Anomalous High p27/KIP1 Expression in a Subset of Aggressive B-Cell Lymphomas Is Associated With Cyclin D3 Overexpression. p27/KIP1—Cyclin D3 Colocalization in Tumor Cells

Abstract p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt’s lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt’s cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.

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Anomalous High p27/KIP1 Expression in a Subset of Aggressive B-Cell Lymphomas Is Associated With Cyclin D3 Overexpression. p27/KIP1—Cyclin D3 Colocalization in Tumor Cells

Blood ◽

10.1182/blood.v94.2.765.414a29_765_772 ◽

1999 ◽

Vol 94 (2) ◽

pp. 765-772 ◽

Cited By ~ 2

Author(s):

Margarita Sánchez-Beato ◽

Francisca I. Camacho ◽

Juan C. Martı́nez-Montero ◽

Ana I. Sáez ◽

Raquel Villuendas ◽

...

Keyword(s):

B Cell ◽

Cyclin D1 ◽

Kinase Inhibitor ◽

Cyclin E ◽

Cyclin D3 ◽

Nuclear Accumulation ◽

Proliferation Index ◽

B Cell Lymphomas ◽

Proliferating Cells ◽

P27 Kip1

p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt’s lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt’s cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.

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A Subset of CD5– Diffuse Large B-Cell Lymphomas Expresses Nuclear Cyclin D1 With Aberrations at theCCND1Locus

American Journal of Clinical Pathology ◽

10.1309/42cq0hu7xey9qmqx ◽

2008 ◽

Vol 129 (4) ◽

pp. 630-638 ◽

Cited By ~ 33

Author(s):

Mats Ehinger ◽

Johan Linderoth ◽

Birger Christensson ◽

Birgitta Sander ◽

Eva Cavallin-Ståhl

Keyword(s):

B Cell ◽

Cyclin D1 ◽

B Cell Lymphomas ◽

Large B Cell

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Depsipeptide in the Treatment of Relapsed and Refractory Multiple Myeloma (MM): A Prospective Evaluation of the Cell Cycle.

Blood ◽

10.1182/blood.v104.11.1497.1497 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1497-1497

Author(s):

Zoe Goldberg* ◽

Scott Ely ◽

Selina Chen-Kiang ◽

Martha Chesi ◽

Peter L. Bergsagel ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Lines ◽

Phase Ii ◽

Caspase 3 ◽

Gene Array ◽

Cyclin D3 ◽

Proliferation Index ◽

G1 Arrest

Abstract Background: Dysregulation of the cell cycle and apoptosis are two critical events in the pathophysiology of MM. This notion is supported by: 1)A high tumor burden is often present despite a low rate of tumor cell proliferation. 2)G1 arrest is common in MM cells while normal plasma cells are permanently withdrawn from cell cycle. 3) Cyclin D1 is often overexpressed without a defined genetic substrate. Herein, we show that cell cycle evaluation in vivo is feasible and that the histone-deacetylase inhibitor depsipeptide might be effective in selected patients with MM. Patients and Methods: In vitro studies were performed in 12 human MM cell lines with defined cytogenetic abnormalities. The IC50 for depsipeptide was determined by evaluation of apoptosis by standard methods. In vivo studies where done as correlates in a phase II protocol. These include: Immunohistochemistry (IHC) for co-expression of CD138/Ki-67 as a proliferation index (PCPI), cyclin D1, D3, caspase 3 cleavege, CD31 and bcl-2 before treatment and at 24 hrs and 30 days after treatment. Gene array studies are being performed on selected patients at those timepoints. To date, four stage III patients (PTS) with relapsed MM with four or fewer prior lines of therapy have been treated with one to three cycles of depsipeptide at a dose of 13mg/m2,as a 4-hour infusion on days 1, 8, and 15, repeated every 28 days. Mean age was 63 years (range, 56 to 72). KPS of >80%. Mean albumin was 3.5, (range, 3.2 to 4), mean LDH was 243 (range, 179 to 315). Results: 1)Depsipeptide induces apoptosis in several MM cell lines. All lines were susceptible to depsipeptide, however, differential sensitivities were noted. Three cell lines (ie U266) that contained 11q13 translocation (cyclin D1 overexpression) were the most sensitive with IC50s at least 2 fold lower than other lines. 2) Cell cycle changes are induced by depsipeptide: In 2/4 PTS, a significant increase of the PCPI was seen, whereas a marked reduction in the PCPI in a patient with cyclin D3 overexpression (27% to 16%) was also noted. One patient had an increase of cyclin D1 post treatment. No changes where seen in bcl-2, CD-31, or cleaved caspase-3 expression. 3) Depsipeptide is safe in a limited cohort of MM PTS: Grade 2 fatigue and anorexia were the most common toxicities. Mild thrombocytopenia (mean of 67) did not require transfusions. One patient had stable disease after 3 cycles of treatment, one patient had progression of disease after 3 cycles, one patient progressed after the 1st cycle, and one patient is too early for evaluation. Conclusions: 1)Patients with 11q13 translocation should be a target for treatment with depsipeptide. 2)Depsipeptide given on this schedule is safe and can stabilize tumor-mass in PTS with otherwise progressive relapsed and refractory disease.3) Evidence of cell cycle modulation can be seen during treatment with depsipeptide. No profound changes in apoptosis is evident.4)Further studies may help to understand the mechanism of transcriptional regulation by depsipeptide and will help design rational therapy and combinations. This study continues to accrue patients as part of New York Phase II Consortium. Supported by NCI grant (SAIC1N01-CO-12400-02) and a SCOR for Myeloma grant from the Leukemia and Lymphoma Society of America.

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Long Distance Trans DNA Hypomethylation in Cyclin D1 Deregulated B Cell Malignancies.

Blood ◽

10.1182/blood.v104.11.390.390 ◽

2004 ◽

Vol 104 (11) ◽

pp. 390-390

Author(s):

Hui Liu ◽

Jin Wang ◽

Jing Huang ◽

Elliot M. Epner

Keyword(s):

B Cell ◽

Cyclin D1 ◽

Normal Chromosome ◽

Cyclin D3 ◽

Chromosome 11 ◽

Dna Hypomethylation ◽

Long Distance ◽

B Cell Malignancies ◽

Mantle Cell ◽

Methylation Patterns

Abstract Cyclin D1 is a common target gene in B cell malignancies. Cyclin D1 is deregulated by translocation in most patients with mantle cell lymphoma (MCL) and 15–20% of patients with multiple myeloma (MM). Cyclin D1 is not expressed in normal lymphocytes. Gene targeting experiments in cyclin D1 overexpressing MCL and MM were carried out and genetic variants isolated which had lost the translocated or inserted 11:14 chromosomes. These clones no longer expressed cyclin D1 but expressed high levels of cyclin D3. Analysis of DNA methylation patterns in these clones demonstrated that the translocated chromosome exerts a long distance trans DNA hypomethylating effect on the normal chromosome (transvection) at the cyclin D1 locus and at least 100 kilobases upstream. Thus, in the absence of the translocated chromosome, the normal chromosome is densely DNA methylated. This long distance trans hypomethylating effect was also demonstrated in a MM cell line (U266) which contains an insertion rather than a translocation of IgH sequences. Combined FISH/ immunofluorescent antibody labelling studies have shown the presence of both the normal and translocated chromosome 11’s at the outer nucleolar membrane, where they are tethered by the proteins CTCF and nucleophosmin, as demonstrated using chromatin immunoprecipitation assays. Tethering of the translocated and nontranslocated chromosomes by CTCF/nucleophosmin provides a mechanism for pairing and long distance DNA transhypomethylation.

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Development of B Cell Lymphoma in Eμ-Cyclin D1 X Mutant p53 Transgenic Mice.

Blood ◽

10.1182/blood.v106.11.1907.1907 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1907-1907

Author(s):

Mitchell R. Smith ◽

Indira J. Joshi ◽

Fang Jin ◽

Tahseen Al-Saleem

Keyword(s):

T Cell ◽

Transgenic Mice ◽

B Cell ◽

Cyclin D1 ◽

Cell Line ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Mutant P53 ◽

B Cell Lymphomas ◽

T Cell Lymphomas

Abstract Background: Mantle cell lymphoma (MCL) is characterized by t(11;14) which dysregulates cyclin D1 expression. Eμ-cyclinD1 transgenic mice, however, are healthy. Additional genetic events must be necessary for lymphomagenesis, and knowledge of these would enhance understanding and therapy of MCL. In addition, a mouse model of MCL would be helpful in drug development. Alterations in p53 have been described in MCL, often associated with the blastic variant. Objectives and Methods: To determine whether p53 and cyclin D1 can cooperate in lymphomagenesis, we cross bred Eμ-cyclinD1 transgenic mice (Bodrug et al EMBO J, 1996, courtesy of Alan Harris) with mice transgenic for mutant p53 (Jackson Labs, Jacks et al Curr Biol, 1994). Progeny mice were monitored for presence of the transgenes by PCR of tail vein DNA and observed for development of disease. Results: Of mice carrying both aberrant genes, 24 of 38 developed B cell lymphoma. Mice did not become visibly ill until at least 12 months of age, with median age at sacrifice 15.5 (range 12–23) months. The lymphoma was generally disseminated, involving spleen, liver, diffuse adenopathy and marrow with occasional extranodal sites. Histology varied between small and large cell, with some having a vaguely follicular growth pattern. T cell lymphomas occurred in 2 other mice, while 5 developed osteosarcoma (1 of these in a mouse that also had B cell lymphoma). The B cell lymphomas were clonal by Cμ-VH PCR. Cyclin D1 expression was documented by Western analysis. A cell line has also been developed from one of the B cell lymphomas and this line rapidly grows into disseminated lymphoma in syngeneic mice. These B cell lymphomas differ from the thymic T cell lymphomas seen in heterozygous p53 mutant mice that do not co-express cyclin D1. The latency period differs from cyclin D1 x myc double transgenic mice. Conclusions: This model demonstrates cooperation between p53 and cyclin D1 pathways in B cell lymphomagenesis and should prove useful in delineating how these signals interact. The cell line may prove useful in pre-clinical testing of new agents for MCL.

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Translocations Involving 8q24 in Burkitt Lymphoma and Other Malignant Lymphomas: A Historical Review of Cytogenetics in the Light of Todays Knowledge

Blood ◽

10.1182/blood.v112.11.2814.2814 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2814-2814

Author(s):

Evert-Jan Boerma ◽

Reiner Siebert ◽

Michael Baudis ◽

Philip Kluin

Keyword(s):

B Cell ◽

Burkitt Lymphoma ◽

Age Distribution ◽

Classification Systems ◽

Proliferation Index ◽

Molecular Profile ◽

Steady Increase ◽

B Cell Lymphomas ◽

The Core ◽

Core Subset

Abstract Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined by a histologic diagnosis of BL, the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, and the absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint. These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile. The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.

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c-Myc or Cyclin D1 Mimics Estrogen Effects on Cyclin E-Cdk2 Activation and Cell Cycle Reentry

Molecular and Cellular Biology ◽

10.1128/mcb.18.8.4499 ◽

1998 ◽

Vol 18 (8) ◽

pp. 4499-4508 ◽

Cited By ~ 152

Author(s):

Owen W. J. Prall ◽

Eileen M. Rogan ◽

Elizabeth A. Musgrove ◽

Colin K. W. Watts ◽

Robert L. Sutherland

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Kinase Inhibitor ◽

Cyclin E ◽

Breast Cancer Cell Lines ◽

Potential Contribution ◽

Estrogen Action ◽

Cell Cycle Reentry ◽

Metallothionein Promoter ◽

Relevant Role

ABSTRACT Estrogen-induced progression through G1 phase of the cell cycle is preceded by increased expression of the G1-phase regulatory proteins c-Myc and cyclin D1. To investigate the potential contribution of these proteins to estrogen action, we derived clonal MCF-7 breast cancer cell lines in which c-Myc or cyclin D1 was expressed under the control of the metal-inducible metallothionein promoter. Inducible expression of either c-Myc or cyclin D1 was sufficient for S-phase entry in cells previously arrested in G1 phase by pretreatment with ICI 182780, a potent estrogen antagonist. c-Myc expression was not accompanied by increased cyclin D1 expression or Cdk4 activation, nor was cyclin D1 induction accompanied by increases in c-Myc. Expression of c-Myc or cyclin D1 was sufficient to activate cyclin E-Cdk2 by promoting the formation of high-molecular-weight complexes lacking the cyclin-dependent kinase inhibitor p21, as has been described, following estrogen treatment. Interestingly, this was accompanied by an association between active cyclin E-Cdk2 complexes and hyperphosphorylated p130, identifying a previously undefined role for p130 in estrogen action. These data provide evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on or prior to the formation of active cyclin E-Cdk2-p130 complexes and loss of inactive cyclin E-Cdk2-p21 complexes, indicating a physiologically relevant role for the cyclin E binding motifs shared by p130 and p21.

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Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas

Blood ◽

10.1182/blood-2007-10-118794 ◽

2008 ◽

Vol 111 (12) ◽

pp. 5683-5690 ◽

Cited By ~ 84

Author(s):

Iwona Wlodarska ◽

Daan Dierickx ◽

Vera Vanhentenrijk ◽

Katrien Van Roosbroeck ◽

Helena Pospís̆ilová ◽

...

Keyword(s):

Cyclin D1 ◽

Cyclin E ◽

Central Nervous System Involvement ◽

Cyclin D3 ◽

Cyclin D ◽

Cyclin D2 ◽

Aberrant Expression ◽

Mantle Cell ◽

The Central Nervous System

Abstract The genetics of t(11;14)(q13;q32)/cyclin D1–negative mantle cell lymphoma (MCL) is poorly understood. We report here 8 MCL cases lacking t(11;14) or variant CCND1 rearrangement that showed expression of cyclin D1 (2 cases), D2 (2 cases), and D3 (3 cases). One case was cyclin D negative. Cytogenetics and fluorescence in situ hybridization detected t(2;12)(p11;p13)/IGK-CCND2 in one of the cyclin D2-positive cases and t(6;14)(p21;q32)/IGH-CCND3 in one of the cyclin D3-positive cases. Moreover, we identified a novel cryptic t(2;14)(p24;q32) targeting MYCN in 2 blastoid MCLs: one negative for cyclin D and one expressing cyclin D3. Interestingly, both cases showed expression of cyclin E. Notably, all 3 blastoid MCLs showed a monoallelic deletion of RB1 associated with a lack of expression of RB1 protein and monoallelic loss of p16. In sum-mary, this study confirms frequent aberrant expression of cyclin D2 and D3 in t(11;14)-negative MCLs and shows a t(11;14)-independent expression of cy-clin D1 in 25% of present cases. Novel findings include cyclin E expression in 2 t(11;14)-negative MCLs characterized by a cryptic t(2;14)(p24;q32) and identification of MYCN as a new lymphoma oncogene associated with a blastoid MCL. Clinically important is a predisposition of t(11;14)-negative MCLs to the central nervous system involvement.

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The Pathologic Spectrum of Bone Marrow Involvement by Double- and Triple-hit Lymphomas

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.205 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S96-S97

Author(s):

H Iqbal ◽

A Harrington ◽

S H Kroft

Keyword(s):

Bone Marrow ◽

B Cell ◽

Bone Marrow Involvement ◽

Laboratory Data ◽

Large Cell ◽

Proliferation Index ◽

High Grade ◽

B Cell Lymphomas ◽

Lymphoma Cells ◽

Pathologic Features

Abstract Introduction/Objective B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (double- and triple-hit lymphomas, DHL/THL) are a distinct entity due to shared biology and aggressive behavior, exhibiting poor outcomes with standard therapies. While pathologic features of DHL/THLs in primary sites have been well described, little information is available regarding the clinicopathologic features of bone marrow involvement by this entity. Methods/Case Report Files were searched from 2010-2020 for all DHL/THLs. Since mid-2016, all aggressive B-cell lymphomas were reflexed to DHL/THL FISH testing. Prior to that, criteria for performing FISH varied. Clinical and laboratory data were obtained through chart review. Both BM and primary diagnostic specimens were reviewed when possible. Results (if a Case Study enter NA) There were 46 DHL/THL cases with initial staging BM evaluations, of which 13 (28%) were positive for DHL/THL; 11 were available for review (5F:6M; 28-95 years). All patients with positive BMs were stage 3 or 4 irrespective of the BM findings. Lymphoma cytology in positive BMs was blastoid in 6, large cell in 2, and high grade, NOS in 3. The cytology in primary tissues was not significantly associated with the rate of marrow involvement. PB smears were available for 9/11 BM(+) cases; of these, 6 (66.7%) had circulating lymphoma cells in the blood, ranging from rare to greater than 40% lymphoma cells (median, 4%). Lymphoma cells with cytoplasmic vacuoles were present in 5 cases (45%). No BM infiltrates had a starry-sky appearance. Infiltration patterns included diffuse (3), diffuse and interstitial (3), and interstitial (3). One exhibited only rare, scattered lymphoma cells in the aspirate and core biopsy, and another with large cell morphology showed random focal (nodular) and focally paratrabecular infiltration. The proliferation index in the marrow infiltrates ranged from 50% to >90% (median, 65%). Flow cytometry was positive in 9 of 10 cases; the single negative study was from an outside institution Conclusion Our study demonstrates 28% of DHL/THLs show BM involvement at diagnosis. Notably, the peripheral blood was involved in 2/3 of cases with marrow infiltration (13% of total cases), ranging from rare circulating cells to frank leukemic involvement. Cytologically, the marrow infiltrates were predominantly blastoid or high grade NOS. Marrow infiltrates generally displayed leukemic rather than lymphomatous patterns of involvement.

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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.

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