Reaction Patterns of TRAP and DBA.44 in Hairy Cell Leukemia, Hairy Cell Variant, and Nodal and Extranodal Marginal Zone B-cell Lymphomas

The cytological and immunocytochemical features of the lymphocytes with villous morphology in peripheral blood and bone marrow in some B-lymphoproliferative disorders were studied. The diagnosis of hairy cell leukemia, a hairy cell leukemia variant, splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma was ascertained in accordance with the new revision of the WHO classification (2016). The neoplastic cells of hairy cell leukemia were determined by the presence of high tartrate resistant acid phosphatase (TRAP) activity. Cell surface expression of CD19, CD20 and CD21 antigens was detected. Also, the expression of CD25, CD103 and CD200, and in some cases cyclin D1, was found out. CD5, CD10 and CD23 were not detected. The immunophenotype of cells in splenic marginal zone lymphoma with villous processes also corresponded to the mature B cells. The expression of CD19, CD20 and CD21 was observed in all cases, CD11c – in 50% of patients, CD25 or CD5 – in 10% of patients. In 80% of patients, the pathologic cells did not show TRAP activity. In the bone marrow and peripheral blood cells of patients with diffuse red pulp lymphoma, TRAP activity was not detected. An immunophenotype in the hairy cell leukemia variant was different from those of classic HCL (CD19+CD20+CD22+CD103+CD11c+CD5–CD10–CD23–). Characterized immunophenotypical markers, which have differential diagnostic values in several forms of lymphoid tumors of B cell origin, will be important for the choice of treatment methods and prognosis

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BRAF and MAP2K1 mutations in hairy cell leukemia and splenic marginal zone B-cell lymphoma

Oncohematology ◽

10.17650/1818-8346-2016-11-1-34-36 ◽

2016 ◽

Vol 11 (1) ◽

pp. 34-36 ◽

Cited By ~ 1

Author(s):

I. A. Yakutik ◽

L. S. Al’-Radi ◽

H. L. Julhakyan ◽

B. V. Biderman ◽

A. B. Sudarikov

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hairy Cell ◽

Cell Leukemia

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A Rare Case of a Patient With Hairy Cell Leukemia Developing Blastoid Marginal Zone B-Cell Lymphoma

Cureus ◽

10.7759/cureus.16239 ◽

2021 ◽

Author(s):

Yeshanew Teklie ◽

Stephen Bell ◽

Precious Idogun ◽

Madhavi Venigalla

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Rare Case ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hairy Cell ◽

Cell Leukemia

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Gene Expression Profiling Classifies Splenic Marginal Zone Lymphoma and Hairy Cell Leukemia-Variant as Related Diseases That Are Distinct From Typical Hairy Cell Leukemia.

Blood ◽

10.1182/blood.v114.22.3467.3467 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3467-3467

Author(s):

Sarah L Hockley ◽

Alison Morilla ◽

Andrew Wotherspoon ◽

Brian A Walker ◽

Nicholas J Dickens ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Hairy Cell Leukemia ◽

Marginal Zone ◽

Expression Profiles ◽

Splenic Marginal Zone Lymphoma ◽

Hairy Cell ◽

Cell Leukemia ◽

Transcription Profiles ◽

Insight Into

Abstract Abstract 3467 Poster Board III-355 Hairy cell leukemia (HCL) is an uncommon B-cell malignancy that shares some features with a variant form, HCL-variant, and splenic marginal zone lymphoma (SMZL). The distinction between these disorders can be difficult, but correct diagnosis is important for patient management and clinical outcome. The recent WHO classification has recognized SMZL as a distinct entity and HCL-variant was included in a provisional category of unclassifiable splenic lymphomas involving the splenic red pulp that also includes splenic diffuse red pulp small B-cell lymphoma (SDSL). The molecular features of these disorders are still largely uncharacterized and genomic studies have been limited due to their rarity. We have used Affymetrix gene expression microarrays to compare the transcription profiles of 31 HCL, 24 HCL-variant, 44 SMZL and 5 cases of SDSL with the aim of elucidating the relationships between these disorders and to identify novel potential therapeutic and disease-specific diagnostic targets. Total RNA was extracted from PBMC samples enriched for tumor cells (median 89%, range 70-98%) and the expression of approximately 18,000 genes was interrogated using the Affymetrix Human Exon 1.0 ST Array. Data were normalized and analyzed using Partek Genomics Suite® and differentially expressed transcripts between the disorders were identified by ANOVA. Unsupervised hierarchical clustering revealed disease-related patterns within the transcription profiles. Strikingly, the HCL-variant, SMZL and SDSL profiles clustered together and separately from those of typical HCL. Using a false discovery rate threshold of <0.001 and an expression fold-change >2 we identified 366 transcripts that distinguished HCL from HCL-variant, SMZL and SDSL. Using these same criteria, and even those less stringent, we could not identify a gene expression signature that could distinguish between HCL-variant, SMZL and SDSL. Biological interpretation of the data revealed many of the differentially expressed transcripts linked to immune response and signal transduction processes, including key oncogenes and tumor suppressor genes. Transcripts with higher expression in HCL-variant, SMZL and SDSL relative to HCL were associated with lymphocyte activation and proliferation, NFκB signaling and integrin signaling. Conversely, transcripts with higher expression in HCL relative to HCL-variant, SMZL and SDSL, comprised amongst others, pathways of antigen processing, MAP kinase signaling, JAK-STAT signaling, and FLT3 signaling. Comparison of the transcription signatures of HCL, HCL-variant and SMZL provides insight into their relationships and for the first time provides strong evidence that HCL-variant and SDSL may be variant forms of SMZL and that HCL remains as a distinct disease entity characterized by different signaling pathways. These data further strengthen our previous observation that showed that the immunoglobulin heavy chain gene (IGH) repertoire of HCL-variant is more similar to SMZL than to HCL and that, in contrast to HCL, both HCL-variant and SMZL contain subsets of cases with unmutated IGHV. Interestingly, the expression profiles of both HCL-variant and SMZL could not be discriminated based on their IGHV mutation status. We are currently performing further analyses of these data, including comparison with the expression profiles of normal B cells, with the aim of gaining further insight into the clonal history and the normal B-cell counterpart of these disorders. Disclosures No relevant conflicts of interest to declare.

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Differential Expression of Enhancer of Zeste Homolog 2 (EZH2) Protein in Low and High Grade B-Cell Non-Hodgkin Lymphomas and Differential Regulation of EZH2 Expression By p-ERK and MYC in High Grade B Cell Lymphomas

Blood ◽

10.1182/blood.v126.23.2660.2660 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2660-2660

Author(s):

Xuejun Tian ◽

Ali Shahsafaei ◽

David M. Dorfman

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Cell Lymphoma ◽

Low Grade ◽

High Grade ◽

Hairy Cell ◽

Cell Leukemia ◽

B Cell Lymphomas ◽

Neoplastic Cells ◽

Ezh2 Expression

Abstract Background: EZH2, amember of the polycomb protein group, is an important methyltransferase that is over-expressed in various carcinomas, some B and T cell lymphomas, as well as myeloid disorders. We investigated EZH2 expression in the range of low and high grade B cell neoplasms and correlated its expression with that of p-ERK, MYC, and p-STAT3, potential regulators of EZH2 expression, in high grade B cell lymphomas. Methods: Immunohistochemical staining (IHC) for EZH2 was performed on a total of 162 low and high grade B cell non-Hodgkin lymphomas, using formalin fixed, paraffin-embedded tissue [Table 1]. We subsequently performed IHC for p-ERK, p-STAT3, and MYC on high grade B cell lymphomas. Cases were scored for percentage positivity of neoplastic cells using the above antibodies. Table 1. EZH2 expression in low grade and high grade B cell lymphomas Lymphoma type Cases (POS/Total) EZH2 positive % low grade MM 10/12 10 LPL 9/12 5-10 CLL/SLL 15/18 10--15 MCL 8/9 30 MZL 20/21 15-20 FL(1-2) 8/10 20 HCL 13/14 5-10 HCL-V 9/10 30-40 High grade DLBCL 29/33 90 BL 19/19 100 CLL-Richter 5/5 80-90 FL-3 6/6 80 DHL 22/22 90-100 PMLBCL 19/19 60-80 B-ALL 11/11 95-100 Abbreviations: MM - multiple myeloma; LPL - lymphoplasmacytic lymphoma; CLL/SLL - chronic lymphocytic leukemia/small lymphocytic lymphoma; MCL - mantle cell lymphoma; MZL - marginal zone lymphoma; FL(1-2) - follicular lymphoma grade 1-2/3; HCL - hairy cell leukemia; HCL-V - hairy cell leukemia-variant; DLBCL - diffuse large B cell lymphoma; BL - Burkitt lymphoma; CLL-Richter transformation of CLL; FL -3 - follicular lymphoma grade 3/3; DHL - double hit lymphoma; PMLBCL - primary mediastinal large B cell lymphoma; B-ALL - B lymphoblastic leukemia/lymphoma. Results: In low grade lymphomas, 5-40% of neoplastic cells were positive for EZH2, with variable intensity of staining. Of note, there was a significant difference in EZH2 expression in hairy cell leukemia versus hairy cell leukemia-variant (p<0.01). In high grade lymphomas, including those transformed from low grade B cell lymphomas, 70-100% of tumor cells were positive for EZH2 expression, a significant difference in EZH2 expression compared with low grade B cell lymphomas (p<0.01). Among the high grade B cell lymphoma, 40-80% of neoplastic cells in DLBCL (24 cases), were positive for p-ERK expression, but <30% of neoplastic cells were positive for p-ERK expression in BL (15 cases) and DHL (17 cases). In contrast, 80-100% and 50-90% of neoplastic cells were positive for MYC expression in BL (17 cases) and DHL (26 cases), respectively, but only 5-50% of neoplastic cells were positive for MYC expression in DLBCL (30 cases). There were significant differences in both MYC and p-ERK expression in BL and DHL versus DLBCL (p<0.01). None of the high grade B cell lymphomas showed significant p-STAT3 positivity in neoplastic cells. Conclusion: EZH2 expression correlates with tumor grade in B cell neoplasms, and the high level of EZH2 expression in high grade B cell lymphomas suggests that this molecule may function as an oncogenic protein in these neoplasms. Furthermore, our findings show there are different signaling cascades in the regulation of EZH2 expression in different types of high grade B cell lymphomas. The p-ERK signaling cascade, but not MYC expression, plays an important role in high EZH2 expression in DLBCL; while in BL and DHL, high MYC expression, but not p-ERK expression, is associated with increased EZH2 expression, possibly through miRNA regulation. These findings suggested that EZH2 and specific disease-related signaling cascades may serve as therapeutic targets for the treatment of high grade B cell lymphomas. Disclosures No relevant conflicts of interest to declare.

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Immunohistochemistry forBRAFV600E in the Differential Diagnosis of Hairy Cell Leukemia vs Other Splenic B-Cell Lymphomas

American Journal of Clinical Pathology ◽

10.1309/ajcp5wvxj2ktlodo ◽

2015 ◽

Vol 144 (1) ◽

pp. 87-93 ◽

Cited By ~ 14

Author(s):

Samir Turakhia ◽

Christopher Lanigan ◽

Fatima Hamadeh ◽

Steven H. Swerdlow ◽

Raymond R. Tubbs ◽

...

Keyword(s):

Differential Diagnosis ◽

B Cell ◽

Hairy Cell Leukemia ◽

Hairy Cell ◽

Cell Leukemia ◽

B Cell Lymphomas

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Splenic Sinusoids Stimulate the Survival and Proliferation of Hairy Cell Leukemia B Cells through BAFF, APRIL and Heparan-Sulphate Proteoglycans.

Blood ◽

10.1182/blood.v108.11.4959.4959 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4959-4959

Author(s):

April Chiu ◽

Weifeng Xu ◽

Bing He ◽

Paul Santini ◽

Stacey R. Dillon ◽

...

Keyword(s):

Endothelial Cells ◽

B Cells ◽

B Cell ◽

Hairy Cell Leukemia ◽

Marginal Zone ◽

Heparan Sulphate ◽

Hairy Cell ◽

Small Interfering Rnas ◽

Cell Leukemia ◽

Heparan Sulphate Proteoglycans

Abstract Introduction. Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder characterized by massive infiltration of the spleen by cells displaying a unique “hairy” morphology and surface phenotype. The ontogeny of hairy cells (HCs) and the mechanism underlying their accumulation in the spleen remain elusive. Growing evidence indicates that B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) play important roles in malignant B cells. BAFF and APRIL are usually produced by myeloid cells and engage three receptors on B cells known as transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). APRIL binding to TACI and BCMA is reinforced by cell-anchored and matrix-associated heparan-sulphate proteoglycans (HSPGs). In this study we verified the role of BAFF and APRIL in HCL. Methods. Splenic tissue sections and B cells from 5 healthy donors and 5 HCL patients were analyzed for expression of BAFF, APRIL, TACI, BCMA, BAFF-R and other molecules through immunohistochemistry, immunofluorescence, flow cytometry, immunoblotting and quantitative real-time RT-PCR. HCs were also cultured with umbilical vein or splenic endothelial cells in the presence or absence of BAFF and APRIL inhibitors, including soluble TACI-Ig decoy receptor, small interfering RNAs (siRNAs) and HSPG-modifying agents, such as heparinitase. HC proliferation, survival and signaling as induced by recombinant BAFF or APRIL were evaluated through standard assays. Results. We found that splenic sinusoids surrounding HCs were comprised of endothelial cells expressing APRIL and, to a lesser extent, BAFF. Endothelial cells up-regulated BAFF and APRIL upon exposure to HC-derived cytokines, including TNF-α. Unlike naïve, germinal center, memory and plasmacytoid B cells but similar to splenic marginal zone B cells, HCs expressed high levels of TACI, BCMA, BAFF-R and HSPGs together with CD1c, CD11c, CD27, CD83, CD123, endocytic receptors, and carbohydrate receptors. Preliminary data indicated that endothelial cells stimulated HCs through a mechanism involving BAFF, APRIL and HSPGs as pretreatment of endothelial cells with BAFF and APRIL small interfering RNAs or heparinitase attenuated the growth and survival of HCs in co-cultures. TACI-Ig, which binds to and neutralizes BAFF and APRIL, had a similar inhibitory effect. Conversely, BAFF, APRIL as well as TACI, BCMA or BAFF-R cross-linking stimulated HC growth. This stimulation was associated with NF-κB activation as well as up-regulation of various pro-survival and growth-inducing intracellular proteins. Conclusions. The present findings suggest that HCs may derive from a splenic marginal zone B cell precursor. In addition, our studies indicate that splenic sinusoids form a BAFF-APRIL-HSPG-rich niche that promotes HC expansion via TACI, BCMA and BAFF-R. Finally, our data suggest that blocking BAFF and APRIL through TACI-Ig, siRNAs and HSPG-modifying agents could have therapeutic value in HCL.

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Frequent Coincident Clonal Hematopoietic Expansions In Patients with Hairy Cell Leukemia

Blood ◽

10.1182/blood.v116.21.2428.2428 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2428-2428

Author(s):

Mikhail Roshal ◽

Sindhu Cherian

Keyword(s):

B Cell ◽

Cell Population ◽

Plasma Cell ◽

Hairy Cell Leukemia ◽

Marginal Zone ◽

Epidemiologic Studies ◽

Hairy Cell ◽

Cell Leukemia ◽

Plasma Cell Neoplasm ◽

Cell Neoplasm

Abstract Abstract 2428 Hairy cell leukemia is usually an indolent clonal proliferation of mature B cells involving blood, bone marrow, and spleen and is often characterized by progressive cytopenias. Patients with HCL have been observed to be at increased risk for a subset non-hematopoietic and hematopoietic neoplasms in some, but not all epidemiologic studies. The reason for such an increase is not entirely clear and has been postulated to be either due to immunosuppressive therapy that is used to treat HCL, an immunosuppressive effect of HCL itself, and/or to the intrinsic cancer susceptibility of the HCL patients. The finding of an increased cancer burden of HCL patients at diagnosis and lack of consistent association with any specific therapy is somewhat supportive of the last explanation. Aside from the epidemiologic studies, reports of second hematologic malignancies in patients with HCL are mostly contained in case reports and series containing very few HCL patients. To our knowledge no large systematic studies of additional clonal hematopoietic proliferations that can be detected in routine clinical specimen in patients with hairy cell leukemia have been performed. We identified 115 patients with hairy cell leukemia documented by flow cytometry in our institution between the years of 2004 and 2010. To qualify for the study the case had to have a clonal mature B cell population with expression of the canonical hairy cell leukemia antigens CD25, CD11c and CD103 on a population with increased side scatter. Immunophenotypic variants lacking one or more of these antigens were excluded to avoid sample contamination with HCL-variant and marginal zone lymphoma. Whenever possible correlation with clinical and morphologic evaluation was also performed. Of those patients 12 (10.4%) had one or more additional clonal hematopoietic proliferations identified either at diagnosis or in a subsequent sample. 7/12 patients had both neoplastic proliferations present at the time of diagnosis while the remaining 5 patients developed the second neoplasm after an established history of hairy cell leukemia. Compared to patients without additional neoplasms, the patients with additional clonal populations were older (average age 66 (47–85) vs. 56 (27–95) year old, p<0.01, two tailed t test). Compared to younger patients, HCL patients over age 60 had a significantly increased probability of having a second hematopoietic neoplasm (20% vs. 5.3%, OR 3.8, p<0.001, two tailed Chi-squared test). The majority 8/12 had another B cell neoplasm while the remainder had evidence of a plasma cell neoplasm. Two patients had coincident chronic lymphocytic leukemia (CLL) with an additional five patients presenting with a monoclonal B lymphocytosis (MBL) having a CLL like immunophenotype. One patient developed mantle cell lymphoma. One patient had three additional neoplastic populations which included a clonal B cell population negative for CD5, CD10, CD11c, or CD103, most consistent with either a marginal zone lymphoma or a lymphoplasmacytic lymphoma, a small clonal plasma cell population suggestive of monoclonal gammopathy of undetermined significance, and an MBL population with a CLL like immunophenotype. Five patients had a plasma cell neoplasm (three with clinical diagnosis of multiple myeloma). We have also identified a clear case of bi-clonal hairy cell leukemia that to our knowledge has only been reported once in the literature and never using contemporary diagnostic criteria. Our study demonstrates that additional clonal hematopoietic proliferations associated with HCL are common. Increased vigilance for coincident hematopoietic neoplasms may be warranted particularly in older patients with this disease. Disclosures: No relevant conflicts of interest to declare.

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