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A t(11;14)(q13;q32)/CCND1::IGH carrying progenitor germinal B-cell with subsequent cytogenetic aberrations contributes to the development of classic Hodgkin lymphoma

Open AccessPublished:October 13, 2022DOI:https://doi.org/10.1016/j.cancergen.2022.09.009

      Highlights

      • First case of a cHL with t(11;14) identified by chromosome and FISH analysis with sustained CCND1 expression.
      • Mantle cell lymphoma and cHL are closely related sharing a common post germinal precursor with t(11;14)+.
      • Early acquisition of genetic lesions, such as loss of 9q, suggests the potential to develop a cHL phenotype with deregulated cell cycle and signaling pathways.

      Abstract

      Classic Hodgkin lymphoma (cHL) is characterized by the presence of Hodgkin Reed-Sternberg (HRS) cells. Although HRS cells express PAX5, cHL frequently lacks other B-cell markers. There is now evidence that HRS cells are monoclonal and are derived from germinal center B-cells. In terms of genetic aberrations, cHL frequently exhibit activated NF-kB signaling pathway. In this study, we present a case of cHL harboring a t(11;14) (q13;q32)/CCND1::IGH, identified by chromosome and fluorescence in situ hybridization analysis and with CCND1 expression in HRS cells. We also analyzed recurrent cytogenetic aberrations in t(11;14) positive mantle cell lymphoma (MCL) and those found in cHL from the literature to assess genetic overlap, clonal evolution, and to identify potential signaling pathways in cHL with CCND1::IGH. This analysis suggests the development of t(11;14)+ cHL and MCL from a transformed precursor cell with t(11;14) through genetic evolution and consequent deregulated pathways, including the NF-κB and NOTCH1 signaling.

      Keywords

      Introduction

      In the World Health Organization (WHO) classification of hematopoietic and lymphoid tissues, Hodgkin lymphoma (HL) is categorized into two major biologically distinct variants: classic Hodgkin lymphoma (cHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). cHL is characterized by large binucleate or multinucleated neoplastic cells or mononuclear variants (collectively termed Hodgkin Reed-Sternberg [HRS] cells) with large macronucleoli embedded in mixed inflammatory background, and this histologic type accounts for most cases of HL [
      • Kuppers R.
      The biology of Hodgkin's lymphoma.
      ,
      • Schmitz R.
      • Stanelle J.
      • Hansmann M.L.
      • Kuppers R.
      Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma.
      ]. The HRS cells are derived from the reprogrammed germinal center B-cells (GCB) [
      • Schmitz R.
      • Stanelle J.
      • Hansmann M.L.
      • Kuppers R.
      Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma.
      ]. Constitutive activation of NF-κB signaling pathway is necessary for survival and proliferation of HRS cells [
      • Schmitz R.
      • Stanelle J.
      • Hansmann M.L.
      • Kuppers R.
      Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma.
      ]. The HRS cells characteristically express CD30 and CD15. Chromosome analysis and fluorescence in situ hybridization (FISH) showed complex karyotypes and intra tumoral heterogeneity reflecting the multi-nucleation of the HRS cells; however, chromosome abnormalities unique to cHL have not been identified [
      • Tilly T.
      • Bastard C.
      • Delastre T.
      • Duva C.
      • Bizet M.
      • Lenormand B.
      • et al.
      Cytogenetic studies in untreated Hodgkin's disease.
      ,
      • Dohner H.
      • Bloomfield C.D.
      • Frizzera G.
      • Frestedt J.
      • Arthur D.C.
      Recurring chromosome abnormalities in Hodgkin's disease.
      ,
      • Weber-Matthiesen K.
      • Deerberg J.
      • Poetsch M.
      • Grote W.
      • B Schlegelberger B.
      Numerical chromosome aberrations are present within the CD30+Hodgkin and Reed-Sternberg cells in Hodgkin's disease.
      ]. Nonetheless, studies using comparative genomic hybridization and exome sequencing methods reported gains of 2p, 5q, 6p, 8q, 9p, 9q, 12q, 17q, 19p, 19q, 20q, loss of Xp, 6q, and 13q and amplification of 4p16, 4q23–24, and 9p23–24 [
      • Hartmann S.
      • Martin-Subero J.L.
      • Gesk S.
      • Husken J.
      • Giefing M.
      • Nagel I.
      • et al.
      Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization.
      ,
      • Reichel J.
      • Chadburn A.
      • Rubinstein P.G.
      • Giulino-Roth L.
      • Tam W.
      • Liu Y.
      • et al.
      Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reedf-Sternberg cells.
      ]. Although the HRS cells originated from GCB and have clonal changes in immunoglobulin genes (IG) [
      • Kuppers R.
      • Rajewsky K.
      • Zhao M.
      • Simons S.
      • Laumann R.
      • Fischer R.
      • et al.
      Hodgkin disease: hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development.
      ], translocations characteristic of B-cell non-Hodgkin lymphoma such as t(8;14) or t(14;18) or t(14;19) have been infrequently documented in HL [
      • Kamranvar S.A.
      • Masucci M.G.
      The Epstein-Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress.
      ,
      • Kanzler H.
      • Kuppers R.
      • Hansmann M.L.
      • Rajewsky K.
      Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells.
      ]. In terms of cHL pathogenesis, perturbations in molecular signaling pathways NF-kB, JAK/STAT, and Epstein-Barr virus infection of HRS cells have been documented [
      • Schwarzer R.
      • Jundt F.
      Notch and NF-κB signaling pathways in the biology of classical Hodgkin lymphoma.
      ]. Although there are no recurrent chromosome abnormalities specific to HL, further investigation to identify potential transforming events in HL is warranted.
      Concurrent histological presentation of mantle cell lymphoma (MCL) and cHL has previously been reported in few cases. In some of these reported cases, MCL and cHL cells were present in the same affected tissue, a co-exhisting or composite lymphoma, and exhibited identical immunophenotype/genotype [
      • Caleo A.
      • Sanchez-Aguilera A.
      • Rodriguez S.
      • Dotor A.M.
      • Beltran L.
      • de Larrinoa A.F.
      • et al.
      Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors.
      ,
      • Tinguely M.
      • Rosenquist R.
      • Sundstrom C.
      • Amini R.M.
      • Kuppers R.
      • Hansmann M.L.
      • et al.
      Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center.
      ,
      • Schneider S.
      • Crescenzi B.
      • Schneider M.
      • Ascani S.
      • Hartmann S.
      • Hansmann M.L.
      • et al.
      Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B-cell-derived mantle cell lymphoma.
      ,
      • Kramer S.
      • Uppal G.
      • Wang Z.X.
      • Gong J.Z.
      Mantle cell lymphoma with Hodgkin and Reed-Sternberg cells: review with illustrative case.
      ,
      • Murray C.
      • Quinn F.
      • Illyes G.
      • Walker J.
      • Castriciano G.
      • O'Sullivan P.
      • et al.
      Composite blastoid variant of mantle cell lymphoma and classical Hodgkin lymphoma.
      ], while in rare cases they are present in different tissues or sequentially developed [
      • Tashkandi H.
      • Petrova-Drus K.
      • Batlevi C.L.
      • Arcila M.E.
      • Roshal M.
      • Sen F.
      • et al.
      Divergent clonal evolution of a common precursor to mantle cell lymphoma and classic Hodgkin lymphoma.
      ]. Nonetheless, clonal relationship between MCL and cHL cells was established by common immunophenotypic and/or genetic markers. Here, we report a rare case of cHL with t(11;14)/CCND1::IGH in a complex karyotype. Since t(11;14) and/or cyclin D1 expression has been reported in cHL cells present in composite lymphomas, we examined the recurring chromosome abnormalities (RCAs) in t(11;14)+ MCL to identify potential cytogenetic evolutionary trajectories that may lead to the development of cHL with t(11;14). We show here that sequential acquisition of abnormalities such as del(13q), del(9q) has the potential to transform a t(11;14)+ initial progenitor transformed cell into cHL. We realize that this is a single rare case not reported previously, and additional study of such cases is needed to establish clonal relatedness between MCL and cHL.

      Materials and methods

      The tumor tissue was evaluated by hematopathology, immunohistochemistry (IHC), chromosome analysis and FISH. The core biopsy from the cervical lymph node was fixed in 10% neutral-buffered formalin, embedded in paraffin and sections were stained with hematoxylin and eosin for histological examination. For immunohistochemical evaluation of cell surface markers antibodies for CD15, CD30, CD20, CD3, PAX5, CD45 (Dako Agilent, Santa Clara CA), ALK1 (Epitomics, France), SOX11 (Cell Marque, Germany) were used and processed following standardized protocols. The presence of Epstein-Barr virus encoded small RNA (EBER) was evaluated on tissue sections using a fluorescein-conjugated PNA probe (Ventana Medical System, Inc, Tucson, AZ).
      Cells prepared from the fresh core biopsy of the cervical lymph node were cultured for 24 h in bone marrow culture medium and harvested for metaphases following standard cytogenetics procedures. G-banded metaphases were analyzed, and the abnormalities were described following ISCN 2020. Fluorescent DNA probes for CCND1 and IGH (Abbott Molecular, Abbott Park, IL, USA) were hybridized to interphase nuclei in cultured cells and in tissue sections and to the abnormal metaphases to evaluate the involvement of these genes in the t(11;14) detected in the karyotype. The tumor karyogram was inspected for candidate cancer genes using the Candidate Cancer Genes Blood database (http://ccgd-starrlab.oit.umn.edu); genes identified here were then evaluated for affected pathways and network interactions by using the STRING package available online (https://string-db.org/). The Institutional Review Board of the University of Texas Southwestern Medical Center in Dallas, Texas reviewed and approved the study protocol, and a waiver of informed consent was granted to this minimal risk study.
      Mitelman data base of Cancer Aberrations and Gene Fusions in Cancer (https://mitelmandatabase.isb-cgc.org, accessed in October 2021) was searched for complete karyotypes of MCL cases with t(11;14) and cHL cases to identify RCAs and to delineate evolutionary trajectories in MCL (see Supplemental Table 1 for these karyotypes). The RCAs from MCL were then applied to the Capri algorithm in the R environment from the Translational Oncology package to generate evolutionary pathways [
      • De Sano L.
      • Caravagna G.
      • Ramazzotti D.
      • Graudenzi A.
      • Mauri G.
      • Mishra B.
      • et al.
      TRONCO: an R package for the inference of cancer progression models from heterogeneous genomic data.
      ]. To determine driver alterations among the RCAs, the DriverNet R package was used for identification of driver chromosomal imbalances [
      • Bashashati A Haffari G.
      • Ding J.
      • Ha G.
      • Lui K.
      • Roser J.
      • et al.
      Drivernet: uncovering somatic driver mutations modulating transcriptional networks in cancer.
      ]. Subsequently, the unique RCAs shared by MCL and cHL from the literature were compared for similarities using linear regression R package (r-project.org); a p-value less than 0.05 was considered significant.

      Results

      Patient characteristics and genetic findings

      A 17-year-male presented for evaluation of a new anterior mediastinal mass. Physical examination on admission also showed palpable right supraclavicular lymph nodes. Laboratory findings revealed a white blood count of 5.9 × 109 /L, hemoglobin of 12.7 g/dl, and hematocrit of 42.1%. The differential count showed 66% neutrophils, 17% lymphocytes, 9.9% monocytes, 6.3% eosinophils and 0.3% basophils. Touch preparation of the core biopsies from the right cervical lymph node showed two cell populations, one composed of crushed lymphocytes and the other of larger atypical cells with prominent nucleoli. The histologic sections showed sclerosis and small lymphocytes intermixed with larger atypical bi- or multinucleated lymphoid cells with prominent nucleoli and abundant eosinophilic cytoplasm (Fig. 1A). IHC studies showed the large-atypical cells to be positive for CD15, CD30, cyclin D1 and weakly positive for PAX; they were negative for CD20, CD45, CD3, ALK-1, SOX11, and EBER. Cyclin D1 was negative in background cells. SOX11 expression which is highly specific to MCL [
      • Mozos A.
      • Royo C.
      • Hartmann E.
      • De Jong D.
      • Baro C.
      • Valera A.
      • et al.
      SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype.
      ,
      • Cho B.B.
      • Kelting S.M.
      • Gru A.A.
      • LeGallo R.D.
      • Pramoonjago P.
      • Goldin T.A.
      • et al.
      Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.
      ] was negative in this case excluding the possibility of undetected MCL cells in the tissue (Fig. 1B). These findings led to a diagnosis of cHL, stage IIIB, without evidence for MCL.
      Fig 1
      Fig. 1(A) Hodgkin/Reed-Sternberg cell with bi-lobed nucleus, vesicular chromatin and prominent nucleoli in eosinophilic cytoplasm, surrounded by small lymphocytes. (B) IHC for SOX11: HRS cells and other cells are negative; (C) The abnormal male karyotype containing multiple structural abnormalities, including a t(11;14) (black arrows), and additional abnormalities of Xq, 9q loss and monosomy13. (D) Sequential FISH on G-banded abnormal metaphase with dual fusion CCND1/IGH probes: fusion signals on der(11) and on der(14) are indicated by black arrows. (E) FISH on tissue sections: HRS cell shows fusion of CCND1 and IGH. (F) Cyclin D1 IHC: scattered HRS cells are positive for cyclin D1.
      Chromosome analysis of the core biopsy revealed an abnormal male karyotype containing multiple structural abnormalities - 45,Y,add(X)(q22),add(9)(q13),t(11;14)(q13;q32),−13,add(21)(p11.2)[2] /46,XY[2] (Fig. 1C). Sequential metaphase FISH analysis with probes for CCND1 and IGH showed fusion between them [ish t(11;14)(CCND1+,IGH+;IGH+,CCND1+)] (Fig. 1D). Interphase FISH analysis in cultured cells identified 1/79 cells positive for CCND1::IGH; the slide was pauci-cellular. Clonality of t(11;14) was further confirmed by FISH with CCND1 and IGH probes on tissue sections which showed fusion signals in HRS cells (Fig. 1E), and also by cyclin D1 IHC which showed nuclear positivity in the scattered HRS cells (Fig. 1F). Evaluation of the abnormal karyotype by String pathway analysis identified genes possibly affected by chromosome abnormalities and in perturbed cellular pathways such a NF-κB, and MTOR signaling or membrane trafficking or in mitotic cycle G2/M transition.
      The patient was treated with EuroNet-Pediatric Hodgkin lymphoma-C1 treatment group 3 (TG-3) protocol combined with radiation therapy (dose of 1980 cGy was delivered in 17 fractions of 180 cGy each). The patient subsequently had 4 cycles of cyclophosphamide, doxorubicin, prednisone, and dacarbazine (COPDAC) with complete remission on repeated image analysis. At the time of writing this report, the patient is doing well (34 months from diagnosis) with no complaints or treatment- related side-effects.

      Recurrent cytogenetic abnormalities in MCL

      Analysis of karyotypes of the 174 t(11;14)(q13;q32)+ MCL identified 32 RCAs (Fig. 2). Among these, the most frequent abnormalities were loss of Xq, 1p, 6q, 8q, 9q, 10p,13q and −17; loss of 1p, 8q, 12q, 13q and MYC rearrangements were identified as driver alterations. Loss of 9q and of Xq was observed in approximately 7% and 6% of the cases respectively. Clonal evolution analysis of the RCAs revealed multiple subclones in the t(11;14)+ MCL (Supplementary Fig. 1). One of the subclones shared the same chromosome abnormalities (13q loss and 9q loss) found in the present case of cHL. A comparison of loss of 13q, 9q, and Xq abnormalities between cohorts of 174 MCL cases and 167 of cHL from the literature (Supplementary Table 1) revealed a close relationship between the two tumor entities containing these aberrations (Fig. 3); however, deletion of 9q was more prevalent in cHL (p=.01). We speculate that dosage-sensitive genes in these abnormalities may contribute to the transformation of a progenitor GCB cell with t(11;14) into cHL. Indeed candidate cancer genes and pathogenetic pathway analysis of these common cytogenetic abnormalities identified multiple pathways possibly involved in the pathogenesis of cHL with t(11;14) (Fig. 4). We also identified 9q loss as a driver aberration from the shared abnormalities between MCL and cHL. The R code for the analyses was placed at github (https://github.com/rolan10141014/Classical-Hodgkin-with-t-11–14-/blob/main/R-CODE).
      Fig 2
      Fig. 2Thirty-two recurring cytogenetic abnormalities and their frequency in t(11;14)+ mantle cell lymphoma (n = 174). Key: l-loss, R-rearrangement, - monosomy, + trisomy.
      Fig 3
      Fig. 3Regression analysis of RCAs between MCL and cHL showing linear regression between MCL and cHL cases containing 9q loss, 13q loss and Xq loss. The R value of 0.75 suggests a good linear relationship between MCL and cHL containing these abnormalities (i.e., both entities share these abnormalities and pathways in their tumor evolution).
      Fig 4
      Fig. 4Postulated pathogenesis of cHL from a t(11;14)+ progenitor cell. Sequential loss of 13q and 9q soon after initial transformation event activate the NF-κB pathway and results in the cHL phenotype. Other pathways possibly affected by these chromosomal changes are also illustrated.

      Discussion

      Here we present a t(11;14)[CCND1::IGH +] cHL that showed characteristic pathological and immunohistochemical features. In addition, secondary abnormalities seen in MCL such as the loss of 9q and monosomy 13 (loss of 13q) were also present in this tumor. To the best of our knowledge this is the first report of a case of cHL containing a t(11;14) and with secondary chromosomal changes seen in MCL. We also have outlined clonal evolution patterns in t(11;14)+ MCL and in cHL, and we have identified 9q loss as a driver alteration and one of the frequent secondary abnormalities perturbing oncogenetic pathways such as NF-kB frequently perturbed in cHL. From these results we hypothesized that a t(11;14)+ progenitor GCB cell with subsequent loss of 13q and 9q has the potential to develop a cHL phenotype with deregulated NF-κB and NOTCH1 signaling pathways. cHL accounts for the majority of HL and constitutes approximately 90% of all HL. The EBER present in 40% of HL plays significant role in pathogenesis and has been implicated as a causative agent in the development of cHL; however, its role is not fully understood [
      • Kamranvar S.A.
      • Masucci M.G.
      The Epstein-Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress.
      ,
      • Schmitz R.
      • Renne C.
      • Rosenquist R.
      • Tinguely M.
      • Distler V.
      • Menestrina F.
      • et al.
      Insights into the multistep transformation process of lymphomas: igH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas.
      ]. Histologically, all subtypes of HL are characterized by the presence of large cells with multiple nuclei and prominent nucleoli, referred to HRS cells. These cells are CD30+ in all cases, and CD15+ in 75–85% of cases, a characteristic immunophenotype in cHL. The origin of HRS cells remained unclear, until studies showed clonal rearrangements in IG in them. One study, using interphase FISH, showed 17% of HRS cells in cHL harbored breakpoints in the IGH locus. Subsequent studies confirmed clonal derivation of HRS cells from GCB [
      • Kuppers R.
      • Rajewsky K.
      • Zhao M.
      • Simons S.
      • Laumann R.
      • Fischer R.
      • et al.
      Hodgkin disease: hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development.
      ,
      • Marafioti T.
      • Hummel M.
      • Foss H.D.
      • Laumen H.
      • Korbjuhn P.
      • Anagnostopoulos I.
      • et al.
      Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription.
      ,
      • Martin-Subero J.I.
      • Klapper W.
      • Sotnikova A.
      • Callet-Bauchu E.
      • Harder L.
      • Bastard C.
      • et al.
      Chromosomal breakpoints affecting immunoglobulin loci are recurrent in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma.
      ]; however, they lack B-cell markers typical of GCBs other than PAX5 and inappropriately express other markers such as TRAF1, CD15, JUN, JAK/STAT and STAT5 [
      • Ehlers A.
      • Oker E.
      • Bentink S.
      • Lenze D.
      • Stein H.
      • Hummel M.
      Histone acetylation and DNA demethylation of B cells result in a Hodgkin-like phenotype.
      ,
      • Janz M.
      • Hummel M.
      • Truss M.
      • Wollert-Wulf B.
      • Mathas S.
      • Johrens K.
      • et al.
      Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells.
      ,
      • Kuppers R.
      • Klein U.
      • Schwering I.
      • Distler V.
      • Brauninger A.
      • Cattoretti G.
      • et al.
      Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling.
      ,
      • Schwering I.
      • Brauninger A.
      • Klein U.
      • Jungnickel B.
      • Tinguely M.
      • Diehl V.
      • et al.
      Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
      ]. Moreover, the NF-κB pathway is constitutively activated and this is implicated in proliferation and survival of HRS cells [
      • Horie R.
      • Watanabe T.
      • Morishita Y.
      • Ito K.
      • Ishida T.
      • Kanegae Y.
      • et al.
      Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells.
      ,
      • Ranuncolo S.M.
      • Pittaluga S.
      • Evbuomwan M.O.
      • Jaffe E.S.
      • Lewis B.A.
      Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival.
      ,
      • Hinz M.
      • Lemke P.
      • Anagnostopoulos I.
      • Hacker C.
      • Krappmann D.
      • Mathas S.
      • et al.
      Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity.
      ,
      • Hopken U.E.
      • Foss H.D.
      • Meyer D.
      • Hinz Leder MK
      • Stein H.
      • et al.
      Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs.
      ]. These cells are also characterized by a high level of chromosome instability resulting in complex karyotypes with numerical abnormalities more frequent than structural abnormalities, although there is no unique cytogenetic aberration. Studies using CGH have reported gains and losses that are notably involved in the NF-kB pathway (e.g., gains of 2p, REL; 20q, CD40; 17q, MAP3K14; 12q, STAT6; 9q, NOTCH1 and 19p, JUNB), and other chromosomes (6q, 11q, 13q) [
      • Hartmann S.
      • Martin-Subero J.L.
      • Gesk S.
      • Husken J.
      • Giefing M.
      • Nagel I.
      • et al.
      Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization.
      ,
      • Steidl C.
      • Telenius A.
      • Shah S.P.
      • Farinha P.
      • Barclay L.
      • Boyle M.
      • et al.
      Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome.
      ].
      To elucidate the clonal evolution and the relationship of HRS cells to lymphoma cells, studies have often evaluated composite lymphomas (CL) [
      • Tinguely M.
      • Rosenquist R.
      • Sundstrom C.
      • Amini R.M.
      • Kuppers R.
      • Hansmann M.L.
      • et al.
      Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center.
      ,
      • Brauninger A.
      • Hansmann M.L.
      • Strickler G.
      • Dummer R.
      • Burg G.
      • Rajewsky K.
      • et al.
      Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma.
      ,
      • van den Berg A.
      • Maggio E.
      • Rust R.
      • Kooistra K.
      • Diepstra A.
      • Poppema S.
      Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma.
      ,
      • Rosenquist R.
      • Menestrina F.
      • Lestani M.
      • Kuppers R.
      • Hansmann M.L.
      • Brauninger A.
      Indications for peripheral light-chain revision and somatic hypermutation without a functional B-cell receptor in precursors of a composite diffuse large B-cell and Hodgkin's lymphoma.
      ]. CL of MCL and cHL is rare with only eight patients in the literature reported thus far. These cases were clonally related with IG rearrangements and/or CCND1::IGH fusion, although the analysis was unable to distinguish whether the t(11;14) was present in MCL, HRS or in both [
      • Caleo A.
      • Sanchez-Aguilera A.
      • Rodriguez S.
      • Dotor A.M.
      • Beltran L.
      • de Larrinoa A.F.
      • et al.
      Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors.
      ,
      • Schneider S.
      • Crescenzi B.
      • Schneider M.
      • Ascani S.
      • Hartmann S.
      • Hansmann M.L.
      • et al.
      Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B-cell-derived mantle cell lymphoma.
      ,
      • Kramer S.
      • Uppal G.
      • Wang Z.X.
      • Gong J.Z.
      Mantle cell lymphoma with Hodgkin and Reed-Sternberg cells: review with illustrative case.
      ,
      • Murray C.
      • Quinn F.
      • Illyes G.
      • Walker J.
      • Castriciano G.
      • O'Sullivan P.
      • et al.
      Composite blastoid variant of mantle cell lymphoma and classical Hodgkin lymphoma.
      ,
      • Shin S.S.
      • Ben-Ezra J.
      • Burke J.S.
      • Sheibani K.
      • Rappapor H.
      Reed-Sternberg-like cells in low-grade lymphomas are transformed neoplastic cells of B-cell lineage.
      ,
      • Hayes S.J.
      • Banerjee SS S.
      • Cook Y.
      • Houghton J.B.
      • Menasce L.P
      Composite mantle-cell lymphoma and classical Hodgkin lymphoma.
      ]. Only one reported case showed the t(11;14) positivity by FISH in both MCL and HRS cells, as well as identical somatic mutation in the IG variable region and the same TP53 mutation [
      • Schneider S.
      • Crescenzi B.
      • Schneider M.
      • Ascani S.
      • Hartmann S.
      • Hansmann M.L.
      • et al.
      Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B-cell-derived mantle cell lymphoma.
      ]. These results suggest that MCL and HRS cells are probably derived from a common post germinal center B-cell with CCND1::IGH rearrangement. Similarly, Tashkandi et al. showed a divergent clonal evolution of a common progenitor precursor with CCND1::IGH rearrangement and TP53, KMT2D, NSD2, IDH1 sequence variants evolving to MCL initially and to cHL subsequently in different sites [
      • Tashkandi H.
      • Petrova-Drus K.
      • Batlevi C.L.
      • Arcila M.E.
      • Roshal M.
      • Sen F.
      • et al.
      Divergent clonal evolution of a common precursor to mantle cell lymphoma and classic Hodgkin lymphoma.
      ]. In agreement with these findings that similar overlapping genetic abnormalities exists between MCL and cHL, our comparison of secondary cytogenetic changes between MCL and HRS cells suggests a high degree of genetic overlap between the two entities (Fig. 3). Indeed, shared abnormalities between these two entities included 9q, 13q loss and X abnormalities. The genetic similarity coupled with CCND1 expression in HRS cells points to a MCL clone that subsequently acquired a HRS phenotype. Potentially, an initial GCB progenitor cell acquired a t(11;14) followed by the loss of chromosome 13, resulting in RB1 deletion, a tumor suppressor gene that increases genomic instability and promotes subclonal evolution, including 9q loss. Although RB1 loss does not have strong propensity to modify other genes to cause progression of a malignant clone [
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • Orlic M.
      • Prigoda N.L.
      • Piovesan B.
      • et al.
      Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma.
      ], we speculate that the subsequent loss of 9q activates certain elements of the NF-κB signaling pathway and downstream oncogenic networks of NOTCH1 which promote tumor cell growth and favor the cHL phenotype. Gain of 9q, not loss of 9q as present in this case, has been reported in HRS cells; it is possible that this region is also dosage sensitive for a-copy number loss at 9q and can result in the NF-kB deregulation through a possible dosage imbalance mechanism. Despite our knowledge of various pathways in NF-kB signaling, some components are not completely understood and thus targeted therapies of this signaling pathway are lacking. Therefore, further work is needed to modulate NF-kB as a therapeutic target. At present, cyclophosphamide, doxorubicin, prednisone, and dacarbazine (COPDAC) with slight modification of this regimen are standard of care and obtain excellent outcomes in children as well as adolescents with intermediate or high-risk HL [
      • Ozuah N.W.
      • Marcus K.J.
      • LaCasce A.S.
      • Billett A.L.
      Excellent Outcomes following response-based omission of radiotherapy in children and adolescents with intermediate or high-risk Hodgkin lymphoma.
      ]. At the time of this writing (34 months from diagnosis), our patient has achieved complete remission with two cycles of vincristine-etoposide-prednisone-doxorubicin (OEPA), four cycles of COPDAC and radiation therapy (1980 cGy in seventeen fractions).
      In summary, we have documented the first case of a cHL with t(11;14)/CCND1::IGH rearrangement identified by chromosome and FISH analysis and with CCND1 expression in HRS cells. A small subset of MCL and cHL is clonally related and share a common post germinal precursor with t(11;14); however, further acquisition of genetic lesions such as loss of 9q promotes development of cHL.

      Declaration of Competing Interest

      The authors declare no competing financial or personal interests that influence the work reported in this paper and there has not been no financial support for this work.

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