How to Diagnose and Treat CD5-Positive Lymphomas Involving the Spleen

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5–10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen.

Download Full-text

Cortactin expression in non-Hodgkin B-cell lymphomas: a new marker for the differential diagnosis between chronic lymphocytic leukemia and mantle cell lymphoma

Human Pathology ◽

10.1016/j.humpath.2018.10.038 ◽

2019 ◽

Vol 85 ◽

pp. 251-259 ◽

Cited By ~ 1

Author(s):

Marco Pizzi ◽

Livio Trentin ◽

Andrea Visentin ◽

Deborah Saraggi ◽

Veronica Martini ◽

...

Keyword(s):

Differential Diagnosis ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

B Cell Lymphomas ◽

Mantle Cell

Download Full-text

Expert-independent classification of mature B-cell neoplasms using standardized flow cytometry: a multicentric study

Blood Advances ◽

10.1182/bloodadvances.2021005725 ◽

2021 ◽

Author(s):

Sebastian Böttcher ◽

Robby Engelmann ◽

Georgiana Grigore ◽

Paula Carolina Fernandez ◽

Joana Caetano ◽

...

Keyword(s):

Flow Cytometry ◽

Differential Diagnosis ◽

Follicular Lymphoma ◽

B Cell ◽

Diagnostic Algorithm ◽

Lymphocytic Leukemia ◽

B Cell Lymphomas ◽

Multicentric Study ◽

Predictive Values ◽

Large B Cell

Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing nine disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis we subsequently utilized Canonical Correlation Analysis of 176 training cases to project the multi-dimensional space of all 26 immunophenotypic parameters into 36 two-dimensional plots for each possible pair-wise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%) and mantle cell lymphoma (95.4%). Burkitt and CD10+ diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD10- diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.

Download Full-text

The immunophenotype of splenic lymphoma with villous lymphocytes and its relevance to the differential diagnosis with other B-cell disorders

Blood ◽

10.1182/blood.v83.6.1558.bloodjournal8361558 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1558-1562 ◽

Cited By ~ 1

Author(s):

E Matutes ◽

R Morilla ◽

K Owusu-Ankomah ◽

A Houlihan ◽

D Catovsky

Keyword(s):

Differential Diagnosis ◽

Monoclonal Antibodies ◽

B Cell ◽

Hairy Cell Leukemia ◽

Lymphocytic Leukemia ◽

Low Grade ◽

Hairy Cell ◽

Cell Leukemia ◽

Splenic Lymphoma ◽

Weak Surface

Splenic lymphoma with villous lymphocytes (SLVL) is a low-grade disorder that regularly presents with peripheral blood involvement. We describe the immunophenotype of the circulating cells from 100 SLVL patients whose disease has been characterized on clinical, morphologic, and histologic grounds. Cells from all cases expressed B-cell antigens (CD19 and CD37) and/or HLA-Dr and showed light chain restriction (kappa/lambda: 1.5/1) with moderate to strong intensity of membrane Ig staining. Cells from most cases (> 80%) were CD24+, FMC7+, and expressed strongly membrane CD22. The monoclonal antibodies CD10, CD23, and CD38 were positive in one-third of the cases; CD11c in 47%; and CD25 in 25% of cases. A minority of cases (< 20%) were positive with HC2, B-ly-7, and CD5. However, none of the 19 CD5+ cases had the phenotype characteristic of chronic lymphocytic leukemia (CD5+, CD23+, FMC7-, weak surface Ig and membrane CD22). None of the 17 CD25+ cases had the immunophenotype typical of hairy cell leukemia (CD25+, CD11c+, HC2+, B-ly-7+). HC2 and B-ly-7 were the most useful reagents to distinguish SLVL from hairy cell leukemia. Our findings demonstrate that SLVL has a distinct immunologic profile and that monoclonal antibodies are important for the differential diagnosis between this disease and other B-lymphoproliferative disorders with which SLVL can be confused.

Download Full-text

The immunophenotype of splenic lymphoma with villous lymphocytes and its relevance to the differential diagnosis with other B-cell disorders

Blood ◽

10.1182/blood.v83.6.1558.1558 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1558-1562 ◽

Cited By ~ 123

Author(s):

E Matutes ◽

R Morilla ◽

K Owusu-Ankomah ◽

A Houlihan ◽

D Catovsky

Keyword(s):

Differential Diagnosis ◽

Monoclonal Antibodies ◽

B Cell ◽

Hairy Cell Leukemia ◽

Lymphocytic Leukemia ◽

Low Grade ◽

Hairy Cell ◽

Cell Leukemia ◽

Splenic Lymphoma ◽

Weak Surface

Abstract Splenic lymphoma with villous lymphocytes (SLVL) is a low-grade disorder that regularly presents with peripheral blood involvement. We describe the immunophenotype of the circulating cells from 100 SLVL patients whose disease has been characterized on clinical, morphologic, and histologic grounds. Cells from all cases expressed B-cell antigens (CD19 and CD37) and/or HLA-Dr and showed light chain restriction (kappa/lambda: 1.5/1) with moderate to strong intensity of membrane Ig staining. Cells from most cases (> 80%) were CD24+, FMC7+, and expressed strongly membrane CD22. The monoclonal antibodies CD10, CD23, and CD38 were positive in one-third of the cases; CD11c in 47%; and CD25 in 25% of cases. A minority of cases (< 20%) were positive with HC2, B-ly-7, and CD5. However, none of the 19 CD5+ cases had the phenotype characteristic of chronic lymphocytic leukemia (CD5+, CD23+, FMC7-, weak surface Ig and membrane CD22). None of the 17 CD25+ cases had the immunophenotype typical of hairy cell leukemia (CD25+, CD11c+, HC2+, B-ly-7+). HC2 and B-ly-7 were the most useful reagents to distinguish SLVL from hairy cell leukemia. Our findings demonstrate that SLVL has a distinct immunologic profile and that monoclonal antibodies are important for the differential diagnosis between this disease and other B-lymphoproliferative disorders with which SLVL can be confused.

Download Full-text

Splenic B-Cell Lymphomas with Diffuse Cyclin D1 Protein Expression and Increased Prolymphocytic Cells: A Previously Unrecognized Diagnostic Pitfall

Case Reports in Hematology ◽

10.1155/2018/5761953 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9

Author(s):

Khaled Algashaamy ◽

Yaohong Tan ◽

Nicolas Mackrides ◽

Alvaro Alencar ◽

Jing-Hong Peng ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Cyclin D1 ◽

D1 Protein ◽

Diagnostic Errors ◽

Lymphocytic Leukemia ◽

Splenic Marginal Zone Lymphoma ◽

B Cell Lymphomas ◽

Prolymphocytic Leukemia ◽

Diagnostic Pitfall

Prolymphocytic transformation is a concept usually applied in the context of chronic lymphocytic leukemia/small lymphocytic lymphoma to describe the presence of a high percentage of prolymphocytes in peripheral blood (usually more than 55%). Prolymphocytic transformation has also been reported in mantle cell lymphoma (MCL) but only rarely in splenic marginal zone lymphoma (SMZL). We present two splenic B-cell lymphomas presenting in the leukemic phase and with increased prolymphocytes, both classified as SMZL with prolymphocytic transformation. One case clinically simulated B-prolymphocytic leukemia (B-PLL). Both lymphomas were very unusual because the tumor cells diffusely and strongly expressed cyclin D1 despite lacking the t(11; 14)(q13; q32) as detected by several approaches including next-generation sequencing, fluorescence in situ hybridization using CCND1 break apart probe and fusion probes for t(11; 14)(q13; q32), and conventional karyotyping. These cases therefore simulated prolymphocytic variants of MCL. The incidence of this phenomenon is unknown, and awareness of this potential alternate protein expression pattern is important in order to avoid diagnostic errors.

Download Full-text

Lack of Association of Human Herpesvirus 6 (hHV-6) with Chronic Lymphocytic Leukemia and Leukemic Low-Grade B-Cell Lymphomas

Internal Medicine Open Access ◽

10.4172/2165-8048.1000273 ◽

2018 ◽

Vol 08 (03) ◽

Author(s):

Panagiotis Diamantopoulos ◽

Christina Nefeli Kontandreopoulou ◽

Theodoros Vassilakopoulos ◽

Maria Angelopoulou ◽

Marina Mantzourani ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Human Herpesvirus ◽

Lymphocytic Leukemia ◽

Low Grade ◽

Human Herpesvirus 6 ◽

B Cell Lymphomas ◽

Herpesvirus 6

Download Full-text

Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling

Cancers ◽

10.3390/cancers13051002 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1002

Author(s):

Ryan N. Rys ◽

Claudia M. Wever ◽

Dominique Geoffrion ◽

Christophe Goncalves ◽

Artin Ghassemian ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Poor Response ◽

Lymphocytic Leukemia ◽

Low Grade ◽

High Grade ◽

Microtubule Inhibitors ◽

Mantle Cell ◽

Induced Apoptosis

To determine causes of apoptotic resistance, we analyzed 124 primary B cell NHL samples using BH3 profiling, a technique that measures the mitochondrial permeabilization upon exposure to synthetic BH3 peptides. Our cohort included samples from chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high-grade B cell lymphoma with translocations in MYC and BCL2 (HGBL-DH), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). While a large number of our samples displayed appropriate responses to apoptosis-inducing peptides, pro-apoptotic functional defects, implicating BAX, BAK, BIM or BID, were seen in 32.4% of high-grade NHLs (12/37) and in 3.4% of low-grade NHLs (3/87, p < 0.0001). The inhibition of single anti-apoptotic proteins induced apoptosis in only a few samples, however, the dual inhibition of BCL2 and MCL1 was effective in 83% of samples, indicating MCL1 was the most common cause of lack of response to the BCL2 inhibitor, venetoclax. We then profiled Toledo and OCI-Ly8 high-grade lymphoma cell lines to determine which drugs could reduce MCL1 expression and potentiate venetoclax responses. Doxorubicin and vincristine decreased levels of MCL1 and increased venetoclax-induced apoptosis (all p < 0.05). Overall, in primary NHLs expressing BCL2 that have no defects in pro-apoptotic signaling, a poor response to venetoclax is primarily due to the presence of MCL1, which may be overcome by combining venetoclax with doxorubicin and vincristine-based chemotherapy or with other anti-microtubule inhibitors.

Download Full-text

CD200 Expression May Help in Differential Diagnosis between Mantle Cell Lymphoma (MCL) and B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽

10.1182/blood.v110.11.4672.4672 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4672-4672

Author(s):

Giuseppe A. Palumbo ◽

Giovanna Forgione ◽

Nunzia Parrinello ◽

Katia Cardillo ◽

Annalisa Chiarenza ◽

...

Keyword(s):

Flow Cytometry ◽

Differential Diagnosis ◽

B Cell ◽

Cyclin D1 ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Neoplastic Cells ◽

Exact Test ◽

Mantle Cell ◽

Cell Chronic Lymphocytic Leukemia

Abstract Mantle cell lymphoma (MCL) is a B-cell malignancy that shares many morphologic and immunophenotyping features with B-cell chronic lymphocytic leukemia (B-CLL). However, these two entities are characterized by a very different prognosis and response to therapies. Differential diagnosis is assessed by a panel of monoclonal antibodies (moAbs) to screen the expression of CD5, CD23 and Cyclin D1. Nevertheless, some of these antibodies work better on fresh or frozen tissues; for example, on fixed tissues (expecially by B5) CD5 and Cyclin D1 can give equivocal or even negative results. In addition, it is cumbersome to evaluate Cyclin D1 by flow cytometry. CD200 (previously referred to as OX2) is a membrane glycoprotein, belonging to the immunoglobulin superfamily, expressed on T and B lymphocytes (but not on NK cells) and it might play an immunosuppressive role. Its expression has also been reported on human myeloma plasmacells and B-CLL cells. We investigated the expression of CD200 on fresh neoplastic cells of 90 patients (82 B-CLL and 8 MCL in leukemic phase) by flow cytometry, using a mouse IgG1 anti-human moAb (MRC OX-104, BD Pharmingen, U.S.A.). In our series, CD200 was present on neoplastic cells of all 82 B-CLL (expression on 62–100% of CD5+ cells, mean 96%, standard deviation 7%). On the contrary, in MCL patients (Cyclin D1+ and/or t(11;14) FISH+) CD200 was positive in less than 20% of CD5+ cells in 3 subjects (4–18%) and totally absent in the remaining 5 (two-sided Fisher’s exact test p<0.0001). To further extend the study, we examined CD200 by immunohistochemistry on paraffin-embedded formalin-fixed lympoid tissues and Lowy-fixed bone marrow (BM) trephine biopsies from 18 B-CLL (12 lymphnodes and 7 BM samples) and 19 MCL (11 lymphoid tissues and 9 BM) patients, using a goat anti-human IgG affinity-purified polyclonal antibody (R&D Systems, U.S.A.). Again, all B-CLL neoplastic cells were positive for CD200 both in lymphnodes and in BM while all MCL cells were negative, both in lympoid tissues and in BM (two-sided Fisher’s exact test p<0.0001). Notably, in all MCL CD200-negative lympoid tissue biopsies, it was possible to observe CD200+ residual dendritic cells (useful as immunohistochemistry reaction positive control). Moreover, results were consistent in old archival samples and even in non-perfectly prepared tissues referred to our Center. We would propose to add CD200 in flow cytometry and immunohistochemistry routine panels, as it can be of diagnostic utility in distinguishing between MCL and B-CLL, in particular in mantle cell leukemia patients. Finally, these data have to be considered in view of the proposed targeted therapy with anti-CD200, to eventually exclude MCL patients.

Download Full-text

Histiocytic Sarcoma: Review, Discussion of Transformation From B-Cell Lymphoma, and Differential Diagnosis

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0220-ra ◽

2018 ◽

Vol 142 (11) ◽

pp. 1322-1329 ◽

Cited By ~ 13

Author(s):

Stephanie L. Skala ◽

David R. Lucas ◽

Rajan Dewar

Keyword(s):

Differential Diagnosis ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Histiocytic Sarcoma ◽

Lymphocytic Leukemia ◽

Western Hemisphere ◽

Low Grade ◽

Small Lymphocytic Lymphoma

Context.— Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In particular, chronic lymphocytic leukemia/small lymphocytic lymphoma is a very common malignancy in the Western hemisphere, and most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma have an indolent course and behavior. However, 2% to 8% of chronic lymphocytic leukemia/small lymphocytic lymphoma cases transform. Histiocytic sarcomatous transformation is rare and portends poor prognosis. Objective.— To review the clinical features, morphology, and key points related to the differential diagnosis for histiocytic sarcoma. We discuss recent understanding of the biology underlying transformation. Data Sources.— University of Michigan case and review of pertinent literature about histiocytic sarcoma and morphologic differential diagnosis. Conclusions.— Histiocytic sarcoma is a rare histiocytic neoplasm that can arise as a result of transdifferentiation from low-grade B-cell lymphomas, and has a wide differential diagnosis including other histiocytic/dendritic cell neoplasms, myeloid neoplasms, lymphomas, melanoma, and carcinoma. However, some key morphologic and immunohistochemical features allow for accurate classification.

Download Full-text