INTRODUCTION — Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a mature B cell neoplasm characterized by a progressive accumulation of monoclonal B lymphocytes.
CLL is considered to be identical (ie, one disease with different manifestations) to the non-Hodgkin lymphoma SLL. The malignant cells seen in CLL and SLL have identical pathologic and immunophenotypic features. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.
The epidemiology, clinical presentation, pathologic features, diagnosis, and differential diagnosis of CLL/SLL will be reviewed here. The pathophysiology, molecular biology, cytogenetic abnormalities, staging, and treatment of CLL/SLL are discussed separately.
EPIDEMIOLOGY — CLL/SLL is the most common leukemia in adults in Western countries, accounting for approximately 25 to 35 percent of all leukemias in the United States (US) . In less than 10 percent of patients, CLL/SLL presents primarily in the lymph nodes as a non-Hodgkin lymphoma (ie, SLL); this presentation accounts for less than 5 percent of all non-Hodgkin lymphomas.
CLL/SLL is more common in men, with a male to female ratio of approximately 1.2:1 to 1.7:1 [1,2]. The incidence rates among men and women in the US are approximately 6.75 and 3.65 cases per 100,000 population per year, respectively . In Europe, these incidence rates are 5.87 and 4.01 cases per 100,000 population per year, respectively . An estimated 20,160 new cases of CLL/SLL are diagnosed annually in the US: 12,630 in males and 7,530 in females . Worldwide, there are approximately 191,000 cases and 61,000 deaths per year attributed to CLL/SLL .
CLL/SLL is considered to be mainly a disease of older adults, with a median age at diagnosis of approximately 70 years ; however, it is not unusual to make this diagnosis in younger individuals (eg, from 30 to 39 years of age) . The incidence increases rapidly with increasing age.
The incidence of CLL/SLL varies by race and geographic location. In the United States, there is a higher incidence among White Americans compared with African Americans or Asian Pacific Islanders (API; as defined in the SEER database) [2,3]. The incidence of CLL/SLL 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 [7-9]. The incidence of CLL/SLL in Africa is not as low as it is in Asia [10,11].
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 noted that Japanese persons who settled in Hawaii do not have a higher incidence of CLL/SLL than native Japanese [12,13]. 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/SLL in other populations . Furthermore, the cytogenetic and molecular genetic characteristics of CLL/SLL appear to be similar throughout the world, although one study suggests that the clinical course may be more aggressive in Japan [15,16].
There are no clearly discernible occupational or environmental risk factors that predispose to CLL/SLL [17-19]. Although there was an increase in all other types of leukemias among atomic bomb survivors, there was no increase in the incidence of CLL/SLL [20,21]. In addition, despite a few reports of an excess risk of CLL/SLL among farmers [17,18], those with benzene and heavy solvent exposure [17-19,22,23], rubber manufacturing workers [23,24], or those with multiple episodes of pneumonia , these associations have not been proven .
Family studies — CLL/SLL and other lymphoid, hematologic, and solid tumors occur with higher than expected frequency among first-degree family members of patients with CLL/SLL [27-33]. 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) . 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.)
While some studies have suggested that CLL develops at an earlier age in successive generations (ie, genetic anticipation) [35,36], others have not [30,37]. Certain genetic polymorphisms may predispose patients to familial cancer, including CLL [38-41]. 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 .
Several candidate chromosomal regions are currently being explored for the presence of susceptibility genes for familial CLL [31,43-48].
Symptoms — Most patients feel entirely well with no symptoms when a routine blood count reveals an absolute lymphocytosis, leading to a diagnosis of CLL. Others 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.
Five to 10 percent of patients present with the typical "B" symptoms of lymphoma which include one or more of the following :
●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 bites). (See "Overview of the complications of chronic lymphocytic leukemia".)
Lymphadenopathy — The most common abnormal finding on physical examination of the patient with CLL/SLL is lymphadenopathy, present in 50 to 90 percent of patients among various series [50,51]. Lymph node enlargement may be generalized or localized, and individual lymph nodes can vary greatly in size. Cervical, supraclavicular, and axillary lymph nodes are affected most commonly.
Characteristically, the enlarged nodes 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, the cervical triangle, axilla or femoral-inguinal areas) may become confluent, forming large spherical lymphoid masses. In addition, enlarged 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 [50,51]. As is the case with enlarged lymph nodes, an enlarged spleen in CLL/SLL is usually painless and nontender to palpation, with a sharp edge and a smooth firm surface. Pain due to splenic infarction 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 [50,51]. The liver is usually only mildly enlarged, ranging from 2 to 6 cm below the right costal margin, with a span (based on dullness to percussion) of approximately 10 to 16 cm. Upon palpation, the liver is usually nontender and firm with a smooth surface.
Skin — CLL/SLL cells may infiltrate any organ, but likely due to the ease of examination, the skin is the nonlymphoid tissue that is most commonly recognized as being involved at diagnosis. Skin lesions (leukemia cutis) most often involve the face and can manifest as macules, papules, plaques, nodules, ulcers, or blisters [52,53]. Involvement can be confirmed by biopsy of lesional skin. Leukemia cutis is seen in fewer than 5 percent of cases and may not significantly affect overall prognosis unless biopsy reveals Richter transformation. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)
Nonspecific secondary cutaneous lesions may be due to infection, bleeding, vasculitis, or paraneoplastic pemphigus . Some patients report what is thought to be an exaggerated reaction to insect bites [55,56]. (See "Eosinophilic cellulitis (Wells syndrome)".)
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 rare in CLL/SLL. Similarly, meningeal leukemia is very uncommon, with a reported incidence in patients with CLL/SLL ranging from 0.2 to 2 percent [57,58].
Membranoproliferative glomerulonephritis (MPGN) has occasionally been described in CLL/SLL and appears to be a paraneoplastic phenomenon mediated by deposition and immune reaction to cryoprecipitating or noncryoprecipitating M-components [59-61]. Rarely, other forms of paraneoplastic renal involvement are also seen, such as minimal change disease and amyloidosis . (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Glomerular diseases due to nonamyloid fibrillar deposits", section on 'Immunotactoid glomerulopathy'.)
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 , a significant proportion of patients present with counts as high as 100,000/microL (100 x 109/L). (See "Approach to the adult with lymphocytosis or lymphocytopenia".)
Although very unusual, extreme lymphocytosis can result in complications due to whole blood hyperviscosity (eg, transient ischemic attack, stroke) . It is difficult to identify a total white blood cell (WBC) count threshold above which the risk for complications is increased enough to warrant a change in management. However, in our clinical practices, we have observed complications of hyperviscosity at total WBC counts as low as 250 x 109/L. While most patients with WBC counts above this threshold will not have complications, clinicians should be alert to the possibility, especially in patients with other risk factors for cerebrovascular disease (eg, hypertension, atherosclerotic disease). For patients with extreme lymphocytosis, hydration is encouraged and diuretics are discouraged. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)
In patients with SLL, the peripheral blood lymphocyte count may be normal or only mildly elevated; by definition, patients with SLL have an absolute lymphocyte count of <5000/microL at the time of diagnosis [64,65].
Cytopenias — Neutropenia, anemia, and thrombocytopenia may be observed at the time of initial diagnosis and are usually not severe. In addition, bone marrow replacement, autoimmune hemolytic anemia, pure red cell aplasia, autoimmune thrombocytopenia, and agranulocytosis may all contribute to the development of cytopenias (see "Overview of the complications of chronic lymphocytic leukemia"):
●Patients with CLL/SLL 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 approximately 10 percent of cases, usually later in the disease course . The positive and negative predictive value of the DAT was reported as part of a prospective clinical trial in patients with CLL . 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 "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evaluation and diagnosis'.)
●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/SLL . Unlike AIHA, PRCA may occur early in the course of CLL. (See "Acquired pure red cell aplasia in adults", section on 'Pathogenesis'.)
●Immune thrombocytopenia (ITP) occurs in 2 to 3 percent of patients with CLL/SLL and may be the initial event that brings the patient to medical attention . Retrospective studies have reported varying impacts of ITP on the clinical course [68,69]. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)
●Rarely, agranulocytosis may be encountered in CLL/SLL (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 25 percent of patients at the time of 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 are low. Significant degrees of hypogammaglobulinemia and neutropenia, when present, increase the vulnerability of CLL/SLL patients to major bacterial infections. (See "Risk of infections in patients with chronic lymphocytic leukemia".)
Polyclonal increases in gamma globulins are seen in up to 15 percent of patients, while a monoclonal protein (M-protein) is present in up to 5 percent of patients [71,72].
In a study of 109 persons who had developed CLL and had serially collected prediagnostic serum samples, the prevalences of an abnormal free light chain (FLC) ratio, an M protein, or hypogammaglobulinemia prior to diagnosis were 38, 13, and 3 percent, respectively . M-proteins and an abnormal FLC 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 . Elevations of uric acid, hepatic enzymes (ALT or AST) and, rarely, calcium may also be observed.
PATHOLOGIC FEATURES — While not all are required for diagnostic purposes, the following section reviews abnormalities that may be seen upon examination of the peripheral smear; immunophenotypic analysis of the circulating lymphocytes and bone marrow aspirate and biopsy; and pathologic evaluation of involved bone marrow, lymph nodes, and spleen. Chromosomal changes seen in CLL/SLL are not diagnostic features of the disease and are presented separately. (See "Pathobiology of chronic lymphocytic leukemia".)
The diagnostic evaluation of a patient suspected of having CLL/SLL differs depending on the clinical presentation and is discussed separately. (See 'Evaluation and diagnosis' below.)
Peripheral smear — The peripheral blood smear of patients with CLL demonstrates lymphocytosis. Typically, the majority of the leukemic cells are small, mature-appearing lymphocytes with a darkly stained nucleus, partially condensed (clumped) chromatin, indiscernible nucleoli, and a narrow rim of slightly basophilic cytoplasm (picture 1A-B) .
In addition, a proportion of circulating cells consists of intermediate-sized lymphocytes with large oval or notched nuclei, lacy-appearing nuclear chromatin, and prominent, single, centrally placed nucleoli. These so-called "prolymphocytes" usually account for a minority of the overall population of lymphocytes, but in some cases comprise up to 55 percent of the lymphoid cells (picture 5B). In one study, a prolymphocyte percentage of >10 percent was associated with more aggressive disease . The smear also often contains "smudge" cells (also called "basket cells"). These are lymphocytes that are mechanically disrupted and smeared out in the process of being spread on the glass slide , probably because CLL cells are more fragile than normal lymphocytes. When complicated by autoimmune hemolytic anemia, spherocytic red cells (spherocytes) may also be prominent.
Immunophenotype — Immunophenotypic analysis, usually by flow cytometry, is a key component to the diagnosis of CLL (table 2 and figure 1) . Most cases can be identified using a panel of antibodies specific for CD5, CD19, CD20, CD23, and kappa and lambda immunoglobulin light chain .
There are three major sets of characteristic immunophenotypic findings [49,65]:
●Expression of the B cell-associated antigens CD19, CD20, and CD23. The staining intensity of CD20 is usually low/dim.
●Expression of CD5, an antigen expressed on T cells and subsets of mature B cells.
●Expression of low levels of surface membrane immunoglobulin (ie, SmIg weak). The immunoglobulin is most often IgM or both IgM and IgD, and typically only a single immunoglobulin light chain is expressed (ie, either kappa or lambda but not both), confirming the clonal nature of these cells.
In addition, CLL cells express HLA-DR and are negative for cyclin D1 and usually negative for CD10. FMC7, CD22, and CD79b are also commonly negative or weakly expressed . Cytoplasmic immunoglobulin is detectable in about 5 percent of the cases. Approximately 40 percent of the cases express CD38 on >30 percent of the cells. Staining for the transcription factor LEF1 can also be helpful in distinguishing CLL/SLL from other tumors comprised of small B cell lymphocytes. Several large studies have reported a sensitivity and specificity of LEF1 staining of 92 to 96 percent and 70 to 93 percent, respectively [78,79]. However, occasional cases of mantle cell lymphoma and other small B cell neoplasms are positive for LEF1, and LEF1 staining must be interpreted together with the results of morphologic examination, immunophenotyping, and genetic/cytogenetic studies. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'IGHV mutation status, ZAP-70, and CD38'.)
The vast majority of cases demonstrates a single clone of abnormal circulating B lymphocytes by flow cytometry. Rarely, flow cytometry identifies biclonal disease, usually recognized by the presence of two populations of cells with the immunophenotype of CLL/SLL, one expressing kappa light chain and the other expressing lambda light chain. In one large study, biclonal disease was estimated to occur in 1.4 percent of cases .
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 1B-D). The pattern of marrow involvement may be interstitial, nodular or, with high disease burden, diffuse.
Lymph node and spleen histology — The architecture of involved lymph nodes is diffusely effaced, sometimes with scattered residual naked germinal centers [49,65]. The lymph node infiltrate is composed predominantly of small lymphocytes with condensed chromatin, round nuclei, and, occasionally, a small nucleolus [81,82]. Larger lymphoid cells (prolymphocytes and paraimmunoblasts) with more prominent nucleoli and dispersed chromatin are always present (picture 2). These larger lymphoid cells are usually clustered in "pseudofollicles" (proliferation centers) (picture 3), a finding that is considered pathognomonic of CLL/SLL.
In some cases, the cells display a moderate nuclear irregularity, which can lead to a differential diagnosis of mantle cell lymphoma [83,84]. Some cases show plasmacytoid differentiation. (See 'Differential diagnosis' below.)
Histologic evaluation of the spleen usually demonstrates infiltration of both the white and red pulp, although white pulp involvement is usually more prominent . Proliferation centers may be seen.
EVALUATION AND DIAGNOSIS — The evaluation of suspected cases differs according to the presentation. The diagnosis of CLL is usually suspected in an adult found to have an absolute lymphocytosis. Evaluation of such patients should include 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 . Evaluation of the bone marrow is not usually necessary but is included in the evaluation of patients with unexplained cytopenias.
In contrast, the diagnosis of SLL is usually suspected in an adult with painless swelling of lymph nodes, often in the cervical area, which may spontaneously wax and wane, but do not altogether disappear. The evaluation of such patients typically includes an excisional or needle core biopsy of a lymph node or biopsy of other involved tissues; a bone marrow biopsy and aspirate is performed for those with cytopenias. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)
CLL can be diagnosed using the 2018 iwCLL update of the National Cancer Institute guidelines, when both of the following criteria are met :
●Absolute B lymphocyte count in the peripheral blood ≥5000/microL [5 x 109/L], sustained for at least three months, with a preponderant population of morphologically mature-appearing small lymphocytes. (See 'Peripheral smear' above.)
●Flow cytometry of the peripheral blood demonstrating immunoglobulin light chain restriction (kappa or lambda) and the following pattern of markers: extremely low levels of SmIg; expression of B cell associated antigens (CD19, CD20, and CD23); and expression of CD5. (See 'Immunophenotype' above.)
The classification of patients with clonal B lymphocytes with an absolute lymphocyte count (ALC) <5000/microL [5 x 109/L] depends on the number and type of the following disease manifestations: lymphadenopathy, hepatosplenomegaly, disease-related cytopenias, or disease-related symptoms .
●Patients with none of these disease manifestations are diagnosed with a monoclonal B cell lymphocytosis. (See "Monoclonal B cell lymphocytosis".)
●Patients with one or more cytopenias due to bone marrow infiltration with typical CLL cells are diagnosed with CLL regardless of the ALC in the peripheral blood or the presence of lymphadenopathy.
●Patients with nodal, splenic, or other extramedullary involvement, without cytopenias due to bone marrow infiltration, are diagnosed with SLL.
Prior to 2008, the diagnosis of CLL was based on an ALC equal to or greater than 5000/microL (5 x 109/L) in the setting of an appropriate immunophenotype. Patients with an absolute B lymphocyte count (B-ALC) <5000/microL and an ALC >5000/microL fell into a gray zone between CLL and monoclonal B cell lymphocytosis. The switch to using B-ALC for the diagnosis of CLL in 2008 eliminated this ambiguity, but sparked controversy [85,86].
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 . 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 adult 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 3). As described above, the diagnosis of CLL is clearly established in a patient with peripheral blood lymphocytosis and a CLL immunophenotype on flow cytometry. Features distinguishing other conditions with blood lymphocytosis from CLL are summarized below.
The differential diagnosis of patients presenting with lymphadenopathy and minimal or no lymphocytosis includes other lymphoid malignancies. The most reliable morphologic distinction in this scenario is that SLL is associated with the presence of proliferation centers in the involved lymph nodes, whereas the other entities are not.
CLL/SLL can also convert to an aggressive histology (Richter transformation), which may be present at the time of diagnosis in a subset of patients. (See 'Histologic transformation' below.)
Infectious causes of lymphocytosis — 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 three months. 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, lymphocytosis due to infectious causes is not clonal, does not show the characteristic immunophenotype of CLL, and does not infiltrate the bone marrow. In the case of viral infections, the lymphocytosis also characteristically includes atypical lymphocytes that represent activated T cells, many of which have abundant cytoplasm containing sparse collections of azurophilic granules. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Causes of lymphocytosis'.)
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, organomegaly, or cytopenias). (See 'Evaluation and diagnosis' above and "Monoclonal B cell lymphocytosis", section on 'Diagnosis'.)
Prolymphocytic leukemia — Both prolymphocytic leukemia (PLL) and CLL can present with lymphocytosis and splenomegaly and have circulating prolymphocytes in the blood that are morphologically distinct from typical CLL cells. Compared with typical CLL cells, these are intermediate- to large-sized cells with somewhat immature-appearing vesicular nuclear chromatin, a prominent nucleolus, and a moderate amount of cytoplasm (picture 5B). In B-PLL, prolymphocytes are of B lineage, express "bright" surface membrane immunoglobulin (SmIg) and usually do not express CD5 (table 2). In contrast, typical CLL cells express "dim" SmIg and CD5.
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".)
Mantle cell lymphoma — CLL/SLL cells sometimes show moderate nuclear irregularity, similar to the malignant cells in mantle cell lymphoma (MCL) [83,84]. In addition, MCL can have a leukemic phase that mimics CLL. Like CLL/SLL, MCL cells coexpress CD5 and CD20 (table 2). However, in a large majority of cases, MCL cells stain strongly for cyclin D1, express high levels of SmIg and CD20, have a t(11;14) chromosomal abnormality, and are negative for CD23 . In contrast, CLL cells are negative for cyclin D1 and are often CD23 positive. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)
Some cases of CLL/SLL may be negative for CD23, and MCL can express CD23; in such tumors, stains for cyclin D1 take on particular importance. Rare cases with an immunophenotype consistent with CLL have cyclin D1 gene rearrangement and/or cyclin D1 overexpression; these tend to pursue an unusually aggressive clinical course distinct from typical CLL [89,90]. The presence of clear-cut proliferation centers in involved tissues (lymph node, marrow, or spleen) excludes the diagnosis of MCL. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)
Lymphoplasmacytic lymphoma — Both lymphoplasmacytic lymphoma (LPL) and SLL are lymphoproliferative disorders of small cells that usually pursue an indolent course. LPL is virtually synonymous with Waldenström macroglobulinemia, a hyperviscosity syndrome caused by high levels of serum IgM. LPL is CD5 positive in a minority of cases, a finding suggestive of CLL/SLL. In addition, CLL/SLL can be associated with a small monoclonal paraprotein spike and show morphologic evidence of plasmacytic differentiation, findings suggestive of LPL. In most instances, however, the M-spike in CLL/SLL is less than 0.5 g/dL, whereas in LPL it virtually always exceeds 0.5 g/dL.
Peripheral blood involvement in LPL is uncommon and when it occurs generally less prominent than in CLL, and circulating malignant cells often have a plasmacytoid appearance (picture 4). Proliferation centers are absent in LPL and are virtually always seen in lymph nodes involved by CLL/SLL. Occasionally, LPL may have variable numbers of admixed larger cells resembling immunoblasts that have several nucleoli, but these cells are morphologically distinct from prolymphocytes.
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 (table 2). In LPL, there also is usually a substantial fraction of the malignant cell population that exhibits overt plasma cell differentiation (a feature that can be identified by flow cytometry), and >95 percent of cases have gain-of-function mutations in the MYD88 gene, an acquired genetic aberration that is infrequent in CLL. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)
Hairy cell leukemia — Hairy cell leukemia (HCL) and CLL/SLL 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. HCL often presents with splenomegaly and cytopenias but almost never involves lymph nodes, whereas lymphadenopathy is almost always present in CLL/SLL.
The diagnosis of HCL is often suspected based on the presence of circulating lymphocytes with cytoplasmic projections (hairy cells) (picture 5A-B) . Classic forms of HCL are distinguished from CLL based on immunophenotypic findings, which include "bright" staining for CD20 and surface immunoglobulin, positivity for CD25, CD11c, annexin A1, and CD103, and (in a large majority of cases) failure to express CD5 (table 2). In marrow biopsies, SLL often is present in a nodular pattern, whereas HCL always involves the marrow in an interstitial pattern without nodularity.
Variant forms of HCL also are recognized that are more likely to be associated with lymphocytosis than is classic HCL. Variant HCL shows more immunophenotypic heterogeneity than classic HCL (eg, variant HCL may be negative for one or more of the "classic" HCL markers, such as CD25, CD11c, annexin A1, or CD103), but like classic HCL is immunophenotypically and morphologically distinct from CLL. (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. Both have tumor cells that are small in size.
On lymph node biopsy, FL has a nodular growth pattern that is not seen in CLL/SLL; however, on occasion, involved lymph nodes in CLL/SLL can have prominent proliferation centers that take on a mottled "pseudo-nodular" appearance that mimics that of FL. FL also tends to be comprised of a mixture of small cells with irregular or “cleaved” nuclear contours (centrocytes) and variable numbers of larger nucleolated forms (centroblasts), whereas in most instances typical CLL cells and prolymphocytes have round to oval nuclei.
FL and CLL/SLL can also be distinguished by immunophenotype. In contrast to FL, tumor cells in CLL/SLL do not express CD10; conversely, unlike CLL/SLL, tumor cells in FL do not express CD5 (table 2). FL is also strongly associated with a (14;18) chromosome translocation involving the IGH gene and the BCL2 gene. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)
Splenic marginal zone lymphoma — Both splenic marginal zone lymphoma (SMZL) and CLL can present with splenomegaly and peripheral blood lymphocytosis (picture 5B). In addition, both CLL and SMZL can express CD23, CD43, CD5, and IgD, although expression of these is much more typical of CLL. Unlike CLL, SMZL may have bright SmIg and CD20 (table 2).
In difficult cases, pathologic evaluation of the bone marrow, spleen, and lymph nodes may be used to determine the most likely diagnosis. Notably, proliferation centers are not seen in SMZL. In addition, cytogenetic changes typically seen in CLL are not usually seen with SMZL. (See "Splenic marginal zone lymphoma".)
Histologic transformation — CLL/SLL can convert to a more aggressive histology (Richter transformation, RT), either diffuse large B cell lymphoma or Hodgkin lymphoma (picture 6) [91-95]. Affected patients usually have a rapid clinical deterioration characterized by a marked increase in lymphadenopathy at one or more sites, splenomegaly, and worsening "B" symptoms (ie, fever, night sweats, weight loss), with or without elevated serum lactate dehydrogenase (LDH). Biopsy is required to confirm the diagnosis. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)
Other patients transform to a condition that resembles B cell prolymphocytic leukemia (B-PLL). These patients often develop very high white cell counts and massive splenomegaly, and also have a poor prognosis. Diagnosis of "prolymphocytoid" transformation should be made with caution if based merely on an increase in prolymphocytes in the peripheral blood, as transient increases in these cells can be seen on occasion in patients with clinically stable CLL/SLL. (See "B cell prolymphocytic leukemia".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic lymphocytic leukemia/small lymphocytic 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 education: Chronic lymphocytic leukemia (CLL) (The Basics)")
●Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")
●Definition and epidemiology – Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a lymphoid neoplasm characterized by a progressive accumulation of monoclonal, functionally incompetent lymphocytes. The term CLL is used when the disease manifests in the blood, whereas SLL is used when involvement is primarily nodal.
CLL/SLL is the most common leukemia in Western countries. It has a male predominance and is more common in White Americans. The median age at diagnosis is approximately 70 years. There are no clearly discernible occupational or environmental risk factors. (See 'Epidemiology' above.)
●Clinical presentation – Most patients are initially asymptomatic and present with abnormalities found on routine blood counts. Some have painless swelling of lymph nodes, often in the cervical area, which may spontaneously wax and wane. Less common presentations include constitutional "B" symptoms (ie, fevers, chills, weight loss), symptoms related to acquired immunodeficiency, or autoimmune complications. (See 'Clinical presentation' above.)
Most patients have a prominent lymphocytosis in the blood and marrow at diagnosis. Neutropenia, anemia, and thrombocytopenia may also be observed at diagnosis and are usually mild. Cytopenias 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. (See 'Laboratory abnormalities' above.)
●Evaluation – Evaluation of suspected cases differs by presentation. For those with an increased lymphocyte count, we perform a complete blood count with differential and flow cytometry to determine the immunophenotype of circulating lymphocytes. For those with lymphadenopathy concerning for SLL, we perform an excisional or core biopsy of an enlarged lymph node. (See 'Evaluation and diagnosis' above.)
●Diagnosis – CLL is diagnosed when both of the following criteria are met:
•Absolute B lymphocyte count in the peripheral blood ≥5000/microL [5 x 109/L], sustained for at least three months, with a preponderant population of morphologically mature-appearing small lymphocytes. (See 'Peripheral smear' above.)
•Clonality of the circulating B lymphocytes confirmed by immunoglobulin light chain restriction (kappa or lambda) on flow cytometry.
A majority of the population should express the following markers: extremely low levels of surface membrane immunoglobulin (SmIg); expression of B cell-associated antigens (CD19, CD20 [typically dim], and CD23); and expression of CD5. (See 'Immunophenotype' above.)
The classification of patients with clonal B lymphocytes with an absolute lymphocyte count <5000/microL [5 x 109/L] depends on the number and type of the following disease manifestations: lymphadenopathy, hepatosplenomegaly, disease-related cytopenias, and disease-related symptoms.
•Patients with none of these manifestations are diagnosed with a monoclonal B cell lymphocytosis. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Monoclonal B lymphocytosis'.)
•Patients with one or more cytopenias due to bone marrow infiltration with typical CLL cells are diagnosed with CLL regardless of the absolute lymphocyte count in the peripheral blood or the presence of lymphadenopathy.
•Patients with nodal, splenic, or other extramedullary involvement and without cytopenias due to bone marrow infiltration are diagnosed with SLL.
●Differential diagnosis – The differential diagnosis of CLL/SLL includes infectious causes of lymphocytosis, monoclonal B lymphocytosis, prolymphocytic leukemia, hairy cell leukemia, and leukemic phases of mantle cell, lymphoplasmacytic, follicular, and splenic marginal zone lymphomas (table 3 and picture 5B). (See 'Differential diagnosis' above.)
ACKNOWLEDGMENTS — UpToDate acknowledges Michael J Keating, MD, and Arnold S Freedman, MD, who contributed to earlier versions of this topic review.