PRCA may occur early in the course of CLL.
(See "Acquired pure red cell aplasia in the adult", section on 'Etiology and pathogenesis'.)

● (Auto)immune thrombocytopenia is suggested when a bone marrow biopsy shows adequate numbers of

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megakaryocytes but the peripheral blood has an abnormally low platelet count. This complication occurs in 2 to
3 percent of patients with CLL and may be the event that initially brings the patient to medical attention [51].
Retrospective studies have reported varying impacts of immune thrombocytopenia on the clinical course
[53,54]. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

● Rarely, agranulocytosis may be encountered in CLL (approximately 0.5 percent). (See "Overview of
neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on
'Major causes of neutropenia'.)

The presence of anemia and/or thrombocytopenia has prognostic implications that are discussed separately. (See
"Staging and prognosis of chronic lymphocytic leukemia".)

Immunoglobulin abnormalities — Hypogammaglobulinemia is present in approximately 8 percent of patients at


the time of initial diagnosis and may develop in up to two-thirds of patients later in the course of the disease. Usually
all three immunoglobulin classes (IgG, IgA, and IgM) are decreased, but in some patients only one or two may be
low. Significant degrees of hypogammaglobulinemia and neutropenia, when present, result in increased vulnerability
of CLL patients to major bacterial infections.

Polyclonal increases in gamma globulins can be seen in up to 15 percent of patients, while a monoclonal protein is
present in up to 5 percent of patients [55,56].

In a study of 109 persons who had developed CLL and had serially collected pre-diagnostic serum samples, the
prevalences of an abnormal free light chain ratio, monoclonal protein (M-protein), and hypogammaglobulinemia
before CLL diagnosis were 38, 13, and 3 percent, respectively [55]. M-proteins and an abnormal free light chain ratio
were detected up to 9.8 years before CLL diagnosis in 48 of the 109 subjects. (See "Recognition of monoclonal
proteins" and "Clinical course and management of monoclonal gammopathy of undetermined significance", section
on 'Clinical course'.)

Other abnormal findings — There are no characteristic abnormalities in blood chemistry, but elevated levels of
serum lactate dehydrogenase (LDH) and beta-2 microglobulin were found in approximately 60 percent in one series
of patients with progressive or advanced CLL entering a therapeutic trial [57]. Elevations of uric acid, hepatic
enzymes (ALT or AST) and, rarely, calcium may also be observed.

PATHOLOGIC FEATURES — The diagnostic evaluation of a patient suspected of having CLL should include a
complete blood count with differential, examination of the peripheral smear, and an immunophenotypic analysis of
the circulating lymphocytes. While a bone marrow aspirate and biopsy and lymph node biopsy are not among the
required elements of the diagnostic work-up, abnormalities seen on these examinations are included in this
discussion of pathologic features. Chromosomal changes seen in CLL are also not diagnostic features of the
disease and are presented separately. (See "Pathophysiology and genetic features of chronic lymphocytic
leukemia".)

Morphology — The peripheral blood smear of patients with CLL demonstrates a lymphocytosis. The leukemic cells
are typically small, mature appearing lymphocytes with a dense nucleus, partially aggregated (clumped) chromatin,
and without discernible nucleoli. There is a narrow border of clear to slightly basophilic cytoplasm (picture 1 and
picture 2) [42].

In addition, a proportion of cells may be comprised of larger lymphocytes with large, somewhat notched nuclei, lacy
appearing nuclear chromatin, and prominent, visible nucleoli. These "prolymphocytes" usually account for a minority
of the overall population of lymphocytes but can comprise up to 55 percent. The smear also often contains "smudge"
cells (also called "basket cells") that are lymphocytes that appear to have been flattened or smudged in the process
of being spread on the glass slide [58].

Immunophenotype — Immunophenotypic analysis, usually by flow cytometry, is a key component to the diagnosis
of CLL (figure 1) [59]. There are three major characteristic immunophenotypic findings [42]:

● Expression of B cell associated antigens including CD19, CD20, and CD23. Expression of CD20 is usually

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weak. Expression of CD21 and CD24 can be seen, but is not required for diagnosis.

● Expression of CD5, an antigen commonly expressed by T cells.

● Low levels of surface membrane immunoglobulin (ie, SmIg weak). The immunoglobulin is most often IgM or
both IgM and IgD, and only a single immunoglobulin light chain is expressed (ie, either kappa or lambda but not
both), confirming the clonal nature of these cells. In rare cases, several Ig clones may coexist.

In addition, CLL cells are usually negative for cyclin D1 and CD10. FMC7, CD22, and CD79b are also commonly
negative or weakly expressed [60].

The vast majority of cases will demonstrate a single clone of abnormal circulating B lymphocytes by flow cytometry.
Rarely, flow cytometry will identify biclonal disease. In one large study, this was estimated to represent 1.4 percent of
cases [61].

Bone marrow aspirate and biopsy — Bone marrow aspirate and biopsy are not required for the diagnosis of CLL.
If bone marrow biopsy and aspiration are performed at the time of initial diagnosis, they usually demonstrate normal
to increased cellularity, with lymphocytes accounting for >30 percent of all nucleated cells (picture 3 and picture 4
and picture 2).

In addition to an increased percentage of mature-appearing lymphocytes in the smears of the bone marrow aspirate,
there are three main types of infiltrative patterns of lymphocytes that are recognized in trephine biopsy specimens of
the bone marrow: nodular, interstitial, and diffuse. Sometimes, in a given biopsy sample, one may see a mixture of
nodular and interstitial, or nodular and diffuse infiltrative, patterns. Historically, patients with diffuse infiltration tend to
have advanced disease and a poorer prognosis, whereas, for prognostic purposes, nodular and interstitial patterns
may be grouped together in the prognostically better "non-diffuse" category [62-64]. However, with the discovery of
additional prognostic markers in CLL, the prognostic value of bone marrow biopsy has become less clear. Prognostic
markers in CLL are discussed in more detail separately. (See "Staging and prognosis of chronic lymphocytic
leukemia".)

Lymph node biopsy — CLL and small lymphocytic lymphoma (SLL) are considered to be the same disease with
different clinically manifestations. Historically, the diagnosis of SLL was made via a lymph node biopsy in a patient
presenting with lymphadenopathy but without peripheral lymphocytosis, while CLL was diagnosed through
examination of the peripheral blood and bone marrow in patients with lymphocytosis. Currently, the diagnosis of SLL
is reserved for patients demonstrating lymph node pathology consistent with CLL/SLL but with an absolute
peripheral clonal lymphocyte count that does not exceed 5000/microL [5 x 109/L] and no evidence of neutropenia,
anemia, or thrombocytopenia related to the disease [42,60].

The histopathologic lymph node findings in SLL and CLL are identical and consist of a diffusely effaced nodal
architecture with occasional residual naked germinal centers [42,60]. The infiltrate is composed of mostly mature-
appearing, small lymphocytes, with an admixture of prolymphocytes and paraimmunoblasts (picture 5). The
pathologic features on lymph node biopsy and the diagnosis of SLL are discussed in more detail separately. (See
"Clinical manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma".)

EVALUATION AND DIAGNOSIS — The diagnosis of CLL is based upon a complete blood count with differential,
flow cytometry of the peripheral blood to determine the immunophenotype of circulating lymphocytes, and
examination of the peripheral smear [42].

To diagnose CLL, the 2008 iwCLL update of the National Cancer Institute guidelines on the diagnosis and treatment
of CLL concluded that the following two criteria must be met [42]:

● Absolute B lymphocyte count in the peripheral blood ≥5000/microL [5 x 109/L], with a preponderant population
of morphologically mature-appearing small lymphocytes.

● Demonstration of clonality of the circulating B lymphocytes by flow cytometry of the peripheral blood. A majority
of the population should express the following pattern of monoclonal B cell markers: extremely low levels of

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SmIg and either kappa or lambda (but not both) light chains; expression of B cell associated antigens (CD19,
CD20, and CD23); and expression of the T cell associated antigen CD5. (See 'Immunophenotype' above.)

In the current system, patients with an absolute lymphocyte count less than 5000/microL [5 x 109/L] are usually
diagnosed with a monoclonal B cell lymphocytosis rather than CLL if they do not have palpably enlarged lymph
nodes, spleen, and/or liver. (See 'Monoclonal B cell lymphocytosis' below.)

As mentioned earlier, CLL and small lymphocytic lymphoma (SLL) have identical pathologic and immunophenotypic
features and are therefore considered two clinical manifestations of the same disease. Patients with
lymphadenopathy and an absolute peripheral B lymphocyte count that is less than 5000/microL [5 x 109/L] are given
the diagnosis of SLL rather than CLL. The diagnosis of SLL is discussed in more detail separately. (See "Clinical
manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma".)

Prior to the current diagnostic criteria, the diagnosis of CLL was based upon an absolute lymphocyte count (ALC)
equal to or greater than 5000/microL [5 x 109/L] in the setting of an appropriate immunophenotype. With this system,
patients with an absolute B lymphocyte count (B-ALC) less than 5000/microL and an ALC more than 5000/microL
represented an overlap between CLL and monoclonal B cell lymphocytosis. The switch to using B-ALC for the
diagnosis of CLL in the current system eliminated this overlap, but has sparked controversy [65,66].

While the current definition uses a cutoff of 5000 B lymphocytes per microL, the ideal cutoff value is still to be
determined. A retrospective analysis of 459 consecutive patients diagnosed with Rai stage 0 CLL over a seven-year
period at one institution found that cutoff values for ALC and B-ALC of 12,000 and 11,000 cells/microL, respectively,
were associated with reduced rates of treatment-free and overall survival [67]. In contrast, a cutoff value of 5000
cells/microL for either ALC or B-ALC was not associated with outcome.

DIFFERENTIAL DIAGNOSIS — The diagnosis of CLL is suspected whenever the peripheral blood in an adult
demonstrates an absolute lymphocytosis. However, blood lymphocytosis may also occur with non-neoplastic
conditions, such as viral or other infections (eg, infectious mononucleosis, pertussis, toxoplasmosis), as well as in
neoplastic conditions other than CLL (eg, the leukemic phase of lymphomas, hairy cell leukemia, prolymphocytic
leukemia, and large granular cell lymphocyte leukemia). (See "Approach to the patient with lymphocytosis or
lymphocytopenia".)

The task is therefore to distinguish between reactive causes of lymphocytosis and clonal (malignant) causes, and,
for the latter, to distinguish CLL from the other malignant lymphoproliferative disorders (table 2). As described above,
if the flow cytometric phenotypic features are consistent with the diagnosis of CLL in a patient with peripheral blood
lymphocytosis, the diagnosis of CLL is clearly established. Features distinguishing these conditions with blood
lymphocytosis from CLL are summarized below.

Infectious causes of lymphocytosis — A transient lymphocytosis can be seen in the peripheral blood of patients
who have an infection. To be diagnosed with CLL, the lymphocytosis must be sustained over a period of time. This
effectively excludes those conditions, such as infectious mononucleosis, pertussis, and toxoplasmosis, in which
blood lymphocyte counts rise and then typically return to normal after a few weeks. In addition, unlike in CLL, a
lymphocytosis does not occur in the bone marrow of patients with these infectious causes of lymphocytosis.
Furthermore, the lymphocytosis is not clonal in those with a non-malignant cause and does not show the
characteristic immunophenotype described above. (See "Approach to the patient with lymphocytosis or
lymphocytopenia".)

Monoclonal B cell lymphocytosis — The term monoclonal B cell lymphocytosis (MBL) is used to categorize
individuals who have an absolute increase in the number of clonal B lymphocytes in the peripheral blood that does
not exceed 5000/microL [5 x 109/L] and who have no lymphadenopathy, organomegaly, cytopenias, or disease-
related symptoms [42,68,69]. (See 'Evaluation and diagnosis' above and "Approach to the patient with lymphocytosis
or lymphocytopenia", section on 'Monoclonal B cell lymphocytosis'.)

MBL with a CLL-phenotype can be detected using high sensitivity flow cytometry in approximately 5 percent of
patients over the age of 60 with normal blood counts and 14 percent of patients over age 60 with lymphocytosis

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[68,70-73]. Patients with CLL-phenotype MBL progress to CLL at a rate of approximately 1 to 2 percent per year
[70,74]. The rate of progression may be even lower among persons with low-count MBL, as defined as a clone size
of 50/microL or less [75,76].

This was best demonstrated in a prospective cohort study that followed 185 patients with CLL-phenotype MBL for a
median of 6.7 years [68]. Chromosomal analysis demonstrated that the CLL-phenotype lymphocytes in patients with
MBL have the same genetic abnormalities as CLL cells, occurring at similar rates.

Conversely, a monoclonal B cell population appears to be present years prior to the diagnosis in virtually all patients
with CLL. This was evaluated in a prospective analysis of lymphocytes obtained from the cryopreserved blood of 45
cancer-free subjects in whom CLL was subsequently diagnosed at a median interval of 32 months after collection
[77]. A monoclonal B cell population was identified by either flow cytometry or molecular analysis in 44 of 45
samples and none of 10 controls.

As only a small minority of these persons develop CLL, it is important not to cause undue anxiety among them. We
follow persons identified with MBL at yearly intervals with repeat flow cytometry of blood lymphocytes performed
according to the physician's clinical judgment.

Prolymphocytic leukemia — Both prolymphocytic leukemia (PLL) and CLL can present with lymphocytosis and
splenomegaly, and have circulating prolymphocytes in the blood. Prolymphocytes are morphologically distinct from
typical CLL cells. Compared with typical CLL cells, these are large cells with somewhat immature-appearing nuclear
chromatin, a prominent vesicular nucleolus, and a moderate amount of cytoplasm (picture 6) [78,79]. In B-PLL,
prolymphocytes are of B lineage, express normal amounts of SmIg and usually do not express CD5. In contrast,
typical CLL cells express only low amounts of SmIg and express CD5.

While prolymphocytes such as these can be seen in CLL, in B-PLL, by definition, more than 55 percent of the
circulating cells in the peripheral blood are prolymphocytes and, more typically, the percentage of prolymphocytes is
greater than 90 percent. (See "B cell prolymphocytic leukemia" and "Clinical manifestations, pathologic features, and
diagnosis of T cell prolymphocytic leukemia".)

Mantle cell lymphoma — Mantle cell lymphoma (MCL) can have a leukemic phase that may mimic CLL. Such
patients have circulating small lymphocytes, often with irregular or cleaved nuclei. Like the malignant cells of CLL,
MCL tumors coexpress CD5 and CD20. However, the neoplastic cells of MCL stain strongly for cyclin D1 and
surface membrane immunoglobulin (SmIg), have a t(11;14) chromosomal abnormality, and are negative for CD23
[80]. In contrast, the malignant cells in CLL are negative for cyclin D1 and are often CD23 positive. (See "Clinical
manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)

Lymphoplasmacytic lymphoma — Both lymphoplasmacytic lymphoma (LPL) and CLL are lymphoproliferative
disorders of small cells that usually have an indolent course. LPL is the lymphomatous counterpart to Waldenström
disease (ie, LPL leukemia). Peripheral blood involvement in LPL is usually less prominent than in CLL; circulating
malignant cells often have a plasmacytoid appearance (picture 7).

LPL can be distinguished from CLL by its lack of CD23 expression, the presence of strong staining for surface IgM
and CD20, and the presence of cytoplasmic Ig. (See "Clinical manifestations, pathologic features, and diagnosis of
lymphoplasmacytic lymphoma".)

Hairy cell leukemia — Both hairy cell leukemia (HCL) and CLL can be associated with an elevated lymphocyte
count in the peripheral blood, although leukocytosis is much less common in HCL, occurring in only approximately
10 to 20 percent of cases. The diagnosis of HCL is often suspected based upon the presence of circulating
lymphocytes with cytoplasmic projections (hairy cells) (picture 8) [60]. HCL is frequently distinguished from CLL
based upon its immunophenotype that is usually CD5 negative, and positive for CD25, CD11c, and CD103. (See
"Clinical features and diagnosis of hairy cell leukemia".)

Follicular lymphoma — Patients with follicular lymphoma (FL) can present in a similar fashion to those with
CLL/SLL with diffuse painless peripheral adenopathy, often waxing and waning over long periods of time. Usually,

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these two disorders have distinct growth patterns on lymph node biopsy. Follicular lymphoma has a nodular growth
pattern which is not seen in CLL/SLL; however, on occasion, involved lymph nodes in CLL/SLL tumors can have
prominent proliferation centers that take on a mottled "pseudo-nodular" appearance that mimics that of FL.

FL and CLL/SLL can be distinguished by immunophenotype. In contrast to the malignant cells in CLL/SLL, most
cells in FL demonstrate bright surface immunoglobulin (SmIg), express CD10 and lack CD5 expression. In contrast,
CLL cells have extremely low levels of SmIg, express CD5, and lack CD10 expression. In addition, FL
characteristically has a t(14;18) translocation, which is rarely seen in CLL/SLL. (See "Clinical manifestations,
pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Splenic marginal zone lymphoma — Both splenic marginal zone lymphoma (MZL) and CLL present with
splenomegaly and peripheral blood lymphocytosis. In addition, both CLL and splenic MZL can express CD23, CD43,
CD5, and IgD, although expression of these is much more typical of CLL. Unlike CLL/SLL, MZL may have bright
SmIg and CD20. In difficult cases, pathologic evaluation of the bone marrow, spleen, and lymph nodes may be used
in concert to determine the most likely diagnosis. Bone marrow morphology in MZL may show notched nuclei. In
addition, cytogenetic changes typically seen in CLL are not usually seen with MZL. (See "Clinical manifestations,
pathologic features, and diagnosis of splenic marginal zone lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient information: Chronic lymphocytic leukemia (CLL) (The Basics)")

● Beyond the Basics topics (see "Patient information: Chronic lymphocytic leukemia (CLL) in adults (Beyond the
Basics)")

SUMMARY

● Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm)


characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually
monoclonal in origin. The disorder is considered to be identical (ie, one disease with different manifestations) to
the mature B cell neoplasm small lymphocytic lymphoma (SLL).

● CLL is the most common leukemia in Western countries, accounting for approximately 30 percent of all
leukemias in the United States. It has a male predominance and is more common in Caucasians. The median
age at diagnosis is 70 years. There are no clearly discernible occupational or environmental risk factors. (See
'Epidemiology' above.)

● The vast majority of patients are asymptomatic at diagnosis and only come to the physician's attention based
upon abnormalities found on routine blood counts. Alternatively, some patients may present with painless
swelling of lymph nodes, often in the cervical area, which spontaneously wax and wane, but do not altogether
disappear. Less common presentations include constitutional "B" symptoms of lymphoma, symptoms related to
an acquired immunodeficiency, or autoimmune complications. (See 'Clinical presentation' above.)

● Lymphadenopathy, splenomegaly, and hepatomegaly are the most common findings on physical examination
at the time of diagnosis. CLL cells may infiltrate and disrupt the function of any organ. At the time of diagnosis,
the skin (leukemia cutis) is the most commonly involved non-lymphoid organ. Gastrointestinal mucosal

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involvement and meningeal leukemia are rare. Membranoproliferative glomerulonephritis (MPGN) is seen on
occasion. (See 'Signs' above.)

● Most patients with CLL have a prominent lymphocytosis in the peripheral blood and bone marrow at diagnosis.
Neutropenia, anemia, and thrombocytopenia may also be observed at the time of initial diagnosis, and are
usually of relatively mild degree. These can be related to autoimmune hemolytic anemia, pure red cell aplasia,
autoimmune thrombocytopenia, or agranulocytosis. Other laboratory abnormalities at presentation may include
hypo- and hypergammaglobulinemia. The peripheral blood smear demonstrates a lymphocytosis. The
circulating leukemic cells typically resemble small, mature lymphocytes (picture 1 and picture 2), but a
proportion of circulating cells may be comprised of prolymphocytes. (See 'Morphology' above.)

● Immunophenotypic analysis reveals a clonal population (kappa or lambda light chain) of cells that express B
cell associated antigens (CD19, CD20, and CD23), the T cell associated antigen CD5, and low levels of
surface immunoglobulin. (See 'Immunophenotype' above.)

● If a bone marrow examination is performed at the time of initial diagnosis, it usually demonstrates normal to
increased cellularity, with lymphocytes accounting for >30 percent of all nucleated cells. (See 'Bone marrow
aspirate and biopsy' above.)

● The histopathologic lymph node findings in SLL and CLL are identical and consist of a diffusely effaced nodal
architecture with an infiltrate composed of mostly mature-appearing, small lymphocytes, with an admixture of
prolymphocytes and paraimmunoblasts. (See 'Lymph node biopsy' above.)

● The diagnosis of CLL is made based upon the results of a complete blood count with differential and flow
cytometry of the peripheral blood to determine the immunophenotype of circulating lymphocytes. (See
'Evaluation and diagnosis' above.)

● The differential diagnosis of CLL includes both non-neoplastic and neoplastic conditions that result in a
lymphocytosis in the peripheral blood. These include infectious causes of lymphocytosis, prolymphocytic
leukemia, mantle cell leukemia, lymphoplasmacytic lymphoma, hairy cell leukemia, follicular lymphoma, splenic
marginal zone lymphoma, and monoclonal B lymphocytosis (table 2). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — UpToDate would like to acknowledge Michael J Keating, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 4513 Version 18.0

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GRAPHICS

Eastern Cooperative Oncology Group (ECOG, Zubrod, WHO)


performance scale

Performance
Definition
status
0 Fully active; no performance restrictions

1 Strenuous physical activity restricted; fully ambulatory and able to carry out
light work

2 Capable of all selfcare but unable to carry out any work activities. Up and
about >50% of waking hours.

3 Capable of only limited selfcare; confined to bed or chair >50% of waking


hours

4 Completely disabled; cannot carry out any selfcare; totally confined to bed
or chair

Excerpted from: Oken MM, et al. Am J Clin Oncol 1982; 5:649.

Graphic 72901 Version 5.0

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Chronic lymphocytic leukemia peripheral blood smear

Peripheral blood smear reveals five CLL cells with prominent chromatin clumping
(snickerdoodle-like) and two smudge (basket) cells. Wright-Giemsa, 150x magnification.

Reproduced with permission from: Clinical application: Chronic lymphocytic leukemia of B-cell
lineage. In: Flow Cytometry, Immunohistochemistry, and Molecular Genetics for Hematologic
Neoplasms, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2012. Copyright © 2012 Lippincott
Williams & Wilkins.

Graphic 96498 Version 2.0

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Chronic lymphocytic leukemia (CLL) peripheral smear and bone marrow aspirate

Peripheral blood smear (A) and bone marrow aspirate (B) from a patient with chronic lymphocytic leukemia. The p
blood smear demonstrates a lymphocytosis. The leukemic cells are small, mature appearing lymphocytes with a de
partially aggregated (clumped) chromatin, and without discernible nucleoli (arrows). There is a narrow border of c
basophilic cytoplasm. The field includes some segmented neutrophils (arrowhead) and a nucleated red blood cell (
arrow). The bone marrow aspirate demonstrates an increased percentage of mature-appearing lymphocytes.

Graphic 97705 Version 1.0

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Flow cytometry of chronic lymphocytic leukemia

Immunophenotypic analysis of chronic lymphocytic leukemia (CLL) is


usually performed using flow cytometry. Typically, the cells express dim
CD20, dim CD5, and CD23. This figure displays flow cytometry results for
CD5 and CD20 expression. The CLL cells are shown in red and
demonstrate weak expression of both CD5 and CD20.

%: percent.

Reproduced with permission from: Armitage JO, Mauch PM, Harris NL, et al.
Non-Hodgkin Lymphomas, 2nd ed, Lippincott Williams & Wilkins, Philadelphia
2010. Copyright © 2010 Lippincott Williams & Wilkins. www.lww.com.

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Bone marrow aspirate in a patient with chronic


lymphocytic leukemia

Low power view of a bone marrow aspirate in a patient with chronic


lymphocytic leukemia shows a monotonous infiltration with small round
cells having only a thin rim of cytoplasm.

Courtesy of David S Rosenthal, MD and Anna J Mitus, MD.

Graphic 63637 Version 2.0

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Chronic lymphocytic leukemia/small lymphocytic


lymphoma involving bone marrow biopsy
specimens

Bone marrow biopsy specimens with hematoxylin and eosin stain


demonstrate infiltration with chronic lymphocytic leukemia/small
lymphocytic lymphoma in three main patterns:
(A) Nodular pattern.
(B) Interstitial pattern.
(C) Diffuse pattern. In this field, a vague pale area is present, consistent
with a pseudofollicle.

Reproduced with permission from: Chronic lymphocytic leukemia/small


lymphocytic lymphoma. In: Ioachim's Lymph Node Pathology, 4th ed,
Ioachim HL, Medeiros LJ (Eds), Lippincott Williams & Wilkins, Philadelphia
2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.

Graphic 97023 Version 1.0

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Lymph node biopsy from a patient with chronic


lymphocytic leukemia

Lymph node biopsy from a patient with chronic lymphocytic leukemia. At low
magnification (A), there is a vaguely nodular (pseudofollicular) pattern. Higher
magnification (B) shows a predominance of small lymphocytes with scattered
larger cells known as prolymphocytes and paraimmunoblasts.

Reproduced with permission from: Armitage JO, Mauch PM, Harris NL, et al.
Non-Hodgkin Lymphomas, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2010.
Copyright © 2010 Lippincott Williams & Wilkins. www.lww.com.

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Differential diagnosis of chronic lymphocytic leukemia

Genetic
Entity Histology Immunophenotype
features/other

Chronic lymphocytic "Typical" CLL cells are Typically express B cell Deletion 13q, trisomy
leukemia/small small, mature- antigens (CD19, CD22, 12, deletion 11q, and
lymphocytic appearing CD79a, FMC7); CD5; and deletion 17p. TCR
lymphoma (CLL/SLL) lymphocytes with a CD23. Expression of genes are not clonally
dense nucleus; CD20 and surface rearranged.
partially aggregated immunoglobulin is dim.
chromatin; no
discernible nucleoli;
and a narrow border
of cytoplasm.
A minority of cells
may have a
prolymphocytic
morphology.

Monoclonal B cell Absolute increase in Immunophenotype Patients have no


lymphocytosis the number of clonal B identical to CLL. lymphadenopathy,
lymphocytes in the organomegaly,
peripheral blood does cytopenias, or disease-
not exceed related symptoms.
5000/microL [5 x
10 9/L].

B cell prolymphocytic >55 percent of Express bright surface t(11;14) must be


leukemia circulating IgM +/– IgD and bright excluded.
lymphocytes are CD20, as well as other B No associated
"prolymphocytes". cell antigens (CD19, paraproteinemia.
The bone marrow is CD22, CD79a, FMC7).
TCR genes are not
infiltrated in an clonally rearranged.
interstitial or nodular
pattern by similar
cells.

Mantle cell lymphoma Can have a leukemic Like CLL, coexpress CD20 t(11;14)
phase that mimics CLL and CD5, and do not
morphologically with express CD23, but stain
circulating small strongly for cyclin D1 and
lymphocytes with surface membrane
irregular or cleaved immunoglobulin.
nuclei.

Hairy cell leukemia Variant has circulating Unlike CLL, most cases of
tumor cells with HCL are negative for CD5
morphology express CD11c, CD103,
intermediate between CD123, cyclin D1, and/or
hairy cells and annexin A1.
prolymphocytes.

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Lymphoplasmacytic Peripheral blood Lacks CD23 expression


lymphoma involvement is usually and stains strongly for
less prominent; surface IgM, CD20, and
circulating malignant cytoplasmic Ig.
cells usually have a
plasmacytoid
appearance.

Splenic marginal zone Circulating tumor cells Like CLL, express CD23,
lymphoma may resemble CLL CD43, CD5, and IgD.
cells. Unlike CLL, can have
bright SmIg and CD20.

TCR: T cell receptor.

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Peripheral blood smear in a patient with


prolymphocytic leukemia

Peripheral blood smear from a 71-year-old male patient with


splenomegaly and a white blood cell count of 50,000/µL, with a
preponderance of prolymphocytes. The prolymphocytes shown here are
large cells with a moderate amount of clear to lightly basophilic
cytoplasm, coarse nuclear chromatin, and a prominent single nucleolus
(arrows).

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

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Lymphoplasmacytic lymphoma associated with


Waldenstrom macroglobulinemia

Bone marrow smear from a patient with lymphoplasmacytic lymphoma


and Waldenstrom macroglobulinemia. The marrow consists largely of
lymphoplasmacytic cells that have the nuclear spoke-wheel pattern of a
plasma cell but the low cytoplasmic volume that is more characteristic
of a small lymphocyte.

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

Graphic 66365 Version 2.0

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Abnormal circulating lymphocytes in hairy cell


leukemia

Peripheral smear from a patient with hairy cell leukemia. Panel A:


normal view of five hairy cells. The cells have abundant, irregularly
distributed cytoplasm. The nuclei vary from round to oval to slightly
lobulated. Panel B: same view but with the contrast adjusted to show
the irregular cytoplasmic outlines, giving the cells their "hairy"
appearance (arrows). Wright-Giemsa stain.

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

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Clinical presentation, pathologic features, diagnosis, and differential dia... http://www.uptodate.com.libproxy.ucl.ac.uk/contents/clinical-presentatio...

Disclosures
Disclosures: Kanti R Rai, MD Consultant/Advisory Boards: Genentech/Roche; Celgene; Teva [chronic lymphocytic leukemia (lenalidomide,
obinutuzumab, bendamustine)]. Stephan Stilgenbauer, MD Nothing to disclose. Richard A Larson, MD Grant/Research/Clinical Trial
Support: Amgen [leukemia (blinatumomab)]; Astellas [leukemia (ASP2215)]; Erytech [leukemia (Erytech)]; Ariad [leukemia (ponatinib)];
Novartis [leukemia (nilotinib)]; Ambit Bioscience [leukemia (quizartinib)]. Grant/Research/Clinical Trial Support (Spouse): Millennium
[lymphoma (bortezomib)]; Janssen [lymphoma (inotuzumab)]; Seattle Genetics [lymphoma (brentuximab vedotin)]; Spectrum [lymphoma
(ibritumomab tiuxetan)]. Consultant/Advisory Boards: Novartis [leukemia (imatinib, nilotinib)]; Ariad [leukemia (ponatinib)]; CVS/Caremark
[leukemia (drug prior authorization)]; Pfizer [leukemia (gemtuzumab, ozogamicin]; Celgene [DSMB, leukemia (azacitidine)]; Sanofi Aventis
[DSMB, myelofibrosis (fedratinib)]; Bristol Myers Squibb [DSMB, leukemia (dasatinib)]. Consultant/Advisory Boards (Spouse): Janssen
[lymphoma (ibrutinib)]; Spectrum [lymphoma (ibritumomab tiuxetan)]. Rebecca F Connor, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
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