Publications by authors named "Konnie M Hebeda"

39 Publications

Multiple Immunoglobulin κ Gene Rearrangements within a Single Clone Unraveled by NGS-Based Clonality Assessment.

J Mol Diagn 2021 May 19. Epub 2021 May 19.

Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address:

Clonality assessment of the Ig heavy- and light-chain genes (IGH and IGK) using GeneScan analysis is an important supplemental assay in diagnostic testing for lymphoma. Occasionally cases with an IGK rearrangement pattern that cannot readily be assigned to monoclonal lymphoma are encountered, whereas the occurrence of biclonal lymphomas is rare, and the result of the IGH locus of these cases is in line with monoclonality. Three such ambiguous cases were assessed for clonality using next-generation sequencing. Information on the sequences of the rearrangements, combined with knowledge of the complex organization of the IGK locus, pointed to two explanations that can attribute seemingly biclonal IGK rearrangements to a single clone. In two cases, this involved inversion rearrangements on the IGK locus, whereas in the third case, the cross-reactivity of primers generated an additional clonal product. In conclusion, next-generation sequencing-based clonality assessment allows for the detection of both inversion rearrangements and the cross-reactivity of primers, and can therefore facilitate the interpretation of cases of lymphoma with complex IGK-rearrangement patterns.
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http://dx.doi.org/10.1016/j.jmoldx.2021.05.002DOI Listing
May 2021

CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis.

J Cell Commun Signal 2021 Mar 11;15(1):25-56. Epub 2021 Jan 11.

Department of Pathology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.

CCN2, formerly termed Connective Tissue Growth Factor, is a protein belonging to the Cellular Communication Network (CCN)-family of secreted extracellular matrix-associated proteins. As a matricellular protein it is mainly considered to be active as a modifier of signaling activity of several different signaling pathways and as an orchestrator of their cross-talk. Furthermore, CCN2 and its fragments have been implicated in the regulation of a multitude of biological processes, including cell proliferation, differentiation, adhesion, migration, cell survival, apoptosis and the production of extracellular matrix products, as well as in more complex processes such as embryonic development, angiogenesis, chondrogenesis, osteogenesis, fibrosis, mechanotransduction and inflammation. Its function is complex and context dependent, depending on cell type, state of differentiation and microenvironmental context. CCN2 plays a role in many diseases, especially those associated with fibrosis, but has also been implicated in many different forms of cancer. In the bone marrow (BM), CCN2 is highly expressed in mesenchymal stem/stromal cells (MSCs). CCN2 is important for MSC function, supporting its proliferation, migration and differentiation. In addition, stromal CCN2 supports the maintenance and longtime survival of hematopoietic stem cells, and in the presence of interleukin 7, stimulates the differentiation of pro-B lymphocytes into pre-B lymphocytes. Overexpression of CCN2 is seen in the majority of B-acute lymphoblastic leukemias, especially in certain cytogenetic subgroups associated with poor outcome. In acute myeloid leukemia, CCN2 expression is increased in MSCs, which has been associated with leukemic engraftment in vivo. In this review, the complex function of CCN2 in the BM microenvironment and in normal as well as malignant hematopoiesis is discussed. In addition, an overview is given of data on the remaining CCN family members regarding normal and malignant hematopoiesis, having many similarities and some differences in their function.
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http://dx.doi.org/10.1007/s12079-020-00602-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798015PMC
March 2021

Artificial intelligence to detect MYC translocation in slides of diffuse large B-cell lymphoma.

Virchows Arch 2020 Sep 26. Epub 2020 Sep 26.

Department of Pathology, Radboud University Medical Center, Geert Grooteplein 10, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

In patients with suspected lymphoma, the tissue biopsy provides lymphoma confirmation, classification, and prognostic factors, including genetic changes. We developed a deep learning algorithm to detect MYC rearrangement in scanned histological slides of diffuse large B-cell lymphoma. The H&E-stained slides of 287 cases from 11 hospitals were used for training and evaluation. The overall sensitivity to detect MYC rearrangement was 0.93 and the specificity 0.52, showing that prediction of MYC translocation based on morphology alone was possible in 93% of MYC-rearranged cases. This would allow a simple and fast prescreening, saving approximately 34% of genetic tests with the current algorithm.
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http://dx.doi.org/10.1007/s00428-020-02931-4DOI Listing
September 2020

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

J Pathol Clin Res 2021 01 27;7(1):10-26. Epub 2020 Aug 27.

Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.
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http://dx.doi.org/10.1002/cjp2.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737785PMC
January 2021

Discrepancies in digital hematopathology diagnoses for consultation and expert panel analysis.

Virchows Arch 2021 Mar 25;478(3):535-540. Epub 2020 Aug 25.

Department of Pathology, Radboud University Medical Center, P. O. Box 9101, 6500, HB, Nijmegen, The Netherlands.

Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.
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http://dx.doi.org/10.1007/s00428-020-02907-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973407PMC
March 2021

Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990-2015.

Br J Haematol 2020 06 6;189(6):1093-1106. Epub 2020 Feb 6.

Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands.

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990-2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18-24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more 'chemotherapy only', different for age group and stage. Patients aged 15-17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15-17 and 18-24 years the 5-year OS improved from 84% and 90% in 1990-1994 to 96% and 97% in 2010-2015, respectively. Survival for patients aged 15-17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.
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http://dx.doi.org/10.1111/bjh.16491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318561PMC
June 2020

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016.

Ann Hematol 2018 Nov 6;97(11):2117-2128. Epub 2018 Aug 6.

Department of Pathology 824, Radboud University Medical Center, POB 9101, 6500 HB, Nijmegen, The Netherlands.

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAF mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.
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http://dx.doi.org/10.1007/s00277-018-3436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182749PMC
November 2018

Challenges in Diagnosing Myelodysplastic Syndromes in the Era of Genetic Testing: Proceedings of the 13th Workshop of the European Bone Marrow Working Group.

Pathobiology 2019 6;86(1):62-75. Epub 2018 Jul 6.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

The 13th workshop of the European Bone Marrow Working Group in Utrecht, The Netherlands, was devoted to studying myelodysplastic syndromes (MDS) and their boundaries. The panel received 44 cases submitted to the 3 invited categories, which included: reactive cytopenias with dysplasia, idiopathic cytopenia of undetermined significance, clonal haematopoiesis of indeterminate potential, idiopathic dysplasia of uncertain significance and overt MDS. For this summary, we have selected 17 cases that highlight difficulties in separating true MDS from other causes of cytopenia and the intricate relationship between clonal haematopoiesis and true MDS. In addition, cases of overt MDS with challenging features were also selected. All cases were stained for p53 expression. Using instructive submitted cases we discuss the following: (1) cytopenia with clonal haematopoiesis not fulfilling MDS criteria, (2) cytopenia and/or dysplasia with germline mutations and/or familial history suggesting an underlying gene defect, (3) MDS based on a recurrent chromosomal abnormality and (4) overt MDS with diagnostic difficulties due to concurrent treatment or disease. The lively discussion in the open forum of the workshop illustrated the need for better integrative understanding of the evolution of acquired genetic abnormalities in haematopoiesis, and the challenge of diagnosing true MDS in cytopenic patients with genetic abnormalities, either germline or acquired.
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http://dx.doi.org/10.1159/000489678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482987PMC
January 2019

Novel developments in the pathogenesis and diagnosis of extranodal marginal zone lymphoma.

J Hematop 2017 Dec 25;10(3-4):91-107. Epub 2017 Sep 25.

Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 AG Nijmegen, The Netherlands.

Extranodal marginal zone lymphoma (EMZL), mostly represented by mucosa-associated lymphoid tissue (MALT) type, also referred to as MALT lymphoma, is a clinically heterogeneous entity within the group of low-grade B cell lymphomas that arises in a wide range of different extranodal sites, including the stomach, lung, ocular adnexa, and skin. It represents the third most common non-Hodgkin lymphoma in the Western world, and the median age of occurrence is around 60 years. One characteristic aspect in a subset of EMZL detectable in about 25% of the cases is the presence of specific chromosomal translocations involving the genes and , which lead to activation of the NF-κB signaling pathway. Another unique aspect is that several infectious agents, such as in the case of gastric EMZL, and autoimmune disorders, like Sjögren syndrome, have been implicated in the pathogenesis of this cancer. Recent findings as summarized in this review have further improved our understanding of the complex pathobiology of this disease and have been essential to better define novel treatment strategies. In addition, many of these specific features are currently being implemented for the diagnosis of EMZL.
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http://dx.doi.org/10.1007/s12308-017-0302-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712330PMC
December 2017

Recurrent mutations in genes involved in nuclear factor-κB signalling in nodal marginal zone lymphoma-diagnostic and therapeutic implications.

Histopathology 2017 Jan 9;70(2):174-184. Epub 2016 Sep 9.

Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Aims: To investigate the spectrum of mutations in 20 genes involved in B-cell receptor and/or Toll-like receptor signalling resulting in activation of nuclear factor-κB (NF-κB) in 20 nodal marginal zone lymphomas (NMZLs), 20 follicular lymphomas (FLs), and 11 cases of B-cell lymphoma, unclassifiable (BCL-u).

Methods And Results: Nodal marginal zone lymphomas were diagnosed according to strict criteria, including the expression of at least one putative marginal zone marker (MNDA and/or IRTA1). Cases that showed features of NMZL but did not fulfil all criteria were included as BCL-u. All FLs were required to have a BCL2 rearrangement. Mutations were found in: nine NMZLs, with recurrent mutations in TNFAIP3 and CD79B; 12 FLs, with recurrent mutations in TNFRSF14, TNFAIP3, and CARD11; and five cases of BCL-u, with recurrent mutations in TNFRSF14. TNFRSF14 mutations were present in FL and BCL-u, but not in any of the NMZLs. In the BCL-u group, TNFRSF14 mutations clustered with a FL immunophenotype.

Conclusions: These results suggest that TNFRSF14 mutations point towards a diagnosis of FL, and can be used in the sometimes difficult distinction between NMZL and FL, but to apply this in diagnostics would require confirmation in an independent cohort. In addition, the presence or absence of specific mutations in pathways converging on NF-κB could be important for decisions regarding targeted treatment.
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http://dx.doi.org/10.1111/his.13015DOI Listing
January 2017

A subset of low-grade B cell lymphomas with a follicular growth pattern but without a translocation shows features suggestive of nodal marginal zone lymphoma.

J Hematop 2016 Mar 2;9(1):3-8. Epub 2015 Sep 2.

Department of Pathology, Radboud University Medical Center, box 9101, 6500 HB Nijmegen, The Netherlands.

In our consultation practice, it was noted that many cases that were considered to represent follicular lymphoma (FL) without a translocation were ultimately classified as nodal marginal zone lymphoma (NMZL). This study set out to define recurrent morphological features of these cases. Thirty-three low-grade B cell lymphomas without a rearrangement were studied for recurrent morphological features. These features were then applied on 20 randomly selected cases to verify if these criteria are able to distinguish between lymphomas with and without a rearrangement, assigning them to one of five categories ranging from "certain FL" to "certain NMZL." Highly recurrent morphological features were noted in the lymphomas without a rearrangement, which were strongly overlapping with the morphological features of NMZL. All six cases that were assigned to the category of certainly FL or most likely FL indeed harbored a rearrangement, whereas all 12 cases assigned to the category of most likely NMZL or certain NMZL had no break. Of the two cases in the ambiguous category, one had received a final diagnosis of FL and the other of NMZL. This study raises the hypothesis that a subset of low-grade B cell lymphomas with a follicular growth pattern but without a translocation actually represents NMZL. This is at present difficult to prove, because no gold standard is available to differentiate between NMZL and FL without a rearrangement, so further investigations are needed.
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http://dx.doi.org/10.1007/s12308-015-0259-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764621PMC
March 2016

Tetraspanin CD37 protects against the development of B cell lymphoma.

J Clin Invest 2016 Feb 19;126(2):653-66. Epub 2016 Jan 19.

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention.
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http://dx.doi.org/10.1172/JCI81041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731177PMC
February 2016

Clinical features of patients with nodal marginal zone lymphoma compared to follicular lymphoma: similar presentation, but differences in prognostic factors and rate of transformation.

Leuk Lymphoma 2016 07 23;57(7):1649-56. Epub 2015 Dec 23.

a Department of Pathology , Radboud University Medical Center , Nijmegen , The Netherlands ;

Nodal marginal zone lymphoma (NMZL) is a rare type of B-cell non-Hodgkin lymphoma. This study assessed the clinical features of 56 patients with NMZL in comparison to 46 patients with follicular lymphoma (FL). Patients with NMZL and FL had a largely similar clinical presentation, but patients with FL had a higher disease stage at presentation, more frequent abdominal lymphadenopathy and bone marrow involvement, and showed more common transformation into diffuse large B-cell lymphoma (DLBCL) during the course of disease. Overall survival and event-free survival were similar for patients with NMZL and FL, but factors associated with worse prognosis differed between the two groups. Transformation into DLBCL was associated with a significantly poorer outcome in both groups, but the phenotypes were different: DLBCL arising in FL was mainly of germinal center B-cell phenotype, whereas DLBCL arising in NMZL was mainly of non-germinal center B-cell phenotype.
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http://dx.doi.org/10.3109/10428194.2015.1106535DOI Listing
July 2016

Microarray-based genomic profiling and in situ hybridization on fibrotic bone marrow biopsies for the identification of numerical chromosomal abnormalities in myelodysplastic syndrome.

Mol Cytogenet 2015 28;8:33. Epub 2015 May 28.

Department of Pathology, Radboud university medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological malignancies. In MDS patients with a fibrotic bone marrow the aspiration of cells often fails (dry-tap), which hampers standard karyotyping. Obtaining genetic data from these fibrotic marrows is therefore challenging, and up till now in situ hybridization applied to bone marrow biopsies is the only option. The microarray-based genomic profiling technology has already proven its value for bone marrow aspirates and peripheral blood samples, but has never been applied to the technically challenging bone marrow biopsies. We describe an approach for microarray-based genomic profiling on bone marrow biopsies and demonstrate its ability to obtain clinically relevant cytogenetic aberrations. In addition the data were compared with those obtained by in situ hybridization and karyotyping.

Results: We have evaluated the success rate of microarray-based genomic profiling by studying twenty-one bone marrow biopsies (7 fibrotic MDS, 12 non-fibrotic MDS and 2 reactive), by microarray-based genomic profiling and in situ hybridization (12 of 21 cases). The data obtained with these techniques were compared with conventional karyotyping data on corresponding bone marrow aspirates. Of the 15 copy number aberrations that were detected by in situ hybridization, 13 were concordant with microarray-based genomic profiling and karyotyping, whereas two hybridizations were misinterpreted. In 20 of 21 patients, the data obtained by microarray-based genomic profiling and karyotyping were identical or differences could be explained by the presence of marker chromosomes, complex karyotypes, clonal heterogeneity or disease progression.

Conclusions: We demonstrate that genome wide microarray-based genomic profiling performed on bone marrow biopsies has a similar success rate compared to in situ hybridization, and prevents misinterpretation of chromosomal losses as observed by FISH. In addition, equal to even higher resolutions were obtained with genomic profiling compared to conventional karyotyping. Our findings indicate that microarray-based profiling, even on bone marrow biopsies, is a valid approach for the identification of genetic abnormalities. This is a valuable substitution in cases of fibrotic MDS lacking cytogenetic results.
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http://dx.doi.org/10.1186/s13039-015-0136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447009PMC
May 2015

Immunoglobulin rearrangement analysis from multiple lesions in the same patient using next-generation sequencing.

Histopathology 2015 Dec 26;67(6):843-58. Epub 2015 Jun 26.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Aims: For patients who have multiple lymphomas with discordant pathology, it is relevant to determine whether there is one disseminated lymphoma or two unrelated lymphomas. Patients with disseminated, clonally related lymphomas are usually treated with the most powerful drugs available, while patients with unrelated (primary) lymphomas receive mainly standard first-line therapies.

Methods And Results: We used next-generation sequencing on the Ion Torrent Personal Genome Machine to characterize the immunoglobulin heavy gene V-D-J rearrangements in two diagnostic tissue samples, including formalin-fixed and paraffin-embedded tissue, of two patients with iatrogenic immunodeficiency-associated Epstein-Barr virus lymphoproliferative disorder, with ulcerative colitis as underlying disease. The immunoglobulin rearrangement sequences obtained by next-generation sequencing revealed undoubtedly clonally related lesions in two tissue biopsies that were taken over time in the first patient, which is concordant with disseminated lymphoma. The other patient showed two clonally unrelated lesions, which is incompatible with clonal dissemination. This information was not inferred from evaluation of the heavy and light chain rearrangements by fragment analysis, which is currently the gold standard.

Conclusion: Our study demonstrates the diagnostic application of next-generation sequencing of immunoglobulin rearrangement assessment in pathology for clinical decision-making in patients with several simultaneous or subsequent lymphoproliferations.
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http://dx.doi.org/10.1111/his.12714DOI Listing
December 2015

A "body armor" of leukemia cutis.

Am J Hematol 2015 Aug 25;90(8):751. Epub 2015 Feb 25.

Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1002/ajh.23948DOI Listing
August 2015

Abundance of IgG4+ plasma cells in isolated reactive lymphadenopathy is no indication of IgG4-related disease.

Am J Clin Pathol 2014 Oct;142(4):459-66

From the Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Objectives: IgG4-related disease is a recently recognized condition that can be associated with lymphadenopathy, with several histologic patterns and increased absolute number and ratio of immunoglobulin G4 (IgG4)-positive plasma cells. However, these findings are considered to be not exclusively specific for IgG4-related disease.

Methods: The occurrence of the histologic patterns reported in patients with isolated lymphadenopathy was studied and correlated with the clinical presentation to determine their predictive value for IgG4-related lymphadenopathy.

Results: We found cases meeting all histologic criteria for IgG4-related lymphadenopathy, without clinical signs of IgG4-related disease. The only pattern that was not seen in this series was an inflammatory pseudotumor-like picture.

Conclusion: Without a clinical suspicion of IgG4-related disease, these morphologic patterns and high numbers of IgG4-positive plasma cells should be interpreted with care to avoid an erroneous diagnosis of IgG4-related disease.
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http://dx.doi.org/10.1309/AJCPX6VF6BGZVJGEDOI Listing
October 2014

Sequential immunohistochemistry: a promising new tool for the pathology laboratory.

Histopathology 2014 Nov 6;65(5):651-7. Epub 2014 Aug 6.

Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Aims: Current immunohistochemical methods to study the expression of multiple proteins in a single tissue section suffer from several limitations. In this article, we report on sequential immunohistochemistry (S-IHC), a novel, easy method that allows the study of numerous proteins in a single tissue section, while requiring very limited optimization.

Methods And Results: In S-IHC, a tissue section is stained for multiple antibodies, with intermediate scanning of the section and elution of chromogen and antibodies. Overlays are made of the digital images, allowing assessment of multiple proteins in the same tissue section. We used S-IHC to study nine nodular lymphocyte-predominant Hodgkin lymphomas (NLPHLs) and 10 T-cell-rich and histiocyte-rich diffuse large B-cell lymphomas (T/HRBCLs) for expression of cyclin D1, CD20, and CD68. We observed cyclin D1 expression in single tumour cells in 44% of NLPHLs and 60% of T/HRBCLs. Comparison of S-IHC with classic single immunohistochemical staining revealed discrepancies in eight cases (42%), demonstrating the difficulty of differentiating tumour cells from histiocytes on morphological grounds, and stressing the additional value of S-IHC.

Conclusions: For research and diagnostic purposes, S-IHC is a promising technique that assesses the expression of numerous proteins in single tissue sections with complete architectural information, allowing phenotypic characterization of single cells.
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http://dx.doi.org/10.1111/his.12446DOI Listing
November 2014

A dominant-negative GFI1B mutation in the gray platelet syndrome.

N Engl J Med 2014 Jan 10;370(3):245-53. Epub 2013 Dec 10.

From the Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen Center for Molecular Life Sciences (D.M., A.E.M., S.M.B., H.V., G.H., F.P., W.V.H., J.H.J., B.A.V.R.) and the Departments of Pathology (K.M.H., B.W.), Hematology (B.A.P.L.G., M.A.M., G.H.), Cardiology (A.L.D.), and Human Genetics (S.S., M.J.E.K.), Radboud University Medical Center - all in Nijmegen, the Netherlands; the Department of Medical Genetics, Antwerp University Hospital and University of Antwerp (N.A.B., E.F., G.V.C., B.L.L., L.V.L.) and the Statua Center for Statistics, University of Antwerp (E.F.), Antwerp, Belgium; and the Department of Hematology, University Hospital, Essen, Germany (C.K., L.B.).

The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development.
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http://dx.doi.org/10.1056/NEJMoa1308130DOI Listing
January 2014

Evaluation of a panel of expert pathologists: review of the diagnosis and histological classification of Hodgkin and non-Hodgkin lymphomas in a population-based cancer registry.

Leuk Lymphoma 2014 May 10;55(5):1018-22. Epub 2013 Sep 10.

Department of Medical Oncology.

Abstract Correct histological classification of malignant lymphomas is important but has always been a difficult challenge. Since 2001 the World Health Organization (WHO) classification has been used, which should make it easier to define distinct disease entities. The purpose of this study was to evaluate the usefulness of a panel of expert hematopathologists in reviewing the diagnosis of malignant lymphomas and to examine whether the discordance between primary and panel diagnoses has declined throughout the years. All patients with a primary malignant lymphoma diagnosed between 2000-2001 and 2005-2006 were identified through the population based cancer registry. All diagnoses were reviewed by a panel of three expert pathologists. In 2000-2001, 344 patients were included, and in 2005-2006, 370 patients. The overall discordance rate decreased from 14% in 2000-2001 to 9% in 2005-2006 (p = 0.06). We were able to identify lymphoma subgroups with the highest discordance rates and lowest discordance rates (mantle cell lymphoma and classical Hodgkin lymphoma), which remained unchanged throughout the years. Based on these results we would propose to review all cases of malignant lymphoma with the exception of mantle cell lymphoma and classical Hodgkin lymphoma, when the initial pathologist has no doubt about the diagnosis.
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http://dx.doi.org/10.3109/10428194.2013.827787DOI Listing
May 2014

Homing characteristics of donor T cells after experimental allogeneic bone marrow transplantation and posttransplantation therapy for multiple myeloma.

Biol Blood Marrow Transplant 2013 Mar 21;19(3):378-86. Epub 2012 Dec 21.

Department of Laboratory Medicine, Laboratory of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Relapse and graft-versus-host disease remain major problems associated with allogeneic bone marrow (BM) transplantation (allo-BMT) and posttransplantation therapy in patients with multiple myeloma (MM) and other hematologic malignancies. A possible strategy for selectively enhancing the graft-versus-myeloma response and possibly reducing graft-versus-host disease is to increase the migration of alloreactive T cells toward the MM-containing BM. In the present study, we characterized the BM-homing behavior of donor-derived effector T cells in a novel allo-BMT model for the treatment of MM. We observed that posttransplantation immunotherapy consisting of donor lymphocyte infusion (DLI) and vaccination with minor histocompatibility antigen-loaded dendritic cells (DCs) was associated with prolonged survival compared with allo-BMT with no further treatment. Moreover, CD8(+) effector T cells expressing inflammatory homing receptors, including high levels of CD44, LFA-1, and inflammatory chemokine receptors, were recruited to MM-bearing BM. This was paralleled by strongly increased expression of IFN-γ and IFN-γ-inducible chemokines, including CXCL9, CXCL10, and CXCL16, especially in mice treated with DLI plus minor histocompatibility antigen-loaded DC vaccination. Remarkably, expression of the homeostatic chemokine CXCL12 was reduced. Furthermore, IFN-γ and TNF-α induced BM endothelial cells to express high levels of the inflammatory chemokines and reduced or unaltered levels of CXCL12. Finally, presentation of CXCL9 by multiple BM endothelial cell-expressed heparan sulfate proteoglycans triggered transendothelial migration of effector T cells. Taken together, our data demonstrate that both post-transplantation DLI plus miHA-loaded DC vaccination and MM growth result in an increased expression of inflammatory homing receptors on donor T cells, decreased levels of the homeostatic BM-homing chemokine CXCL12, and strong induction of inflammatory chemokines in the BM. Thus, along with increasing the population of alloreactive T cells, post-transplantation immunotherapy also might contribute to a more effective graft-versus-tumor response by switching homeostatic T cell migration to inflammation-driven migration.
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http://dx.doi.org/10.1016/j.bbmt.2012.12.014DOI Listing
March 2013

Automated measurement of MIB-1 positive area as an alternative to counting in follicular lymphoma.

Cytometry A 2012 Jun 12;81(6):527-31. Epub 2012 Apr 12.

Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Manual counting of MIB-1 positive cells which has been suggested as an alternative to centroblast counting for the diagnostic grading of follicular lymphoma is a laborious task. In this study, the validity of automated measurement of the MIB-1 positive area is analyzed as an alternative approach. Archival MIB-1 stained tissue sections of 15 follicular lymphomas were assessed manually and automatically by three independent observers. Concordance correlation coefficients and coefficients of variation were calculated to study reproducibility and variability of both methods and to compare result from both methods. A good concordance was observed between the two methods. The reproducibility of the automated method was slightly better than the manual counting of positive nuclei. Measurement of MIB-1 positive surface area may be used as a simple and fast alternative to tedious manual counting of positive nuclei as a potential help in follicular lymphoma grading.
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http://dx.doi.org/10.1002/cyto.a.22053DOI Listing
June 2012

Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-hodgkin lymphomas.

Am J Surg Pathol 2012 Feb;36(2):296-304

Hematopathology and Hematology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain.

Bone marrow involvement by lymphoma is considered a systemic dissemination of the disease arising elsewhere, although some tumors may arise primarily in the bone marrow microenvironment. Primary bone marrow lymphoma (PBML) is a rare entity whose real boundaries and clinicobiological significance are not well defined. Criteria to diagnose PBML encompass isolated bone marrow infiltration, with no evidence of nodal or extranodal involvement, including the bone, and the exclusion of leukemia/lymphomas that are considered to primarily involve the bone marrow. Twenty-one out of 40 lymphomas retrospectively reviewed by the International Extranodal Lymphoma Study Group from 12 institutions in 7 different countries over a 25-year period fulfilled the inclusion criteria. These cases comprised 4 follicular lymphomas (FLs), 15 diffuse large B-cell lymphomas (DLBCLs), and 2 peripheral T-cell lymphomas, not otherwise specified. The FL cases showed paratrabecular infiltration, BCL2 protein and CD10 expression, and BCL2 gene rearrangement. DLBCL showed nodular infiltration in 6 cases and was diffuse in 9 cases; it also showed positivity for BCL2 protein (9/10) and IRF4 (6/8). Median age was 65 years with male predominance. All but 3 FL patients were symptomatic. Most cases presented with cytopenias and high lactate dehydrogenase. Four patients (3 FL cases and 1 DLBCL case) had leukemic involvement. Most DLBCL patients received CHOP-like or R-CHOP-like regimens. The outcome was unfavorable, with a median overall survival of 1.8 years. In conclusion, PBML is a very uncommon lymphoma with particular clinical features and heterogenous histology. Its recognition is important to establish accurate diagnosis and adequate therapy.
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http://dx.doi.org/10.1097/PAS.0b013e31823ea106DOI Listing
February 2012

Reproducibility of histologic classification in nonfibrotic myeloproliferative neoplasia.

Am J Clin Pathol 2011 Oct;136(4):618-24

Dept. of Pathology, University Hospital Maastricht, Maastricht, the Netherlands.

Early phases of polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF) can be difficult to distinguish by morphologic studies alone because they share many morphologic characteristics. Histologic criteria according to the 2008 World Health Organization (WHO) classification are part of the myeloproliferative neoplasia (MPN) diagnosis. Our aim was to assess the reproducibility of morphologic characteristics and determine their relative importance for histologic diagnoses on selected trephine biopsy sections. For the study, 56 prefibrotic MPN trephine specimens were blindly reviewed by 4 hematopathologists using a scoring list of 16 histologic characteristics mentioned in the WHO classification. Consensus was defined as agreement by 3 of 4 hematopathologists. High degrees of consensus were reached for individual major morphologic features used in the WHO classification, especially for the nuclear features of megakaryocytes (83%). Some of the features correlated positively or negatively with the histologic diagnosis of PMF. Consensus for the histologic classification of MPN was reached in 39 (70%) of 56 cases without knowledge of clinical data. This finding indicates a difference in the relative importance assigned to individual histologic characteristics by different hematopathologists.
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http://dx.doi.org/10.1309/AJCP2UG9SGGWAHUADOI Listing
October 2011

Splenic gas as a result of a non-Hodgkin's lymphoma in a patient with common variable immunodeficiency.

J Clin Oncol 2011 Aug 6;29(23):e666-7. Epub 2011 Jun 6.

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1200/JCO.2011.35.6659DOI Listing
August 2011

Biomarkers as disease definition: mantle cell lymphoma as an example.

Proteomics Clin Appl 2010 Dec;4(12):922-5

Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

The introduction in pathology practice of a new biomarker that is contributing to define a disease requires a series of investigations. Now that new biomarkers are being discovered continuously it is important to learn from successful examples of markers that are presently widely used. In this historical account the steps are described that have led to the use of immunohistochemical staining of tissue samples with an antibody against cyclinD1 to diagnose mantle cell lymphoma. Furthermore, a short outlook is given on the introduction of proteomics as a tool in the diagnosis of lymphoma and the potential route to be taken for introducing this technology into clinical practice.
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http://dx.doi.org/10.1002/prca.201000048DOI Listing
December 2010
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