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Chronic lymphocytic leukemia or CLL is a common leukemia characterized by a neoplastic proliferation of well-differentiated and mature lymphocytes. Over 95% of cases are of the B-cell immunophenotype.


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SYNONYMS B-cell chronic lymphocytic leukemia
INCIDENCE 3/100,000 in USA
AGE RANGE-MEDIAN Median 65-69 years
Uncommon in Japan



Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection.

Cerroni L, Hofler G, Back B, Wolf P, Maier G, Kerl H.

Departments of Dermatology and Pathology, University of Graz, Austria.


J Cutan Pathol 2002 Mar;29(3):142-7 Abstract quote

BACKGROUND: : Cutaneous manifestations of B-cell chronic lymphocytic leukemia (B-CLL) comprise a wide spectrum of clinicopathologic presentations. In some cases, onset of skin lesions is triggered by antigenic stimulation, and specific skin infiltrates at sites of previous herpes simplex or herpes zoster infection have been well documented. Specific skin manifestations of B-CLL can also be observed at sites typical for lymphadenosis benigna cutis (nipple, scrotum, earlobe), a Borrelia burgdorferi-associated cutaneous B-cell pseudolymphoma.

METHODS: We studied specific skin manifestations of B-CLL arising at sites typical for B. burgdorferi-induced lymphadenosis benigna cutis, analyzing tissues for presence of B. burgdorferi DNA using the polymerase chain reaction (PCR) technique. Six patients with B-CLL (M : F = 4 : 2; mean age: 67.8) presented with specific skin lesions located on the nipple (four cases) and scrotum (two cases).

RESULTS: Clinically there were solitary erythematous plaques or nodules. Histology revealed in all cases a dense, monomorphous infiltrate of small lymphocytes showing an aberrant CD20+/CD43+ phenotype. In all cases monoclonality was demonstrated by PCR analysis of the JH gene rearrangement. PCR analysis showed in four of the six cases the presence of DNA sequences specific for B.burgdorferi.

CONCLUSIONS: Our study demonstrates that infection with B. burgdorferi can trigger the development of specific cutaneous infiltrates in patients with B-CLL.


Chromosomal abnormalities 13q
Expression of bcl-3 in Chronic Lymphocytic Leukemia Correlates With Trisomy 12 and Abnormalities of Chromosome 19.

Schlette E, Rassidakis GZ, Canoz O, Medeiros LJ.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston.

Am J Clin Pathol. 2005 Mar;123(3):465-71. Abstract quote  

The bcl-3 gene at chromosome 19q13 encodes a member of the IkB family involved in regulating the nuclear factor kB pathway. Originally identified by its involvement in the t(14:19)(q32;q13), bcl-3 expression recently has been reported in 12% of non-Hodgkin lymphomas and 41% of Hodgkin lymphomas.

Because the t(14;19) is detected most commonly in chronic lymphocytic leukemia (CLL), we assessed for bcl-3 expression using immunohistochemical analysis in 72 CLL cases with immunophenotypic and cytogenetic data. Of 72 CLL cases, 12 (17%) were bcl-3+. Expression of bcl-3 correlated with an atypical immunophenotype, defined using the World Health Organization scoring system. Expression also correlated with trisomy 12 and chromosome 19 abnormalities but was not limited to cases with the t(14:19)(q32;q13).

Although the mechanism of bcl-3 expression is unclear, these results raise the possibility that bcl-3 may be involved in the pathogenesis of this subset of tumors and could be a potential target for investigational therapies.


Subclinical chronic lymphocytic leukaemia associated with a 13q deletion presenting initially in the skin: apropos of a case.

Khandelwal A, Seilstad KH, Magro CM.

School of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA.

J Cutan Pathol. 2006 Mar;33(3):256-9. Abstract quote  

INTRODUCTION: B-cell chronic lymphocytic leukaemia (B-CLL) represents a low-grade B-cell lymphoproliferative disease that is the most common leukaemia in adults. The neoplastic cell is an autoreactive CD5 CD23 B lymphocyte. B-CLL may involve the skin, typically in the context of known disease. We present a case of subclinical B-CLL presenting initially in the skin.

CASE REPORT: A 73-year-old male developed a lesion on his right cheek in April 2003 compatible with basal cell carcinoma. The re-excision specimen contained a well-differentiated atypical lymphocytic infiltrate consistent with B-CLL along with residual carcinoma. Subsequent laboratory studies revealed peripheral blood lymphocytosis with smudge cells. A diagnosis was made of Rai stage 0 CLL. Chromosomal studies on peripheral blood showed a deletion at 13q14.3. Excision of a second primary skin carcinoma revealed a squamous cell carcinoma in association with B-CLL that was identical to his previously diagnosed skin involvement.

CONCLUSION: This case identifies a cutaneous presentation of subclinical B-CLL. There are two prior reports describing B-CLL presenting initially in the skin. In one case, the infiltrates were incidental on a re-excision specimen. The second report suggests 16% of B-CLL patients have cutaneous manifestations as the first sign of disease.

Concurrent Chronic Lymphocytic Leukemia Cutis and Acute Myelogenous Leukemia Cutis in a Patient with Untreated CLL

Michael K. Miller, M.D.; James A. Strauchen, M.D.; Khanh T. Nichols, M.D.; Robert G. Phelps, M.D.

From the Departments of Dermatopathology, Dermatology, and Pathology, Mount Sinai School of Medicine, New York, New York.

Am J Dermatopathology 2001;23:334-340 Abstract quote

Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL.

The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies.

This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.


Pathology of chronic lymphocytic leukemia: an update.

Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.


Ann Diagn Pathol. 2007 Oct;11(5):363-89. Abstract quote

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a clonal lymphoproliferative disorder characterized by proliferation of morphologically and immunophenotypically mature lymphocytes. CLL/SLL may proceed through different phases: an early phase in which tumor cells are predominantly small in size, with a low proliferation rate and prolonged cell survival, and a transformation phase with the frequent occurrence of extramedullary proliferation and an increase in large, immature cells. Although some patients with CLL have an indolent disease course and die after many years of unrelated causes, others have very rapidly disease progression and die of the disease within a few years of the diagnosis. In the past few years, considerable progress has been made in our ability to diagnose and classify CLL accurately.

Through cytogenetics and molecular biology, it has been shown that CLL and variants are associated with a unique genotypic profile and that these genetic lesions often have a direct bearing on the pathogenesis and prognosis of the disease. Similarly, the development of antibodies to new biologic markers has allowed the identification of a unique immunophenotypic profile for CLL and variants. Moreover, accumulating evidence suggests that CLL cells respond to selected microenvironmental signals and that this confers a growth advantage and an extended survival to CLL cells.

In this article, we will review the progress in the pathobiology of CLL and give an update on prognostic markers and tools in current pathology practice for risk stratification of CLL.

Necrotizing granulomas in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.

Blanco M, Ratzan J, Cabello-Inchausti B, Fernandes L.

Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine and the Comprehensive Cancer Center, Mt Sinai Medical Center of Greater Miami, Miami Beach, FL.

Ann Diagn Pathol 2002 Aug;6(4):216-21 Abstract quote

We present three cases of patients with B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia that were retrieved from our files during a period of 11 months and who suddenly developed lymphadenopathy.

Clinically, this lymphadenopathy was thought to represent a manifestation of their background disease and, for this reason, no cultures were performed on fresh tissue. However, histologic studies in all cases showed necrotizing granulomas. When results of our special stains were negative, we submitted the specimens for molecular studies, which demonstrated the presence of tuberculous bacilli in two out of three cases.

We believe that tuberculosis can present as a sudden lymphadenopathy in immunocompromised people and we would like to raise the awareness among the clinicians and nursing and pathology laboratory staff about the risks of handling these specimens without proper precautions. Also, we emphasize the fact that, in some cases, tuberculous bacilli cases may need molecular studies to be demonstrated.


Incidental small lymphocytic lymphoma/chronic lymphocytic leukemia in pelvic lymph nodes excised at radical prostatectomy.

Weir EG, Epstein JI.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md 21231, USA.

Arch Pathol Lab Med 2003 May;127(5):567-72 Abstract quote

CONTEXT: Incidental non-Hodgkin lymphoma is often unrecognized at the time of radical prostatectomy in patients with prostate cancer because of nonspecific symptoms and an inconspicuous pathology. The early identification of lymphoma allows optimal long-term management and prevention of significant morbidity.

OBJECTIVE: To show the subtlety of pathologic findings in cases of non-Hodgkin lymphoma in pelvic lymph nodes and the need for scrupulous attention to detail for diagnostic accuracy.

DESIGN: Histologic and immunohistochemical profiles of 18 consecutive cases of small lymphocytic lymphoma (SLL) incidentally identified in pelvic lymph node dissections were reviewed and compared with 22 cases of benign pelvic lymph node dissections.

RESULTS: Malignant nodes were grossly enlarged and averaged 3.2 cm in their greatest dimension. Histologically, 16 of the SLL cases were characterized by diffuse architectural effacement with obliterated sinuses and rare cortical follicles. Twelve of these cases showed evidence of pseudofollicles. Two cases showed an interfollicular growth pattern with occasional small pseudofollicles. In contrast, benign pelvic lymph nodes averaged 1.7 cm in their greatest dimension. Although most were architecturally distorted by fibrosis, all benign nodes were notable for patent sinuses. Immunohistochemistry was diagnostically helpful in several cases with equivocal morphology. All malignant cases had a B-cell phenotype with aberrant coexpression of T-cell-related antigens typical of SLL.

CONCLUSION: Incidental low-grade non-Hodgkin lymphoma identified at radical prostatectomy is often overlooked by both the urologist and the pathologist. Although malignant pelvic lymph node dissections frequently lack overt manifestations of lymphoma, attention to subtle morphologic features coupled with lymph node size and immunohistochemical findings should permit diagnostic accuracy.


Genetic characterization of the paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia: A case report and review of the literature.

Espinet B, Larriba I, Salido M, Florensa L, Woessner S, Sans-Sabrafen J, Barranco C, Serrano S, Sole F.

Laboratori de Citogenetica i Biologia Molecular, Departament de Patologia, Escola de Citologia Hematologica Soledad Woessner-IMAS, Barcelona, Spain.

Hum Pathol 2002 Nov;33(11):1145-8 Abstract quote

Paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is characterized by a diffuse proliferation of cells, called paraimmunoblasts, normally located on the pseudoproliferation centers. Patients usually present with multiple lymphadenopathies and a rapid and aggressive progression of the disease.

We report a case with paraimmunoblastic variant of SLL/CLL genetically well-characterized by conventional cytogenetics, comparative genomic hybridization (CGH), IgH/BCL-1, IgH/BCL-2, and p53 fluorescent in situ hybridization (FISH) probes and polymerase chain reaction (PCR) for detection of IgH/BCL-2 translocation. A complex karyotype was found, with p53 deletion confirmed by CGH and FISH; however, no translocations involving either BCL-2 or BCL-1 and the immunoglobulin heavy chain gene were identified.

A literature review shows only 20 previously reported cases, 6 of which involve genetic studies.

Paraimmunoblastic variant of small lymphocytic lymphoma/leukemia.

Pugh WC, Manning JT, Butler JJ.

Department of Pathology, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.


Am J Surg Pathol 1988 Dec;12(12):907-17 Abstract quote

We report 16 cases of a distinctive, biologically aggressive variant of small lymphocytic lymphoma/leukemia (SLL/L) that is characterized by the diffuse proliferation of cells normally comprising the pseudoproliferation centers (so-called paraimmunoblasts).

Demographically, the patients differed in no significant regard from patients with SLL/L of usual type. Rapidly progressive, generalized lymphadenopathy was the dominant clinical finding in 15 of the 16 patients; one patient presented with symptoms related to lymphomatous involvement of the stomach and regional lymph nodes. Splenomegaly was observed in five patients. Seven patients, two of whom had a history of indolent-phase chronic lymphocytic leukemia, had an absolute lymphocytosis at diagnosis.

In most patients, bone marrow involvement was noted at diagnosis. It consisted predominantly of small lymphocytic infiltrates indistinguishable from those observed in SLL/L of usual type; significant paraimmunoblastic infiltration was infrequent and generally occurred late in the disease course. Immunohistochemical and cytogenetic study further substantiated the hypothesized relationship of these cases to SLL/L. Findings included (a) coexpression of sIg and Leu-1 antigen in the majority of cases and (b) the presence of a t(11;14) (q13;q32) chromosome translocation in two of three cases with analyzable metaphases.

Although treatment protocols were not uniform, follow-up data indicated an accelerated clinical course. Eleven patients have died of their disease between 3 and 39 months after diagnosis; the median survival was 28 months.


Hypogammaglobulinemic 50-75% of patients
Decrease in IgG most common
IgG autoimmune hemolytic anemia 15-35% of patients
Primary red blood cell aplasia  

High Resolution Immunophenotypic Analysis of Chronic Lymphocytic Leukemic Cells by Enzymatic Amplification Staining

David Kaplan, MD, PhD
Howard Meyerson, MD
Kristine Lewandowska, MS

Am J Clin Pathol 2001;116:429-436 Abstract quote

Immunophenotypic analysis of chronic lymphocytic leukemia (CLL) cells is essential for the diagnosis of this disorder. Unfortunately, surface immunoglobulin light chains and CD79b are expressed faintly or not at all by CLL cells from many patients.

We developed an enzymatic amplification staining procedure that amplifies the fluorescent signal by 10- to 100-fold. By using this technology, we have been able to resolve immunoglobulin light chain exclusion and CD79b expression on the cells from most cases.

This new capability can be used for high-resolution immunophenotypic analysis of leukemias and lymphomas.

Flow Cytometric Analysis of CD5+ B Cells A Frame of Reference for Minimal Residual Disease Analysis in Chronic Lymphocytic Leukemia

Ritu Gupta, MD, Paresh Jain, MD, S.V.S. Deo, MS, and Atul Sharma, MD, DM
Am J Clin Pathol 2004;121:368-372 Abstract quote

Recent reports suggest that CD5+ B cells constitute up to 47% of the total B cells in normal peripheral blood (PB), a finding that would restrict the sensitivity of the CD5/CD19 flow cytometric assay for minimal residual disease (MRD) analysis in chronic lymphocytic leukemia (CLL).

We studied 40 normal samples (PB, 20; bone marrow [BM], 20) using CD5–fluorescein isothiocyanate (FITC)/CD19-phycoerythrin (PE) immunostaining to evaluate the reference range of CD5+ B cells. The mean percentage of CD5+ B cells per total number of B cells was 12.2% (range, 3.6%-23.9%) in PB and 11.7% (range, 4.4%-19.5%) in BM. On serial dilution, this assay could detect 1 CLL cell in 1,000 leukocytes (sensitivity, 0.1%). A distinct "bright" CD5+ B-cell subpopulation, consistent with a CLL-like-phenotype, was observed in 3 samples.

Our results suggest that the CD5-FITC/CD19-PE assay has a clinically useful sensitivity for MRD analysis in CLL. The usefulness of this assay as a screening tool to identify the earliest stage of indolent CLL needs further study.



Clumped nuclear chromatin exhibiting a compartmentalization phenomenon

May vary from medium to large size

Diffuse and dark blue staining lymphoid tissue on low power magnification
Scattered throughout are pale staining, rounded non-expansile foci representing proliferation centers (pseudofollicles)-DIAGNOSTIC of B-CLL/SLL

Pale foci composed of small to medium-sized cells with distinct nucleoli (prolymphocytes and paraimmunoblasts) with a background of small lymphocytes

Peripheral Blood Absolute lymphocyte count >5x10*9
Bone marrow Diffuse, focal, or interstitial distribution
Increased reticulin fibers in 25% of cases
Increasing splenomegaly and lymphadenopathy
Increased prolymphocytes in the blood
ATYPICAL B-CLL >10% circulating prolymphocytoid cells or >10% circulating cells with cleaved nuclei or plasmacytoid features
Much larger proliferation centers
More likely than classical B-CLL to show trisomy 12

Atypical Chronic Lymphocytic Leukemia Differ Clinically and Immunophenotypically

John L. Frater, MD
Karen F. McCarron, MD
Jeffrey P. Hammel, MS
Joel L. Shapiro, MD
Michael L. Miller, DO
Raymond R. Tubbs, DO
James Pettay, MT(ASCP)
and Eric D. Hsi, MD

Am J Clin Pathol 2001;116:655-664 Abstract quote

We compared the features of 17 cases of atypical chronic lymphocytic leukemia (aCLL) with those of a clinical control group of 24 cases of CLL.

Quantitative flow cytometric data, available for 12 cases, were compared with an immunophenotypic control group of 58 cases using a relative fluorescence index for CD5, CD23, CD79b, and surface immunoglobulin light chain (sIg).

Compared with the clinical control group, patients with aCLL had a higher mean WBC count and a lower platelet count. Patients with aCLL had a significantly higher probability of disease progression. Compared with an immunophenotypic control group of 58 CLL cases, 12 cases of aCLL demonstrated significantly higher expression of CD23. There was no significant difference in expression of sIg, CD79b, or CD5 between the groups. CD38 expression was noted in only 1 (9%) of 11 tested cases; 2 (18%) of 11 cases had trisomy 12.

aCLL can be distinguished from typical CLL morphologically, clinically, and immunophenotypically. Atypical morphologic features in CLL seem to be a marker of aggressive clinical behavior.

The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Soma LA, Craig FE, Swerdlow SH.

Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-2582, USA.

Hum Pathol. 2006 Feb;37(2):152-9. Epub 2006 Jan 10. Abstract quote  

Prognostication in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) based, in part, on ZAP-70 and CD38 expression, and to a lesser extent, on MUM1/IRF4 expression, is currently of great interest. The more aggressive type of CLL/SLL is reportedly characterized by neoplastic cells that are more responsive to B-cell signaling with proliferation centers (PCs), a potentially important site of neoplastic cell stimulation.

To study the relationship of these markers to each other and to the pattern of PCs, immunohistochemical stains for ZAP-70 and MUM1/IRF4 were performed and the PC patterns assessed (where possible) in 29 tissue biopsies with CLL/SLL. CD38 expression was assessed in 18 cases using flow cytometry. Ten evaluable cases had a typical PC pattern and 16 an atypical pattern with larger or more confluent PCs and/or more numerous paraimmunoblasts/transformed cells. ZAP-70 was positive in 14 of 28 cases, including 3 with atypical PCs and enhanced PC staining. All 29 cases showed MUM1/IRF4 expression in PCs. Seven cases, none with atypical PC, also showed uniform positivity throughout, 14 showed weaker staining of surrounding lymphocytes, and 8 had PC staining only. CD38 was positive in 14 of 18 cases. The only significant association identified was between uniform MUM1/IRF4 positivity and typical PCs (P = .004).

These findings highlight the complex interrelationship of prognostic markers in CLL/SLL and demonstrate potentially important microenvironmental variations in their expression. They support the hypothesis that PCs are a site for B-cell receptor signaling, which helps explain reported site-dependent antigenic variation in CLL/SLL, and suggest that PC morphology may correlate with other biological features.

Rare transformation with weight loss, fever, localized lymphadenopathy, dysgammaglobulinemia

Large cell lymphoma which has evolved from the CLL
Death often within 1 year
Large cells may or may not be clonally related to B-CLL
Sometimes supervening Hodgkin lymphoma is also considered a special type of Richter syndrome

Distinct Clonal Origin in Two Cases of Hodgkin's Lymphoma Variant of Richter's Syndrome Associated With EBV Infection.

De Leval L, Vivario M, De Prijck B, Zhou Y, Boniver J, Harris NL, Isaacson P.

*Department of Pathology, CHU Sart-Tilman, Liege, Belgium; Department of Hematology, CHR Citadelle, Liege, Belgium; the Department of Histopathology, University College London, UK; and the Department of Pathology, Massachusetts General Hospital, Boston, MA.
Am J Surg Pathol. 2004 May;28(5):679-686. Abstract quote  

Occurrence of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL), clinically referred to as Richter's syndrome, occasionally manifests as a lymphoproliferation resembling Hodgkin's lymphoma (HL) and often containing the Epstein-Barr virus (EBV). Only a limited number of HL variants have been subject to informative analysis regarding their clonal relationship to the CLL, with evidence of a same clonal origin in some cases and of clonally unrelated neoplasms in other cases.

In this paper, we performed a detailed pathologic, virologic, and molecular analysis of two cases of Richter's syndrome with HL features. The first case occurred in a 65-year-old man with a 5-year history of CLL as a mediastinal and supraclavicular mass histologically diagnosed as lymphocyte depleted HL with no background CLL. The second case occurred in a 78-year-old woman with a 4-year history of CLL as an inguinal mass with a composite histologic appearence comprising areas of CLL, areas of CLL with Hodgkin Reed-Sternberg cells, and areas of HL. Both patients had received fludarabine therapy. The HRS cells were CD20-/CD30+/CD15-/J-chain- in case no. 1 and CD20+/-/CD30+/CD15-/J-chain- in case no. 2. In both cases, the Hodgkin's Reed-Sternberg cells (HRS) were positive for type A EBV, and a 30-bp deletion of the LMP-1 gene was detected in case no. 2. Using microdissection and polymerase chain reaction amplification of the immunoglobulin heavy chain gene (IgH) complementarity determining region III of each cell type, we demonstrated a distinct clonal origin for the CLL cells and the HRS in both cases.

These cases bring support to the hypothesis that EBV+ HL in CLL patients occurs as unrelated secondary neoplasms most likely as the result of the immune depression associated with CLL and also raise the question of a possible causal role of fludarabine.
Clonal T-cell Populations and Increased Risk for Cytotoxic T-cell Lymphomas in B-CLL Patients: Clinicopathologic Observations and Molecular Analysis.

Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, Montserrat E, Campo E, Jaffe ES.

*Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; and the daggerHematopathology Unit, Laboratory of Pathology and Department of Hematology Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Am J Surg Pathol. 2004 Jul;28(7):849-858. Abstract quote  

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare.

We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells.

The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.


Positive Surface Ig
Occasionally Positive CD11c
Negative CD3
Bimodal Cell Populations Are Common in Chronic Lymphocytic Leukemia but Do Not Impact Overall Survival

Amy E. Cocco, MD, etal.
Am J Clin Pathol 2005;123:818-825 Abstract quote

Flow cytometric histograms were evaluated for bimodal antigen expression on samples from 246 patients diagnosed with chronic lymphocytic leukemia (CLL) at University Hospitals of Cleveland, Cleveland, OH. Survival data were obtained, and the clinical significance of bimodality was evaluated using the Kaplan-Meier method and the log-rank test.

Bimodal antigen expression was found in 107 cases (43.5%). CD38 and CD13 were the most common antigens to demonstrate bimodality at 14.5% and 12.9%, respectively, and CD20, CD11c, CD5, FMC-7, and surface immunoglobulin also were frequently bimodal. Bimodal antigen expression, the number of bimodal antigens, and bimodality of a specific antigen were not associated with decreased survival in patients with CLL, although bimodality for CD38 trended toward worse overall survival.

Therefore, although bimodal antigen expression is common in CLL, the presence of bimodality does not seem to have significant prognostic importance.

Higher Levels of Surface CD20 Expression on Circulating Lymphocytes Compared With Bone Marrow and Lymph Nodes in B-Cell Chronic Lymphocytic Leukemia

Yang O. Huh, MD
Michael J. Keating, MD
Helene L. Saffer, MD
Iman Jilani, MS
Susan Lerner, MS
Maher Albitar, MD

Am J Clin Pathol 2001;116:437-443 Abstract quote

Differential expression of CD20 surface antigen in B-cell neoplasms at different sites is largely unknown. The number of CD20 antibodies bound per cell (CD20 ABC) in bone marrow (BM), peripheral blood (PB), and lymph node aspirate (LNA) samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) or other B-cell disease was studied using quantitative flow cytometry.

CD20 ABC differed significantly with the specimen type in B-CLL, being highest in PB (mean, 9,051) and lower in BM (mean, 4,067) and LNA (mean, 3,951). No difference in CD20 ABC between BM and PB samples was found in splenic lymphoma, mantle cell lymphoma, or follicular lymphoma. Also, we found a significant difference of CD20 ABC by type of disease: lowest in B-CLL; higher in splenic, follicular, and mantle cell lymphoma; and highest in hairy cell leukemia.

The lower CD20 surface antigen levels in BM and LNA than in PB in B-CLL may have clinical relevance with regard to the efficacy of rituximab therapy.

Diagnostic Usefulness of Aberrant CD22 Expression in Differentiating Neoplastic Cells of B-Cell Chronic Lymphoproliferative Disorders From Admixed Benign B Cells in Four-Color Multiparameter Flow Cytometry

James Huang, MD, Guang Fan, MD, PhD, Yanping Zhong, MD, Ken Gatter, MD, Rita Braziel, MD, JD, Gary Gross, and Antony Bakke, PhD
Am J Clin Pathol 2005;123:826-832 Abstract quote

The diagnosis of B-cell chronic lymphoproliferative disorders is a great challenge when made in a background of polyclonal B cells.

We studied the diagnostic usefulness of aberrant CD22 expression for differentiating neoplastic from benign B cells by 4-color flow cytometry. Of 56 cases of B-cell chronic lymphoproliferative disorders, we found that neoplastic cells showed aberrant CD22 expression in 39 (70%) of 56 cases, including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia, and follicular lymphoma. In 4 cases, monoclonality was detected definitively only by evaluating the immunoglobulin light chain restriction in B cells with aberrant CD22 expression because numerous polyclonal B cells were present.

Aberrant CD22 expression is a useful marker for detection of monoclonal B cells admixed with numerous benign polyclonal B cells.

CD79b expression in chronic lymphocytic leukemia. Association with trisomy 12 and atypical immunophenotype.

Schlette E, Medeiros LJ, Keating M, Lai R.

Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Arch Pathol Lab Med 2003 May;127(5):561-6 Abstract quote

CONTEXT: CD79b is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases.

OBJECTIVE: To systematically correlate CD79b expression with specific morphologic and immunophenotypic findings and trisomy 12.

DESIGN: We assessed CD79b expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79b expression, we then assessed 43 additional CLL cases with trisomy 12. CD79b expression was correlated with morphology and expression of other immunophenotypic markers.

RESULTS: Eighteen (18%) of 100 consecutively accrued cases were CD79b positive. No significant association was found between CD79b expression and atypical morphology. CD79b expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79b positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases with trisomy 12 (including 8 cases from the initial study group) showed that CD79b was positive in 26 cases (49%), a frequency significantly higher than that of the consecutively accrued CLL cases without trisomy 12 (P <.05).

CONCLUSIONS: We conclude that CD79b immunoreactivity is positive in approximately 20% of CLL cases and that expression correlates with trisomy 12 and atypical immunophenotypic findings.



Leukemic phase of B-cell lymphomas mimicking chronic lymphocytic leukemia and variants at presentation.

Nelson BP, Variakojis D, Peterson LC.

Section of Hematopathology, Northwestern University Medical School, Chicago, Illinois.


Mod Pathol 2002 Nov;15(11):1111-20 Abstract quote

Six cases of non-Hodgkin B-cell lymphoma that mimicked either chronic lymphocytic leukemia (CLL) or a CLL variant at presentation are reported. The patients ranged from 54 to 89 years and included three females and three males. All six patients had prominent peripheral blood lymphocytosis at presentation; the initial morphologic impression was CLL in three cases, CLL/prolymphocytic leukemia (PLL) in two cases, and PLL in one. Five patients had bone marrow biopsies; each showed a lymphoid infiltrate in a focally random, interstitial, and/or diffuse pattern.

Flow cytometric immunophenotyping showed CD20-positive B cells with surface immunoglobulin (Ig) light chain restriction in all six patients. The five cases resembling CLL or CLL/PLL had at least a subset of CD5-positive B cells, whereas CD5 was absent in the one case that resembled PLL. CD23 was positive in three of the four cases studied that resembled CLL or CLL/PLL; CD79b was positive in three, FMC7 was positive in two, and surface Ig and CD20 were brightly positive in three. A t(11;14) (q13;q32) was found in four cases that resembled CLL or CLL/PLL; they were subsequently diagnosed as mantle cell lymphoma. The remaining two cases mimicking CLL or PLL were diagnosed as lymphomas of follicle center origin with leukemic phase based on the presence of t(14;18) (q32;q21).

Thus although the morphology of these six cases resembled CLL or variants, and immunophenotyping by flow cytometry showed overlapping features, genetic studies enabled distinction of these leukemic non-Hodgkin lymphoma from chronic lymphocytic leukemia or variants.

Intravascular bone marrow accumulation in persistent polyclonal lymphocytosis: a misleading feature for B-cell neoplasm.

Feugier P, De March AK, Lesesve JF, Monhoven N, Dorvaux V, Braun F, Gregoire MJ, Jonveaux P, Lederlin P, Bene MC, Labouyrie E.

Department of Hematology-Internal Medicine, University Hospital of Nancy, France.
Mod Pathol. 2004 Sep;17(9):1087-96. Abstract quote  

Persistent polyclonal B-cell lymphocytosis is usually reported in young smoking women. Whether this syndrome represents a premalignant or benign disease remains unclear. Indeed, because of the association of Bcl-2/IgH rearrangement and cytogenetic abnormalities, such cases may be misdiagnosed as the leukemic phase of a non-Hodgkin's lymphoma.

We report eight new cases of persistent polyclonal B-cell lymphocytosis, which displayed a misleading bone marrow histological pattern, that is, intravascular B-cell infiltrate, constantly associated with Bcl-2 immunohistostaining, as seen in some lymphoma. We also show the absence or low expression of adhesion molecules on persistent polyclonal B-cell lymphocytes, suggesting that migration abnormalities might lead to bone marrow and peripheral blood accumulation. Although most cases presented multiple Bcl-2/IgH gene rearrangements and appeared to be polyclonal, oligoclonal expansion was identified in one out of eight patients, yet was not associated with clinical aggressiveness. The occasional reports of oligoclonal IgH and Bcl-2/IgH rearrangements in this disorder suggest that polyclonal expansion may be followed by the emergence of a predominant clone.

However, the benign clinical course and lack of biological evolution in most cases imply that it is mandatory to distinguish this disorder from other malignant lymphoproliferations, so that unnecessary aggressive therapy can be avoided.

Mature B-cell leukemias with more than 55% prolymphocytes: report of 2 cases with Burkitt lymphoma-type chromosomal translocations involving c-myc.

Merchant S, Schlette E, Sanger W, Lai R, Medeiros LJ.

Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Arch Pathol Lab Med 2003 Mar;127(3):305-9 Abstract quote

CONTEXT: The molecular genetic events involved in the pathogenesis of mature B-cell leukemias with more than 55% prolymphocytes are not well characterized. We have encountered 2 such cases in which conventional cytogenetic analysis identified Burkitt lymphoma-type chromosomal translocations involving 8q24.

OBJECTIVE: To assess these 2 cases for involvement of the c-myc gene using fluorescence in situ hybridization analysis with probes specific for the c-myc and immunoglobulin heavy-chain (IgH) genes.

RESULTS: In both cases, conventional cytogenetic analysis demonstrated complex karyotypes, including chromosomal translocations involving 8q24. In case 1, a case of de novo prolymphocytic leukemia, the t(8;14)(q24;q32) was detected. In case 2, a case of chronic lymphocytic leukemia in prolymphocytoid transformation, the t(8;22)(q24;q11) was identified. Fluorescence in situ hybridization studies showed c-myc/IgH fusion signals in case 1, proving the presence of the t(8;14). Split c-myc signals without fusion to IgH were observed in case 2, proving c-myc gene rearrangement and consistent with the t(8;22).

CONCLUSION: These results suggest that c-myc gene alterations may be involved in the pathogenesis of a subset of mature B-cell leukemias with more than 55% prolymphocytes.


0 Lymphocytosis in blood and bone marrow only >120
I Lymphocytosis and lymphadenopathy 95
II Lymphocytosis and hepatomegaly or splenomegaly, or both; enlarged lymph nodes may or may not be present 72
III Lymphocytosis and anemia (Hb,10 g/dL);
Lymph nodes, spleen, and liver may or may not be enlarged
IV Lymphocytosis and thrombocytopenia (platelets <100x10*9/L)
Anemia and organomegaly may or may not be present


A Hb>/=10 g/dL
Platelets >/=100x10*9/L
</=three anatomic sites involved
B Hb>/=10 g/dL
Platelets >/=100x10*9/L
>/=three anatomic sites involved
C Hb<10 g/dL
Platelets <100x10*9/L or both, regardless of the anatomic sites involved
  Anatomic sites include cervical, axillary, and inguinal lymph nodes (unilateral or bilateral), spleen, and liver  
Phenotypic Heterogeneity of B Cells in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Bal Kampalath, MD
Maurice P. Barcos, MD, PhD
and Carleton Stewart, PhD

Am J Clin Pathol 2003;119:824-832 Abstract quote

Although some studies have examined the expression of aberrant markers such as CD2, CD7, CD10, CD13, CD33, and CD34 on B cells in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a uniform multiparametric analysis of the frequency of expression of these markers using stringent criteria is lacking.

By using 3-color flow cytometry, we analyzed 117 cases (bone marrow, 71; blood, 31; lymph nodes, 15) for coexpression of aberrant markers with CD19. Marker expression was considered positive when present on at least 20% of CD19+ cells. Of 117 cases, 40 (34.2%) showed expression of 1 or more aberrant markers. Expression of 4 aberrant markers was seen in 1 case, 3 in 4 cases, 2 in 15 cases, and 1 in 20 cases.

Kaplan-Meier survival curves and the log-rank test revealed that the group with aberrant markers showed significantly shortened overall survival compared with the group without aberrant markers (P < .001).

There is considerable phenotypic heterogeneity in CLL/SLL, and expression of aberrant markers indicates aggressiveness.

Comparative analysis of flow cytometric techniques in assessment of ZAP-70 expression in relation to lgVH mutational status in chronic lymphocytic leukemia.

Department of Pathology, John H Stroger, Jr Hospital of Cook County, Chicago, IL, USA.


Am J Clin Pathol. 2007 Feb;127(2):182-91. Abstract quote

We compared 1 subjective and 5 objective flow cytometric methods to evaluate zeta-associated protein (ZAP-70) expression in relation to immunoglobulin heavy-chain variable-region (IgVH) gene mutational status in 154 samples from 125 patients with chronic lymphocytic leukemia (CLL). ZAP-70 expression determined by all methods used correlated with IgVH gene mutational status, but none of them demonstrated high concordance rates.

Of the objective methods, ZAP-70 staining determined as a ratio of molecules of equivalent soluble fluorochrome intensity in CLL cells to that in normal B cells (ZAP-70+ staining in IgVH germline cases, 59%; ZAP-70- in IgVH mutated cases, 75%) or T cells (ZAP-70+ in IgVH germline cases, 66%; ZAP-70- in IgVH mutated cases, 57%) provides the best combination for assigning ZAP-70+ status to IgVH germline and ZAP-70- status to IgVH mutated cases.

The subjective method based on ZAP-70 expression in natural killer/T cells gave a similar result, but reproducibility between laboratories may be difficult. Further studies on ZAP-70 expression in relation to clinical parameters may address whether ZAP-70 is an independent prognostic marker for CLL.

Flow Cytometric Detection of ZAP-70 in Chronic Lymphocytic Leukemia: Correlation With Immunocytochemistry and Western Blot Analysis
Graham W. Slack, MD; Juanita Wizniak, BSc; Laith Dabbagh, MSc; Xinzhe Shi, MD; Pascal Gelebart, PhD; Raymond Lai, MD, PhD

From the Department of Laboratory Medicine and Pathology, University of Alberta (Drs Slack, Shi, Gelebart, and Lai); and the Department of Laboratory Medicine and Pathology, Cross Cancer Institute (Ms;thWizniak, Mr Dabbagh, and Drs Gelebart and Lai), Edmonton, Alberta


Archives of Pathology and Laboratory Medicine: Vol. 131, No. 1, pp. 50–56.

Expression of ZAP-70 in chronic lymphocytic leukemia (CLL) predicts worse clinical outcome in patients with early-stage disease. It has become important to include ZAP-70 in the immunophenotyping panel used to diagnose CLL, commonly performed by flow cytometry (FC). Nevertheless, the methodology used to detect ZAP-70 by FC has not been extensively evaluated.

Objective.—To describe our FC method for detecting ZAP-70 in CLL and assess whether this assay is useful in estimating the ZAP-70 protein level in CLL cells.


Design.—ZAP-70 expression was assessed by FC in 45 consecutive newly diagnosed CLL patients, and the results were correlated with those of immunocytochemistry and Western blot analysis.

Results.—With >25% ZAP-70–positive B cells as the cutoff, the FC results had a perfect concordance with those of immunocytochemistry (39/39, 100%) and Western blot analysis (7/7, 100%). The use of autofluorescence controls was found to be superior to other alternatives. Overall, 19 (42%) of 45 cases were ZAP-70 positive in our series. Since only 7 cases (16%) had >20% to 30% ZAP-70–positive B cells, the cutoff of >25% readily separated CLL into positive and negative groups in most cases. ZAP-70 positivity was significantly associated with atypical morphology but not other laboratory parameters evaluated.

Conclusions.—With proper specimen processing and the use of directly fluorescence-conjugated anti–ZAP-70 antibody, one can readily incorporate ZAP-70 into the routine FC study panel for CLL. Our data suggest that FC is a rapid and useful method to estimate the ZAP-70 protein expression level in CLL.


Blood 1998;92 (suppl 1):414a
Eur J Haematol 1999;62:76-82

Monoclonal anti-CD20 antibody therapy
May act via antibody dependent cell mediated cytotoxicity

Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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