Concurrent lymphoid and Philadelphia chromosome-negative myeloproliferative neoplasms

Torregrosa, Jose Miguel; Soler, Gloria; Cancio, Shirley; Ferrer-Marin, Francisca
doi:10.1016/j.medcle.2016.02.030
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    "titulo" => "Concurrent lymphoid and Philadelphia chromosome-negative myeloproliferative neoplasms"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Three studies have shown that patients with chronic myeloproliferative neoplasms &#40;cMPN&#41; have 2&#46;8&#8211;3&#46;4 times higher risk of developing a lymphoproliferative neoplasim &#40;LPN&#41; compared to general population&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#8211;3</span></a> In most cases&#44; the diagnosis of LPN is subsequent to cMPN&#44; and in less than 10&#37; cases it is synchronous or prior to the development of myeloid disease&#44; possibly by the increased aggressiveness of lymphoid neoplasms&#46; Therefore&#44; these patients would die before developing a cMPN&#46; The molecular basis underlying this association is not well understood&#46; In recent years&#44; in addition to <span class="elsevierStyleItalic">JAK2</span><span class="elsevierStyleSup">V617F</span>&#44; in cMPN patients&#44; an increasing number of mutations have been identified in other genes&#44; such as&#58; <span class="elsevierStyleItalic">DNMT3A</span>&#44; <span class="elsevierStyleItalic">TET2</span>&#44; <span class="elsevierStyleItalic">ASXL1</span>&#44; <span class="elsevierStyleItalic">NRAS&#47;KRAS</span>&#44; <span class="elsevierStyleItalic">TP53</span>&#44; <span class="elsevierStyleItalic">AML1&#47;RUNX1</span>&#44; <span class="elsevierStyleItalic">CBL</span>&#44; <span class="elsevierStyleItalic">CALR</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4&#44;5</span></a> Defects in some of these genes have also been identified in patients with lymphoid neoplasms&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4&#44;6&#44;7</span></a> In fact&#44; recent studies have shown that epigenetic changes might have a role in lymphogenesis&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this study&#44; the prevalence and timing of LPN was assessed in patients diagnosed with cMPN &#40;according to the World Health Organization criteria at the time of reporting data<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a>&#41; recorded in our database from 2000 to 2013&#46; In patients with both diseases it was studied whether mutations in genes related to myeloid condition lead to this association&#46; In genomic DNA obtained from whole blood after venipuncture at diagnosis&#44; the presence of the JAK2<span class="elsevierStyleSup">V617F</span> mutation was analyzed in all patients&#59; c-KIT<span class="elsevierStyleSup">D816V</span> in patients with suspected systemic mastocytosis &#40;SM&#41; &#40;both by polymerase chain reaction &#91;PCR&#93;&#44; quantitative in real-time&#41;&#59; CALR in JAK2<span class="elsevierStyleSup">V617F</span>-negative patients &#40;by analysis of PCR fragments&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> and in patients with both neoplasms &#40;cMPN and LPN&#41;&#44; a selected panel of genes &#40;CBL &#91;exons 8 and 9&#93;&#44; ASXL1 &#91;exon 12&#93;&#44; NRAS&#47;KRAS &#91;exons 1 and 2&#93;&#44; IDH1&#47;2 &#91;exon 4&#93; and the complete coding region of TET2 and RUNX1&#41; by Sanger-type sequencing&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The overall study included 216 patients &#40;122 cases of essential thrombocythemia &#91;ET&#93;&#44; 50 of polycythemia vera &#91;PV&#93;&#44; 38 of myelofibrosis and 6 SM&#41;&#44; with a median age at diagnosis of 49 years &#40;IQR 22&#8211;92&#41; and a median follow-up of 82 months &#40;IQR 42&#8211;132&#41;&#46; Of the 216 cMPN patients included&#44; 4 &#40;1&#46;85&#37;&#41; had a concurrent LPN&#46; Clinical and biological characteristics of these 4 patients are reported in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The lymphoid neoplasms identified were two chronic lymphatic leukemia &#40;CLL&#44; cases 1 and 2&#41;&#44; 1 Primary cutaneous centrofollicular non-Hodgkin lymphoma &#40;case 3&#41; and a T-cell large granular lymphocyte leukemia&#40;T-LGL&#41; &#40;case 4&#41;&#46; Unlike other studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a> in ours&#44; LPN diagnosis was prior to &#40;case 3&#41;&#44; or synchronous to the cMPN &#40;remaining cases&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; One patient &#40;case 3&#41; required specific treatment for lymphoid neoplasm &#40;R-CHOP chemotherapy plus local radiation therapy&#41;&#44; while the rest remain in therapeutic abstention regarding this disease&#46; Regarding the mutational status of the 3 cMPN patients with negative Philadelphia chromosome &#40;1 PV and 2 ET&#41; JAK2 was mutated in 2 of them&#46; In the third patient&#44; negative for JAK2<span class="elsevierStyleSup">V617F</span>&#44; mutations in CALR &#40;case 1&#41; were not found either&#46; The SM patient presented mutation in c-KIT<span class="elsevierStyleSup">D816V</span>&#46; However&#44; none of the 4 patients with concurrent cMPN and LPN showed mutations in the panel of selected genes &#40;KRAS&#44; NRAS&#44; CBL&#44; ASXL1&#44; IDH1&#47;2&#44; TP53&#44; RUNX1 and TET2&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Association between cMPN and LPN is a rare event&#58; &#8764;1&#8211;1&#46;34&#37; incidence&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#8211;3</span></a> According to the medical literature&#44;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a> in our study&#44; the incidence of this association is higher in men&#44; and CLL is the LPN most frequently associated&#46; We describe the second case ever reported on the association between a cMPN and T-LGL<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> and the first in which the association is with a primary cutaneous lymphoma&#46; The latter patient also developed&#44; while under cytoreductive therapy with hydroxyurea&#44; a prostate neoplasm and a colon neoplasm&#46; Although it has been suggested that hydroxyurea can induce mutations in TP53&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> one of the genes most frequently mutated in human cancers&#44; no mutations were reported in this gene&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Also it is interesting in our study the association between SM with a B-CLL&#46; The SM associated to clonal hematological disease of line other than mast cell&#44; account for 30&#37; of SM&#44; but are frequently associated with myeloid neoplasms&#44; mainly chronic myelomonocytic leukemia&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> The association with lymphoid neoplasm&#44; as in our case&#44; is unusual&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In summary&#44; previous studies have attempted to address the question of whether there is a genetic predisposition to both hematological diseases &#40;cMPN-LPN&#41;&#44; with poor results&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a> In our study&#44; we have not detected additional mutations other than c-KIT<span class="elsevierStyleSup">D816V</span> and JAK2<span class="elsevierStyleSup">V617F</span>&#44; previously known&#46; The small size of our sample&#44; along with the low frequency of these mutations in cMPN&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> is the main limitation of this study&#46; Despite these results&#44; we cannot rule out that genes other than the selected genes &#40;such as DNMT3A&#44; SF3B1&#44; NOTCH&#41;&#44; or even not discovered yet&#44; might promote genetic predisposition to both hematological neoplasms&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Torregrosa JM&#44; Soler G&#44; Cancio S&#44; Ferrer-Marin F&#46; Neoplasias mieloproliferativas cr&#243;nicas con cromosoma Filadelfia negativo y neoplasias linfoides concurrentes&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;318&#8211;319&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">CLL&#44; chronic lymphocytic leukemia&#59; NHL&#44; non-Hodgkin lymphoma&#59; SM&#44; systemic mastocytosis&#59; LPN&#44; lymphoproliferative neoplasm&#59; CMPN&#44; chronic myeloproliferative neoplasia&#59; PV&#44; polycythemia vera&#59; RT&#44; radiotherapy&#59; M&#44; male&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">cMPN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age at diagnosis</th><th class="td" title="table-head  " align="left" valign="top" scope="col">LPN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Cytogenetics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Accompanying solid tumors &#40;stage&#44; treatment&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">cMPN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LPN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B-CLL &#40;Rai-Binet 0-A&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">JAK2</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">V617F</span></span> non mutated&#46; <span class="elsevierStyleItalic">CALR</span> non mutated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B-CLL &#40;Rai-Binet 0-A&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c-<span class="elsevierStyleItalic">KIT</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">D816V</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trisomy 12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Primary cutaneous follicular NHL &#40;stage 3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">JAK2</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">V617F</span></span> mutated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prostate neoplasm &#40;in situ&#44; local RT&#41; Rectal adenocarcinoma &#40;B Coller&#44; surgery&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T-cell large granular lymphocyte leukemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">JAK2</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">V617F</span></span> mutated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients diagnosed with chronic myeloproliferative neoplasm and lymphoproliferative neoplasm&#46;</p>"
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