Top

Published in:

01-10-2017 | Review and Perspectives

The clinicopathologic spectrum of mature aggressive B cell lymphomas

Authors: Lisa Rimsza, Stefania Pittaluga, Stephan Dirnhofer, Christiane Copie-Bergman, Laurence de Leval, Fabio Facchetti, Stefano Pileri, Andreas Rosenwald, Andrew Wotherspoon, Falko Fend

Published in: Virchows Archiv | Issue 4/2017

Abstract

Our understanding of mature aggressive B cell lymphomas has evolved significantly in the last years as reflected in the 2016 update of the WHO lymphoma classification. A main topic of the 2016 European Association for Haematopathology/Society of Hematopathology lymphoma workshop in Basel therefore was the clinicopathological spectrum of mature aggressive B cell lymphomas with the exception of conventional diffuse large B cell lymphoma. In this review, we summarize two sessions dedicated to “high-grade B cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (so-called double/triple-hit lymphomas)” and “high-grade B cell lymphomas, NOS” as defined in the 2016 update of the WHO lymphoma classification, Burkitt lymphoma and related neoplasms, and terminally differentiated aggressive B cell lymphomas. One focus was on cases of Burkitt lymphoma with unusual clinical features such as spontaneous regression or association with immunosuppression, and the new provisional category of Burkitt-like lymphoma with 11q aberration. The large numbers of cases submitted for the new high-grade categories with or without genetic “double/triple hit” demonstrated the broad clinical and pathological spectrum of this group and gave ample opportunity for discussion. In this review, current definitions and our understanding of the main high-grade categories, potential problem areas, and suggestions for the immunophenotypic and genetic work-up of these neoplasms are discussed and illustrated by many interesting and challenging cases submitted to the workshop.

Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM (2006) Lymphoma/leukemia molecular profiling project: molecular diagnosis of Burkitt’s lymphoma. N Engl J Med 354:2431–2442CrossRefPubMed

Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kuhn M, Lenze D, Lichter P, Martin-Subero JI, Moller P, Muller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Sturzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trumper L, Stein H, Siebert R (2006) Molecular mechanisms in malignant lymphomas network project of the Deutsche Krebshilfe: a biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med 354:2419–2430CrossRefPubMed

Leoncini L, Raphael M, Stein H, Harris NL, Jaffe ES, Kluin P (2008) Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC press, Lyon, pp 262–264

Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B, Rosolowski M, Ammerpohl O, Wagener R, Bernhart SH, Lenze D, Szczepanowski M, Paulsen M, Lipinski S, Russell RB, Adam-Klages S, Apic G, Claviez A, Hasenclever D, Hovestadt V, Hornig N, Korbel JO, Kube D, Langenberger D, Lawerenz C, Lisfeld J, Meyer K, Picelli S, Pischimarov J, Radlwimmer B, Rausch T, Rohde M, Schilhabel M, Scholtysik R, Spang R, Trautmann H, Zenz T, Borkhardt A, Drexler HG, Moller P, RA ML, Pott C, Schreiber S, Trumper L, Loeffler M, Stadler PF, Lichter P, Eils R, Kuppers R, Hummel M, Klapper W, Rosenstiel P, Rosenwald A, Brors B, Siebert R (2012) Project IM-S: recurrent mutation of the id3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44:1316–1320CrossRefPubMed

Lenze D, Leoncini L, Hummel M, Volinia S, Liu CG, Amato T, De Falco G, Githanga J, Horn H, Nyagol J, Ott G, Palatini J, Pfreundschuh M, Rogena E, Rosenwald A, Siebert R, Croce CM, Stein H (2011) The different epidemiologic subtypes of Burkitt lymphoma share a homogenous microRNA profile distinct from diffuse large B-cell lymphoma. Leukemia 25:1869–1876CrossRefPubMedPubMedCentral

Piccaluga PP, De Falco G, Kustagi M, Gazzola A, Agostinelli C, Tripodo C, Leucci E, Onnis A, Astolfi A, Sapienza MR, Bellan C, Lazzi S, Tumwine L, Mawanda M, Ogwang M, Calbi V, Formica S, Califano A, Pileri SA, Leoncini L (2011) Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes. Blood 117:3596–3608CrossRefPubMed

Chisholm KM, Bangs CD, Bacchi CE, Molina-Kirsch H, Cherry A, Natkunam Y (2015) Expression profiles of myc protein and MYC gene rearrangement in lymphomas. Am J Surg Pathol 39:294–303CrossRefPubMed

Haralambieva E, Schuuring E, Rosati S, van Noesel C, Jansen P, Appel I, Guikema J, Wabinga H, Bleggi-Torres LF, Lam K, van den Berg E, Mellink C, van Zelderen-Bhola S, Kluin P (2004) Interphase fluorescence in situ hybridization for detection of 8q24/myc breakpoints on routine histologic sections: validation in Burkitt lymphomas from three geographic regions. Genes Chromosomes Cancer 40:10–18CrossRefPubMed

Baumgaertner I, Copie-Bergman C, Levy M, Haioun C, Charachon A, Baia M, Sobhani I, Delchier JC (2009) Complete remission of gastric Burkitt’s lymphoma after eradication of Helicobacter pylori. World J Gastroenterol 15:5746–5750CrossRefPubMedPubMedCentral

10.

Bluming AZ, Ziegler JL (1971) Regression of Burkitt’s lymphoma in association with measles infection. Lancet 2:105–106CrossRefPubMed

11.

Parekh S, Hebert T, Ratech H, Sparano J (2005) Variable problems in lymphomas: case 3. Spontaneous regression of HIV-associated Burkitt’s lymphoma of the cecum. J Clin Oncol 23:8116–8117CrossRefPubMed

12.

Ziegler JL (1976) Spontaneous remission in Burkitt’s lymphoma. Natl Cancer Inst Monogr 44:61–65PubMed

13.

Haralambieva E, Rosati S, van Noesel C, Boers E, van Marwijk KM, Schuuring E, Kluin P (2004) Florid granulomatous reaction in Epstein-Barr virus-positive nonendemic Burkitt lymphomas: report of four cases. Am J Surg Pathol 28:379–383CrossRefPubMed

14.

Schrager JA, Pittaluga S, Raffeld M, Jaffe ES (2005) Granulomatous reaction in Burkitt lymphoma: correlation with EBV positivity and clinical outcome. Am J Surg Pathol 29:1115–1116PubMed

15.

Li JN, Gao LM, Wang WY, Chen M, Li GD, Liu WP, Zhang WY (2014) HIV-related Burkitt lymphoma with florid granulomatous reaction: an unusual case with good outcome. Int J Clin Exp Pathol 7:7049–7053PubMedPubMedCentral

16.

Fu T, Voo KS, Wang RF (2004) Critical role of EBNA1-specific CD4⁺ T cells in the control of mouse Burkitt lymphoma in vivo. J Clin Invest 114:542–550CrossRefPubMedPubMedCentral

17.

Guech-Ongey M, Simard EP, Anderson WF, Engels EA, Bhatia K, Devesa SS, Mbulaiteye SM (2010) AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology? Blood 116:5600–5604CrossRefPubMedPubMedCentral

18.

Gopal S, Patel MR, Yanik EL, Cole SR, Achenbach CJ, Napravnik S, Burkholder GA, Reid EG, Rodriguez B, Deeks SG, Mayer KH, Moore RD, Kitahata MM, Eron JJ, Richards KL (2013) Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst 105:1221–1229CrossRefPubMedPubMedCentral

19.

Davi F, Delecluse HJ, Guiet P, Gabarre J, Fayon A, Gentilhomme O, Felman P, Bayle C, Berger F, Audouin J, Bryon PA, Diebold J, Raphael M (1998) Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin’s lymphomas. Burkitt’s lymphoma study group. J Clin Oncol 16:3788–3795CrossRefPubMed

20.

Raphael MM, Audouin J, Lamine M, Delecluse HJ, Vuillaume M, Lenoir GM, Gisselbrecht C, Lennert K, Diebold J (1994) Immunophenotypic and genotypic analysis of acquired immunodeficiency syndrome-related non-Hodgkin’s lymphomas. Correlation with histologic features in 36 cases. French study group of pathology for HIV-associated tumors. Am J Clin Pathol 101:773–782CrossRefPubMed

21.

Ferreiro JF, Morscio J, Dierickx D, Marcelis L, Verhoef G, Vandenberghe P, Tousseyn T, Wlodarska I (2015) Post-transplant molecularly defined Burkitt lymphomas are frequently myc-negative and characterized by the 11q-gain/loss pattern. Haematologica 100:e275–e279CrossRefPubMedPubMedCentral

22.

Gong JZ, Stenzel TT, Bennett ER, Lagoo AS, Dunphy CH, Moore JO, Rizzieri DA, Tepperberg JH, Papenhausen P, Buckley PJ (2003) Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases. Am J Surg Pathol 27:818–827CrossRefPubMed

23.

Picarsic J, Jaffe R, Mazariegos G, Webber SA, Ellis D, Green MD, Reyes-Mugica M (2011) Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder. Cancer 117:4540–4550CrossRefPubMed

24.

Xicoy B, Ribera JM, Esteve J, Brunet S, Sanz MA, Fernandez-Abellan P, Feliu E (2003) Post-transplant Burkitt’s leukemia or lymphoma. Study of five cases treated with specific intensive therapy (PETHEMA ALL-3/97 trial). Leuk Lymphoma 44:1541–1543CrossRefPubMed

25.

Pienkowska-Grela B, Rymkiewicz G, Grygalewicz B, Woroniecka R, Krawczyk P, Czyz-Domanska K, Walewski J (2011) Partial trisomy 11, dup(11)(q23q13), as a defect characterizing lymphomas with Burkitt pathomorphology without MYC gene rearrangement. Med Oncol 28:1589–1595CrossRefPubMed

26.

Poirel HA, Cairo MS, Heerema NA, Swansbury J, Auperin A, Launay E, Sanger WG, Talley P, Perkins SL, Raphael M, McCarthy K, Sposto R, Gerrard M, Bernheim A, Patte C, Committee FLIS (2009) Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. Leukemia 23:323–331CrossRefPubMed

27.

Salaverria I, Martin-Guerrero I, Wagener R, Kreuz M, Kohler CW, Richter J, Pienkowska-Grela B, Adam P, Burkhardt B, Claviez A, Damm-Welk C, Drexler HG, Hummel M, Jaffe ES, Kuppers R, Lefebvre C, Lisfeld J, Loffler M, Macleod RA, Nagel I, Oschlies I, Rosolowski M, Russell RB, Rymkiewicz G, Schindler D, Schlesner M, Scholtysik R, Schwaenen C, Spang R, Szczepanowski M, Trumper L, Vater I, Wessendorf S, Klapper W, Siebert R (2014) Molecular mechanisms in malignant lymphoma network P, Berlin-Frankfurt-Munster non-Hodgkin lymphoma group: a recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 123:1187–1198CrossRefPubMedPubMedCentral

28.

Colomo L, Vazquez I, Papaleo N, Espinet B, Ferrer A, Franco C, Comerma L, Hernandez S, Calvo X, Salar A, Climent F, Mate JL, Forcada P, Mozos A, Nonell L, Martinez A, Carrio A, Costa D, Dlouhy I, Salaverria I, Martin-Subero JI, Lopez-Guillermo A, Valera A, Campo E (2017) LMO2-negative expression predicts the presence of MYC translocations in aggressive B-cell lymphomas. Am J Surg Pathol

29.

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127:2375–2390CrossRefPubMedPubMedCentral

30.

Kanagal-Shamanna R, Medeiros LJ, Lu G, Wang SA, Manning JT, Lin P, Penn GM, Young KH, You MJ, Vega F, Bassett R, Miranda RN (2012) High-grade B cell lymphoma, unclassifiable, with blastoid features: an unusual morphological subgroup associated frequently with BCL2 and/or MYC gene rearrangements and a poor prognosis. Histopathology 61:945–954CrossRefPubMed

31.

Copie-Bergman C, Cuilliere-Dartigues P, Baia M, Briere J, Delarue R, Canioni D, Salles G, Parrens M, Belhadj K, Fabiani B, Recher C, Petrella T, Ketterer N, Peyrade F, Haioun C, Nagel I, Siebert R, Jardin F, Leroy K, Jais JP, Tilly H, Molina TJ, Gaulard P (2015) MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood 126:2466–2474CrossRefPubMed

32.

Pedersen MO, Gang AO, Poulsen TS, Knudsen H, Lauritzen AF, Nielsen SL, Gang UO, Norgaard P (2012) Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma—a single centre’s experience. Eur J Haematol 89:63–71CrossRefPubMed

33.

Pedersen MO, Gang AO, Poulsen TS, Knudsen H, Lauritzen AF, Nielsen SL, Klausen TW, Norgaard P (2014) MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations. Eur J Haematol 92:42–48CrossRefPubMed

34.

Munoz-Marmol AM, Sanz C, Tapia G, Marginet R, Ariza A, Mate JL (2013) Myc status determination in aggressive B-cell lymphoma: the impact of FISH probe selection. Histopathology 63:418–424CrossRefPubMed

35.

Pillai RK, Sathanoori M, Van Oss SB, Swerdlow SH (2013) Double-hit B-cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphomas. Am J Surg Pathol 37:323–332CrossRefPubMed

36.

Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, Scott DW, Tan KL, Steidl C, Sehn LH, Chan WC, Iqbal J, Meyer PN, Lenz G, Wright G, Rimsza LM, Valentino C, Brunhoeber P, Grogan TM, Braziel RM, Cook JR, Tubbs RR, Weisenburger DD, Campo E, Rosenwald A, Ott G, Delabie J, Holcroft C, Jaffe ES, Staudt LM, Gascoyne RD (2012) Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3452–3459CrossRefPubMedPubMedCentral

37.

Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282CrossRefPubMed

38.

Moench L, Sachs Z, Aasen G, Dolan M, Dayton V, Courville EL (2016) Double- and triple-hit lymphomas can present with features suggestive of immaturity, including TdT expression, and create diagnostic challenges. Leuk Lymphoma 57:2626–2635CrossRefPubMed

39.

Tzankov A, Xu-Monette ZY, Gerhard M, Visco C, Dirnhofer S, Gisin N, Dybkaer K, Orazi A, Bhagat G, Richards KL, Hsi ED, Choi WW, van Krieken JH, Ponzoni M, Ferreri AJ, Ye Q, Winter JN, Farnen JP, Piris MA, Moller MB, You MJ, McDonnell T, Medeiros LJ, Young KH (2014) Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Mod Pathol 27:958–971CrossRefPubMed

40.

Menter T, Medani H, Ahmad R, Flora R, Trivedi P, Reid A, Naresh KN (2016) Myc and bcl2 evaluation in routine diagnostics of aggressive B-cell lymphomas—presentation of a work-flow and the experience with 248 cases. Br J Haematol. doi:10.1111/bjh.14250

41.

Yoon SO, Jeon YK, Paik JH, Kim WY, Kim YA, Kim JE, Kim CW (2008) Myc translocation and an increased copy number predict poor prognosis in adult diffuse large B-cell lymphoma (DLBCL), especially in germinal centre-like B cell (GCB) type. Histopathology 53:205–217CrossRefPubMed

42.

Stasik CJ, Nitta H, Zhang W, Mosher CH, Cook JR, Tubbs RR, Unger JM, Brooks TA, Persky DO, Wilkinson ST, Grogan TM, Rimsza LM (2010) Increased myc gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica 95:597–603CrossRefPubMedPubMedCentral

43.

Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, Kridel R, Barry GS, Hother C, Abrisqueta P, Boyle M, Meissner B, Telenius A, Savage KJ, Sehn LH, Slack GW, Steidl C, Staudt LM, Connors JM, Rimsza LM, Gascoyne RD (2015) Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol 33:2848–2856CrossRefPubMedPubMedCentral

44.

McPhail ED, Maurer MJ, Ketterling RP, Macon WR, Feldman AL, Kurtin PJ, Witzig TE, Vaidya R, Habermann TM (2016) Prognostic impact of morphology, MYC gene partner and BCL2/BCL6 translocation status in “high grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements”. Blood 128:1750–1750

45.

Read JA, Koff JL, Nastoupil LJ, Williams JN, Cohen JB, Flowers CR (2014) Evaluating cell-of-origin subtype methods for predicting diffuse large B-cell lymphoma survival: a meta-analysis of gene expression profiling and immunohistochemistry algorithms. Clin Lymphoma Myeloma Leuk 14:460–467 e462CrossRefPubMedPubMedCentral

46.

Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W, Jaffe ES, Rosenwald A, Campo E, Chan WC, Connors JM, Smeland EB, Mottok A, Braziel RM, Ott G, Delabie J, Tubbs RR, Cook JR, Weisenburger DD, Greiner TC, Glinsmann-Gibson BJ, Fu K, Staudt LM, Gascoyne RD, Rimsza LM (2014) Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123:1214–1217CrossRefPubMedPubMedCentral

47.

Sesques P, Johnson NA (2017) Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. Blood 129:280–288CrossRefPubMed

48.

Chadburn A, Said J, Gratzinger D, Chan JK, de Jong D, Jaffe ES, Natkunam Y, Goodlad JR (2017) HHV8/KSHV-positive lymphoproliferative disorders and the spectrum of plasmablastic and plasma cell neoplasms: 2015 SH/EAHP workshop report-part 3. Am J Clin Pathol 147:171–187CrossRefPubMed

49.

Matolcsy A, Nador RG, Cesarman E, Knowles DM (1998) Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation. Am J Pathol 153:1609–1614CrossRefPubMedPubMedCentral

50.

Valera A, Colomo L, Martinez A, de Jong D, Balague O, Matheu G, Martinez M, Taddesse-Heath L, Jaffe ES, Bacchi CE, Campo E (2013) Alk-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements. Mod Pathol 26:1329–1337CrossRefPubMed

51.

Oksenhendler E, Boulanger E, Galicier L, Du MQ, Dupin N, Diss TC, Hamoudi R, Daniel MT, Agbalika F, Boshoff C, Clauvel JP, Isaacson PG, Meignin V (2002) High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood 99:2331–2336CrossRefPubMed

52.

Du MQ, Diss TC, Liu H, Ye H, Hamoudi RA, Cabecadas J, Dong HY, Harris NL, Chan JK, Rees JW, Dogan A, Isaacson PG (2002) KSHV- and EBV-associated germinotropic lymphoproliferative disorder. Blood 100:3415–3418CrossRefPubMed

Title: The clinicopathologic spectrum of mature aggressive B cell lymphomas
Authors: Lisa Rimsza
Stefania Pittaluga
Stephan Dirnhofer
Christiane Copie-Bergman
Laurence de Leval
Fabio Facchetti
Stefano Pileri
Andreas Rosenwald
Andrew Wotherspoon
Falko Fend
Publication date: 01-10-2017
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 4/2017
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-017-2199-7

At a glance: The STEP trials

Springer Medicine

The clinicopathologic spectrum of mature aggressive B cell lymphomas

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

Ultrastructure of pheochromocytoma: undescribed morphologic features

Epstein-Barr virus-positive ileal carcinomas associated with Crohn’s disease

Chondrolipoma of the breast as a rare variant of myofibroblastoma: an immunohistochemical study of two cases

Composite tumor with pheochromocytoma and immature neuroblastoma: report of two cases with cytogenetic analysis and discussion of current terminology

Histiocytic and dendritic cell neoplasms: what have we learnt by studying 67 cases

Is Rosai-Dorfman disease a reactve process? Detection of a MAP2K1 L115V mutation in a case of Rosai-Dorfman disease