Discordant Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma: Comparative Molecular Analysis Reveals a Heterogeneous Group of Disorders

Kremer, Marcus; Spitzer, Martin S.; Mandl-Weber, Sonja; Stecker, Katrin; Schmidt, Burkhard; Höfler, Heinz; Quintanilla-Martı́nez, Leticia; Fend, Falko

doi:10.1097/01.lab.0000050762.61660.27

Cited by 63 publications

(45 citation statements)

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“…Whether bone marrow monoclonal small B cells in DLBCL is the lower end of the spectrum of discordant marrow lymphoma cannot be excluded. However, the lymphoma in the bone marrow of cases with discordant extra-medullar DLBCL is mostly follicular lymphoma; 24 none of the monoclonal small B cells associated with DLBCL in our study display the immunophenotype of follicular lymphoma.…”

Section: Discussionmentioning

confidence: 77%

“…The bone marrow lymphoma can be clonally related as well as be clonally unrelated to the DLBCL. 24 Such cases with discordant marrow involvement are rare in our series (n=4) and have been excluded from the study. Whether bone marrow monoclonal small B cells in DLBCL is the lower end of the spectrum of discordant marrow lymphoma cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…Two similar cases have previously been reported. 24 To better characterize monoclonal small B cells in patients with DLBCL, it will be necessary to prospectively collect bone marrow from patients with DLBCL, to isolate the small B cells and perform clonal identity analyses as well as genetic analyses to compare the results with those obtained in the DLBCL of the respective patients.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22][23] Discordant bone marrow involvement in DLBCL has been reported before and its frequency may be as high as 38%. [24][25][26][27] It is defined as the presence of small cell nonHodgkin's lymphoma in the bone marrow of patients with DLBCL at diagnosis. The bone marrow lymphoma can be clonally related as well as be clonally unrelated to the DLBCL.…”

Section: Discussionmentioning

confidence: 99%

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Low levels of monoclonal small B cells in the bone marrow of patients with diffuse large B-cell lymphoma of activated B-cell type but not of germinal center B-cell type

Tierens¹,

Holte²,

Warsame³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMultiparameter flow cytometry allows the detection of minor monoclonal B-cell populations. Using this technique combined with morphology, we were struck by the presence of minor populations of small monoclonal B cells in bone marrows of patients with diffuse large B-cell lymphoma in routine diagnostic samples and performed a systematic retrospective study. Design and MethodsBone marrows of 165 patients with primary diffuse large B-cell lymphoma without histological evidence of concurrent non-Hodgkin's lymphoma were studied by routine microscopy of trephines and smears, immunohistochemistry and multiparameter flow cytometry. ResultsDiffuse large B-cell lymphoma infiltration in marrows was documented in 11 of 165 patients. Morphological examination consistently revealed a higher tumor load than evidenced by flow cytometry. Of interest, only 3 of 119 patients with diffuse large B-cell lymphoma not otherwise specified, the largest subtype, showed marrow infiltration. By contrast, flow cytometry revealed a minor monoclonal B-cell population in 24 of 165 patients, none of whom showed diffuse large B-cell lymphoma infiltration by morphology. Of interest, morphological examination revealed the presence of small B cells in the marrows of those patients. Moreover, 11 of 39 (28.2%) of patients with diffuse large B-cell lymphoma not otherwise specified of ABC subtype and only 3 of 80 (3.7%) with the GCB subtype showed these monoclonal small B cells (P=0.0002). In addition 4 of 8 (50%), 4 of 15 (26.7%) and 2 of 3 (66.7%) patients with primary testicular, primary central nervous system and leg-type diffuse large B-cell lymphoma, respectively, showed monoclonal small B cells. ConclusionsBone marrow infiltration with diffuse large B-cell lymphoma in patients with diffuse large Bcell lymphoma not otherwise specified is rare at diagnosis. By contrast, a high number of diffuse large B-cell lymphoma not otherwise specified of the ABC subtype but not of GCB subtype is associated with monoclonal small B cells in the marrow. Whether these monoclonal small B cells are precursors of diffuse large B-cell lymphoma of the ABC type or arise in a common background that favors clonal B-cell expansion remains to be demonstrated. -cell type. Haematologica 2010;95(8):1334-1341. doi:10.3324/haematol.2009 This is an open-access paper.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Low levels of monoclonal small B cells in the bone marrow of patients with diffuse large B-cell lymphoma of activated B-cell type but not of germinal center B-cell type

Tierens¹,

Holte²,

Warsame³

et al. 2010

Haematologica

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“…23,24 Cloning, sequencing, and the mutational analysis of the obtained segments are described in detail in the Online Supplementary Methods.…”

Section: Sequence Analysis Of Igv H Genes and Definition Of Mutationamentioning

confidence: 99%

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

et al. 2013

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ABSTRACTdeveloped algorithm to describe clonal hierarchy and migration patterns more thoroughly. Methods Patients, histology, and immunohistochemistryThis study comprised three patients with synchronous LN and BM infiltration by FL at presentation. Biopsies were performed during the diagnostic and staging procedures. The selection criteria were the diagnosis of FL according to the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.1 Clinical information was obtained from the patients' medical records. Material was collected from patients after their informed consent in accordance with the Declaration of Helsinki. The study was approved by the responsible institutional ethic boards. Further details are provided in the Online Supplementary Methods. Sequence analysis of IgV H genes and definition of mutational patternsDNA from the IgV H gene segments was extracted and amplified as described elsewhere. 23,24 Cloning, sequencing, and the mutational analysis of the obtained segments are described in detail in the Online Supplementary Methods. Delineation of tumor cell evolution by construction of pedigreesFor each patient and each compartment (LN and BM separately), the mutational patterns of IgV H gene segments were arranged in an ascending order of mutations to illustrate the mutational hierarchy of intraclonal sequence heterogeneity. Consequently, mutational patterns of early clones with few mutations had to be included in successor clones. When direct transition of one mutation pattern into that of successor clones with higher mutation loads was not observable, hypothetical predecessor clones (HPC) were introduced to retrace the evolution of sequenced clones back to the determined initial V H DJ H gene rearrangement (wild-type sequence). Accordingly, compartment-specific pedigrees were constructed. Thereafter, a third "summary-pedigree" comprising all sequenced clones was constructed, to evaluate the possibility of inter-compartmental exchange between LN and BM. Generation of hypothetical predecessor clones and delineation of migration probabilityFor each sequenced FL population (i.e. LN, BM, and LN and BM together) the pool of possible HPC was derived from mutations shared by at least two sequenced clones. To select the most appropriate predecessor clones from the abundance of generated HPC, the probability measurement was introduced (Figure 1). Only HPC with the highest probability measurement values were introduced until the evolution of sequenced clones could be retraced to the "wild-type sequence". Already established clone groups could not be disrupted by HPC with lower probability measurement values. These calculations resulted in a LN, a BM and an inter-compartment pedigree. If HPC of the inter-compartment pedigree displayed a higher probability measurement value than the corresponding LN or BM counterparts, inter-compartment migration was considered. The LN or BM allocation of these inter-compartment HPC was directed by the LN or BM affiliation of the majority of ev...

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Lymphoproliferative Disorders

Alper¹

2019

Bone Marrow Pathology

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Background and Objectives. Trisomy 12 is one of the most common chromosomal abnormalities in B-cell chronic lymphocytic leukemia (CLL). The aberration is readily detected by fluorescence in situ hybridization (FISH). There are only a few reports in which FISH analyses have been used to study the expansion of the trisomy 12 clone over time.Design and Methods. Repeat FISH analyses were performed in 77 patients with a chronic leukemic B-cell disorder. The aim was to study the development of the trisomy 12 clone throughout the course of the disease, to measure the effect of therapy on the proportion of trisomic cells, and to relate the findings to the response to therapy.Results. Fifty-eight of the 60 patients with no trisomy 12 at the initial test were consistently disomic for chromosome 12, while 2 patients seemingly acquired trisomy 12 during follow-up. Seventeen patients showed trisomy 12 at the first test. Expansion of the trisomy 12 clone was seen in all patients with a progressive lymphocytosis. In contrast to poor responders, patients responding well to chemotherapy showed a significant decrease in the proportion of CD19 + cells with trisomy 12. The effect of purine analogs in patients with trisomy 12 seemed inferior, both clinically and when studying the effect on the trisomic clone. Interpretations and Conclusions.There is a strong association between expansion of the trisomy 12 clone and progressive disease, both in treated and untreated patients. Conversely, reduction of the trisomic B-cell clone was linked to clinical response to chemotherapy. Acquisition of trisomy 12 remains a rare event. ©2001, Ferrata Storti FoundationKey words: chronic leukemic B-cell disorders, CLL, trisomy 12, APAAP-FISH, treatment. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n

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Discordant Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma: Comparative Molecular Analysis Reveals a Heterogeneous Group of Disorders

Cited by 63 publications

References 28 publications

Low levels of monoclonal small B cells in the bone marrow of patients with diffuse large B-cell lymphoma of activated B-cell type but not of germinal center B-cell type

Low levels of monoclonal small B cells in the bone marrow of patients with diffuse large B-cell lymphoma of activated B-cell type but not of germinal center B-cell type

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

Lymphoproliferative Disorders

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