16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Official reprint from UpToDate®

www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

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

Authors: Kanti R Rai, MD, Stephan Stilgenbauer, MD

Section Editor: Richard A Larson, MD
Deputy Editor: Rebecca F Connor, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2018. | This topic last updated: Feb 01, 2018.

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
1.3:1 to 1.7:1 [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]. Worldwide, there are approximately 191,000 cases and 61,000 deaths per year attributed to CLL [5].

CLL is considered to be mainly a disease of older adults, with a median age at diagnosis of approximately 70 years [6]; 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 20,940 new cases of CLL will be diagnosed in the United States in 2018: 12,990 in males and
7,950 in females [1].

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 [18-20]. 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
[21,22]. In addition, despite a few reports of an excess risk of CLL among farmers [18,19], those with benzene and heavy solvent
exposure [18-20,23,24], rubber manufacturing workers [24,25], or those with multiple episodes of pneumonia [26], these
associations have not been proven [27].

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 [28-33]. 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) [34]. Of note, while

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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) [35]. Although there is no available proof of genetic
transmission of this disease, certain genetic polymorphisms may predispose patients to familial cancer, including CLL [36-39]. 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 [40].

A number of candidate chromosomal regions are currently being explored for the presence of susceptibility genes for familial CLL
[32,41-46].

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 [47]:

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

● Fevers of >100.5°F (>38°C) 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 [48,49]. 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 [48,49]. 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 cases [48,49]. 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 [50]. 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 "Richter's transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Nonspecific secondary cutaneous lesions may be due to infection, bleeding, vasculitis, or paraneoplastic pemphigus [51]. An
exaggerated reaction to insect bites, especially mosquito bites, has been reported, and may alert the clinician to the diagnosis of
CLL [52].

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 [53].

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 [54-56].
(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 [47], a significant proportion of patients present with counts as high as 100,000/microL [100 x 109/L]. (See "Approach
to the child 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 in hematologic malignancies".)

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 [57]. The positive and negative predictive value of the DAT was reported as part of a prospective clinical trial
in patients with CLL [58]. 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 [57]. 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 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 [57]. Retrospective studies have reported varying impacts
of immune thrombocytopenia on the clinical course [59,60]. (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 '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.

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 [61,62].

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 [61]. 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 "Laboratory methods for analyzing 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 [63]. 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) [47].

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 [64].

Immunophenotype — Immunophenotypic analysis, usually by flow cytometry, is a key component to the diagnosis of CLL (figure
1) [65]. There are three major characteristic immunophenotypic findings [47]:

● Expression of B cell associated antigens including CD19, CD20, and CD23. Expression of CD20 is usually 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 [66].

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 [67].

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 [68-70]. 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".)

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 [47,66,71].

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 [47,66]. 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 [47].

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 [47]:

● 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 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] and no evidence of other
disease manifestations (eg, enlarged lymph node) are diagnosed with a monoclonal B cell lymphocytosis rather than CLL even if
they have cytopenias [71]. (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 [72,73].

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 [74]. 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 child 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.

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 adult 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 other disease manifestations (eg, lymphadenopathy or organomegaly) [71]. (See 'Evaluation and diagnosis'
above and "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Monoclonal B lymphocytosis'.)

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) [75,76]. 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 [77]. 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) [66]. 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, 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 "Splenic marginal zone lymphoma".)
https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 education: Chronic lymphocytic leukemia (CLL) (The Basics)")

● Beyond the Basics topics (see "Patient education: 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 approximately 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 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 lymphoma (leukemic

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

phase), 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.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68:7.
2. Hernández JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer 1995; 75:381.
3. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic
characteristics, 1997-2002. Cancer Causes Control 2008; 19:379.
4. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the
HAEMACARE project. Blood 2010; 116:3724.
5. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, Regional, and National Cancer
Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups,
1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2017; 3:524.
6. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological
Malignancy Research Network. Br J Cancer 2011; 105:1684.
7. Kobayashi T, Kita K, Ohno T, Shirakawa S. [Chronic lymphocytic leukemia in Japan]. Rinsho Ketsueki 1990; 31:554.
8. Yang C, Zhang X. Incidence survey of leukemia in China. Chin Med Sci J 1991; 6:65.
9. Zheng W, Linet MS, Shu XO, et al. Prior medical conditions and the risk of adult leukemia in Shanghai, People's Republic of
China. Cancer Causes Control 1993; 4:361.
10. Wu SJ, Huang SY, Lin CT, et al. The incidence of chronic lymphocytic leukemia in Taiwan, 1986-2005: a distinct increasing
trend with birth-cohort effect. Blood 2010; 116:4430.
11. Fleming AF. The epidemiology of lymphomas and leukaemias in Africa--an overview. Leuk Res 1985; 9:735.
12. Oloo AJ, Ogada TA. Chronic lymphocytic leukaemia (CLL): clinical study at Kenyatta National Hospital (KNH). East Afr Med J
1984; 61:797.
13. Haenszel W, Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the
United States. J Natl Cancer Inst 1968; 40:43.
14. Yanagihara ET, Blaisdell RK, Hayashi T, Lukes RJ. Malignant lymphoma in Hawaii-Japanese: a retrospective morphologic
survey. Hematol Oncol 1989; 7:219.
15. Coombs CC, Rassenti LZ, Falchi L, et al. Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia
among African Americans. Blood 2012; 120:1687.
16. Asou H, Takechi M, Tanaka K, et al. Japanese B cell chronic lymphocytic leukaemia: a cytogenetic and molecular biological
study. Br J Haematol 1993; 85:492.
17. Gunawardana C, Austen B, Powell JE, et al. South Asian chronic lymphocytic leukaemia patients have more rapid disease
progression in comparison to White patients. Br J Haematol 2008; 142:606.
18. Blair A, White DW. Leukemia cell types and agricultural practices in Nebraska. Arch Environ Health 1985; 40:211.
19. Burmeister LF, Van Lier SF, Isacson P. Leukemia and farm practices in Iowa. Am J Epidemiol 1982; 115:720.
20. Talibov M, Auvinen A, Weiderpass E, et al. Occupational solvent exposure and adult chronic lymphocytic leukemia: No risk in
a population-based case-control study in four Nordic countries. Int J Cancer 2017; 141:1140.
21. Preston DL, Kusumi S, Tomonaga M, et al. Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and
multiple myeloma, 1950-1987. Radiat Res 1994; 137:S68.
22. Schubauer-Berigan MK, Daniels RD, Fleming DA, et al. Chronic lymphocytic leukaemia and radiation: findings among workers
at five US nuclear facilities and a review of the recent literature. Br J Haematol 2007; 139:799.

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

23. Arp EW Jr, Wolf PH, Checkoway H. Lymphocytic leukemia and exposures to benzene and other solvents in the rubber
industry. J Occup Med 1983; 25:598.
24. Monson RR, Fine LJ. Cancer mortality and morbidity among rubber workers. J Natl Cancer Inst 1978; 61:1047.
25. McMichael AJ, Andjelkovic DA, Tyroler HA. Cancer mortality among rubber workers: an epidemiologic study. Ann N Y Acad
Sci 1976; 271:125.
26. Landgren O, Rapkin JS, Caporaso NE, et al. Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia.
Blood 2007; 109:2198.
27. Brandt L. Environmental factors and leukaemia. Med Oncol Tumor Pharmacother 1985; 2:7.
28. Cuttner J. Increased incidence of hematologic malignancies in first-degree relatives of patients with chronic lymphocytic
leukemia. Cancer Invest 1992; 10:103.
29. Yuille MR, Matutes E, Marossy A, et al. Familial chronic lymphocytic leukaemia: a survey and review of published studies. Br J
Haematol 2000; 109:794.
30. Goldin LR, Ishibe N, Sgambati M, et al. A genome scan of 18 families with chronic lymphocytic leukaemia. Br J Haematol
2003; 121:866.
31. Goldin LR, Pfeiffer RM, Li X, Hemminki K. Familial risk of lymphoproliferative tumors in families of patients with chronic
lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 2004; 104:1850.
32. Fuller SJ, Papaemmanuil E, McKinnon L, et al. Analysis of a large multi-generational family provides insight into the genetics
of chronic lymphocytic leukemia. Br J Haematol 2008; 142:238.
33. Brown JR, Neuberg D, Phillips K, et al. Prevalence of familial malignancy in a prospectively screened cohort of patients with
lymphoproliferative disorders. Br J Haematol 2008; 143:361.
34. Goldin LR, Lanasa MC, Slager SL, et al. Common occurrence of monoclonal B-cell lymphocytosis among members of high-
risk CLL families. Br J Haematol 2010; 151:152.
35. Wiernik PH, Ashwin M, Hu XP, et al. Anticipation in familial chronic lymphocytic leukaemia. Br J Haematol 2001; 113:407.
36. Calin GA, Trapasso F, Shimizu M, et al. Familial cancer associated with a polymorphism in ARLTS1. N Engl J Med 2005;
352:1667.
37. Novak AJ, Grote DM, Ziesmer SC, et al. Elevated serum B-lymphocyte stimulator levels in patients with familial
lymphoproliferative disorders. J Clin Oncol 2006; 24:983.
38. Crowther-Swanepoel D, Wild R, Sellick G, et al. Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through
analysis of IgVH gene usage and mutation status in familial CLL. Blood 2008; 111:5691.
39. Campa D, Butterbach K, Slager SL, et al. A comprehensive study of polymorphisms in the ABCB1, ABCC2, ABCG2, NR1I2
genes and lymphoma risk. Int J Cancer 2012; 131:803.
40. Chen L, Widhopf G, Huynh L, et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic
lymphocytic leukemia. Blood 2002; 100:4609.
41. Sellick GS, Webb EL, Allinson R, et al. A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-
susceptibility loci. Am J Hum Genet 2005; 77:420.
42. Ng D, Toure O, Wei MH, et al. Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial
chronic lymphocytic leukemia. Blood 2007; 109:916.
43. Goldin LR, McMaster ML, Rotunno M, et al. Whole exome sequencing in families with CLL detects a variant in Integrin β 2
associated with disease susceptibility. Blood 2016; 128:2261.
44. Speedy HE, Kinnersley B, Chubb D, et al. Germline mutations in shelterin complex genes are associated with familial chronic
lymphocytic leukemia. Blood 2016.
45. Sidaway P. Haematological cancer: Shelterin complex mutated in familial CLL. Nat Rev Clin Oncol 2016; 13:591.
46. Blackburn NB, Marthick JR, Banks A, et al. Evaluating a CLL susceptibility variant inITGB2in families with multiple subtypes of
hematological malignancies. Blood 2017; 130:86.
47. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report
from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group
1996 guidelines. Blood 2008; 111:5446.
48. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219.

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

49. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a
multivariate survival analysis. Cancer 1981; 48:198.
50. Agnew KL, Ruchlemer R, Catovsky D, et al. Cutaneous findings in chronic lymphocytic leukaemia. Br J Dermatol 2004;
150:1129.
51. Robak E, Robak T. Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma 2007; 48:855.
52. WEED RI. EXAGGERATED DELAYED HYPERSENSITIVITY TO MOSQUITO BITES IN CHRONIC LYMPHOCYTIC
LEUKEMIA. Blood 1965; 26:257.
53. Strati P, Uhm JH, Kaufmann TJ, et al. Prevalence and characteristics of central nervous system involvement by chronic
lymphocytic leukemia. Haematologica 2016; 101:458.
54. Moulin B, Ronco PM, Mougenot B, et al. Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas.
Kidney Int 1992; 42:127.
55. Favre G, Courtellemont C, Callard P, et al. Membranoproliferative glomerulonephritis, chronic lymphocytic leukemia, and
cryoglobulinemia. Am J Kidney Dis 2010; 55:391.
56. Da'as N, Polliack A, Cohen Y, et al. Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic
leukemia: a retrospective study in 700 patients. Eur J Haematol 2001; 67:158.
57. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell
aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998; 25:80.
58. Dearden C, Wade R, Else M, et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic
leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia.
Blood 2008; 111:1820.
59. Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and
prognostic features. Blood 2000; 95:2786.
60. Visco C, Ruggeri M, Laura Evangelista M, et al. Impact of immune thrombocytopenia on the clinical course of chronic
lymphocytic leukemia. Blood 2008; 111:1110.
61. Tsai HT, Caporaso NE, Kyle RA, et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of
chronic lymphocytic leukemia: a prospective study. Blood 2009; 114:4928.
62. Maurer MJ, Cerhan JR, Katzmann JA, et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic
lymphocytic leukemia. Blood 2011; 118:2821.
63. Keating MJ, O'Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving
fludarabine regimens as initial therapy. Blood 1998; 92:1165.
64. Nowakowski GS, Hoyer JD, Shanafelt TD, et al. Using smudge cells on routine blood smears to predict clinical outcome in
chronic lymphocytic leukemia: a universally available prognostic test. Mayo Clin Proc 2007; 82:449.
65. Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring
in chronic lymphocytic leukaemia. Leukemia 2007; 21:956.
66. Swerdlow, SH, Campo, E, Harris, NL, Jaffe, ES, Pileri, SA, Stein, H, Thiele, J, editors. World Health Organization Classificatio
n of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition. IARC Press: Lyon 2008.
67. Kern W, Bacher U, Schnittger S, et al. Flow cytometric identification of 76 patients with biclonal disease among 5523 patients
with chronic lymphocytic leukaemia (B-CLL) and its genetic characterization. Br J Haematol 2014; 164:565.
68. Lipshutz MD, Mir R, Rai KR, Sawitsky A. Bone marrow biopsy and clinical staging in chronic lymphocytic leukemia. Cancer
1980; 46:1422.
69. Pangalis GA, Boussiotis VA, Kittas C. B-chronic lymphocytic leukemia. Disease progression in 150 untreated stage A and B
patients as predicted by bone marrow pattern. Nouv Rev Fr Hematol 1988; 30:373.
70. Rozman C, Montserrat E, Rodríguez-Fernández JM, et al. Bone marrow histologic pattern--the best single prognostic
parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood 1984; 64:642.
71. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid
neoplasms. Blood 2016; 127:2375.
72. Marti GE. The changing definition of CLL. Blood 2009; 113:4130.
73. Hillmen, P, Cheson, BD, Catovsky, D, et al. Letters regarding Blood. 2008;111:5446-5456 by Hanson et al and Mulligan et al.
Blood 2009; 113:6497.

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

74. Shanafelt TD, Kay NE, Jenkins G, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from
monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009; 113:4188.
75. Catovsky D, Foa R. The Lymphoid Leukaemias, Butterworths, London 1990.
76. Stone RM. Prolymphocytic leukemia. Hematol Oncol Clin North Am 1990; 4:457.
77. DiRaimondo F, Albitar M, Huh Y, et al. The clinical and diagnostic relevance of CD23 expression in the chronic
lymphoproliferative disease. Cancer 2002; 94:1721.

Topic 4513 Version 29.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

GRAPHICS

Eastern Cooperative Oncology Group (ECOG, Zubrod, World Health Organization) performance
scale

Performance status Definition

0 Fully active; no performance restrictions.

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

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

3 Capable of only limited self-care; confined to bed or chair >50% of waking hours.

4 Completely disabled; cannot carry out any self-care; totally confined to bed or chair.

Adapted from: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol
1982; 5:649.

Graphic 72901 Version 10.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 4.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 peripheral blood smear
demonstrates a lymphocytosis. The leukemic cells are small, mature-appearing lymphocytes with a dense nucleus, partially aggregated
(clumped) chromatin, and without discernible nucleoli (arrows). There is a narrow border of clear to slightly basophilic cytoplasm. The field
includes some segmented neutrophils (arrowhead) and a nucleated red blood cell (dashed arrow). The bone marrow aspirate demonstrates an
increased percentage of mature-appearing lymphocytes.

Graphic 97705 Version 2.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Flow cytometry of chronic lymphocytic leukemia

Immunophenotypic analysis of chronic lymphocytic leukemia (CLL) is usually

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

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.

Graphic 51190 Version 12.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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 3.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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.

Graphic 51681 Version 11.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate
Differential diagnosis of chronic lymphocytic leukemia
Entity
Chronic lymphocytic
leukemia/small lymphocytic
lymphoma (CLL/SLL)
Monoclonal B cell lymphocytosis
B cell prolymphocytic leukemia
Mantle cell lymphoma
Hairy cell leukemia and hairy cell
leukemia variant
Lymphoplasmacytic lymphoma
Splenic marginal zone lymphoma
TCR: T cell receptor.
Graphic 90133 Version 5.0
https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
Histologic morphology
"Typical" CLL cells are small,
mature-appearing lymphocytes
with a dense nucleus; partially
aggregated chromatin; no
discernible nucleoli; and a narrow
border of cytoplasm.
A minority of cells may have a
prolymphocytic morphology.
Absolute increase in the number
of clonal B lymphocytes in the
peripheral blood does not exceed
5000/microL [5 x 10 9/L].
>55 percent of circulating
lymphocytes are
"prolymphocytes".
The bone marrow is infiltrated in
an interstitial or nodular pattern
by similar cells.
Can have a leukemic phase that
mimics CLL morphologically with
circulating small lymphocytes
with irregular or cleaved nuclei.
Typical hairy cells are
mononuclear and one to two
times the size of a mature
lymphocyte. The nuclei are often
eccentric, lack prominent
nucleoli, and have a reticular
chromatin pattern. The
cytoplasmic outline is indistinct
with projections. Hairy cell
variant has circulating tumor cells
with morphology intermediate
between hairy cells and
prolymphocytes.
Peripheral blood involvement is
usually less prominent;
circulating malignant cells usually
have a plasmacytoid appearance.
Circulating tumor cells may
resemble CLL cells.
Immunophenotype Genetic features/other
Typically express B cell antigens Deletion 13q, trisomy 12,
(CD19, CD22, CD79a, FMC7); deletion 11q, and deletion 17p.
CD5; and CD23. Expression of TCR genes are not clonally
CD20 and surface rearranged.
immunoglobulin is dim.
Immunophenotype identical to Patients have no
CLL. lymphadenopathy,
organomegaly, cytopenias, or
disease-related symptoms.
Express bright surface IgM +/– t(11;14) must be excluded.
IgD and bright CD20, as well as No associated paraproteinemia.
other B cell antigens (CD19,
TCR genes are not clonally
CD22, CD79a, FMC7).
rearranged.
Like CLL, coexpress CD20 and t(11;14)
CD5, and do not express CD23,
but stain strongly for cyclin D1
and surface membrane
immunoglobulin.
Unlike CLL, most cases of HCL BRAF V600E positive
are negative for CD5, express
CD11c, CD103, CD123, cyclin
D1, and/or annexin A1.
Lacks CD23 expression and
stains strongly for surface IgM,
CD20, and cytoplasmic Ig.
Like CLL, express CD23, CD43,
CD5, and IgD. Unlike CLL, can
have bright SmIg and CD20.
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

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.

Graphic 58721 Version 3.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Bone marrow histology of lymphoplasmacytic lymphoma

Bone marrow aspirate from a patient with Waldenström macroglobulinemia

demonstrating excess mature lymphocytes (thin arrow), lymphoplasmacytic
cells, and plasma cells (thick arrow) consistent with lymphoplasmacytic
lymphoma.

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.

Graphic 52862 Version 8.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Hairy cell leukemia in peripheral blood

Peripheral smear from a patient with hairy cell leukemia. Wright-Giemsa stain showing two hairy cells. The cells have
abundant, irregularly distributed cytoplasm with irregular cytoplasmic outlines, giving the cells their "hairy" appearance. The
nuclei vary from round to oval.

This image was originally published in ASH Image Bank. Maslak P. Hairy cell leukemia - 2. ASH Image Bank. 2008; image number
00003741. Copyright © the American Society of Hematology.

Graphic 102936 Version 4.0

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545
16/5/2018 Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia - UpToDate

Contributor Disclosures
Kanti R Rai, MD Advisory Boards: Pharmacyclics [CLL (ibrutinib)], Gilead [CLL (idelalisib)], Roche/Genentech [CLL
(obinutuzumab, rituximab)], Cellectis [CLL (not named, generic: allogeneic CAR-T cells)]. Stephan Stilgenbauer,
MD Grant/Research/Clinical Trial Support: AbbVie (CLL, NHL [venetoclax]); Amgen (CLL, NHL [blinatumumab]); Boehringer-
Ingelheim (CLL, NHL); Celgene (CLL, NHL [lenalidomide]); Genentech (CLL, NHL [venetoclax, rituximab, obinutuzumab]);
Genzyme (CLL, NHL [alemtuzumab]); Gilead (CLL, NHL [idelalisib]); GSK (CLL, NHL); Janssen (CLL, NHL [ibrutinib]);
Mundipharma (CLL, NHL [bendamustine]); Novartis (CLL, NHL); Pharmacyclics (CLL, NHL[ibrutinib]); Roche (CLL, NHL
[venetoclax, rituximab, obinutuzumab]). Consultant/Advisory Boards: AbbVie (CLL, NHL [venetoclax]); Amgen (CLL, NHL
[blinatumumab]); Boehringer-Ingelheim (CLL, NHL); Celgene (CLL, NHL [lenalidomide]); Genentech (CLL, NHL [venetoclax,
rituximab, obinutuzumab]); Genzyme (CLL, NHL [alemtuzumab]); Gilead (CLL, NHL [idelalisib]); GSK (CLL, NHL); Janssen (CLL,
NHL [ibrutinib]); Mundipharma (CLL, NHL [bendamustine]); Novartis (CLL, NHL); Pharmacyclics (CLL, NHL[ibrutinib]); Roche (CLL,
NHL [venetoclax, rituximab, obinutuzumab]). Richard A Larson, MD Grant/Research/Clinical Trial Support: Astellas [leukemia
(gilteritinib)]; Erytech [leukemia (eryaspase)]; Novartis [leukemia (nilotinib, ascininib)]; Daiichi Sankyo [leukemia (quizartinib)];
Celgene [leukemia (enasidenib)]. Consultant/Advisory Boards: Novartis [leukemia (imatinib, nilotinib)]; Ariad Data Safety Monitoring
Board [leukemia (ponatinib)]; CVS/Caremark [leukemia (drug prior authorization program)]; Celgene Data Safety Monitoring Board
[leukemia (azacitidine, durvalumab)]; Amgen [leukemia (blinatumomab)]; Astellas [leukemia (gilteritinib)]; Jazz [leukemia (CPX-
351)]. Rebecca F Connor, MD Nothing to disclose

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.

Conflict of interest policy

https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia/print?topicRef=4545