The facts that cancer represents tissues consisting of heterogeneous neoplastic, as well as reactive, cell populations and that cancers of the same histotype may show profound differences in clinical behavior have long been recognized. With the advent of new technologies and the demands of precision medicine, the investigation of tumor heterogeneity has gained much interest. An understanding of intertumoral heterogeneity in patients with the same disease entity is necessary to optimally guide personalized treatment. In addition, increasing evidence indicates that different tumor areas or primary tumors and metastases in an individual patient can show significant intratumoral heterogeneity on different levels. This phenomenon can be driven by genomic instability, epigenetic events, the tumor microenvironment, and stochastic variations in cellular function and antitumoral therapies. These mechanisms may lead to branched subclonal evolution from a common progenitor clone, resulting in spatial variation between different tumor sites, disease progression, and treatment resistance. This review addresses tumor heterogeneity in lymphomas from a pathologist's viewpoint. The relationship between morphologic, immunophenotypic, and genetic heterogeneity is exemplified in different lymphoma entities and reviewed in the context of high-grade transformation and transdifferentiation. In addition, factors driving heterogeneity, as well as clinical and therapeutic implications of lymphoma heterogeneity, will be discussed.

Swanton C: Intratumor heterogeneity: evolution through space and time. Cancer Res 2012;72:4875-4882.
Ding L, Wendl MC, McMichael JF, Raphael BJ: Expanding the computational toolbox for mining cancer genomes. Nat Rev Genet 2014;15:556-570.
McGranahan N, Swanton C: Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 2015;27:15-26.
Marusyk A, Polyak K: Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 2010;1805:105-117.
Visvader JE: Cells of origin in cancer. Nature 2011;469:314-322.
Greaves M, Maley CC: Clonal evolution in cancer. Nature 2012;481:306-313.
Zhou H, Neelakantan D, Ford HL: Clonal cooperativity in heterogenous cancers. Semin Cell Dev Biol 2017;64:78-89.
Heppner GH, Miller BE: Tumor heterogeneity: biological implications and therapeutic consequences. Cancer Metastasis Rev 1983;2:5-23.
Izzo F, Landau DA: Genetic and epigenetic determinants of B-cell lymphoma evolution. Curr Opin Hematol 2016;23:392-401.
Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, Lindeman NI, Murphy C, Akhavanfard S, Yeap BY, Xiao Y, Capelletti M, Iafrate AJ, Lee C, Christensen JG, Engelman JA, Janne PA: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010;17:77-88.
Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, Van Wier S, Blackburn PR, Baker AS, Dispenzieri A, Kumar S, Rajkumar SV, Carpten JD, Barrett M, Fonseca R, Stewart AK, Bergsagel PL: Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120:1067-1076.
Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, Vartanov A, Fernandes SM, Saksena G, Cibulskis K, Tesar B, Gabriel S, Hacohen N, Meyerson M, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ: Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013;152:714-726.
Kreso A, Dick JE: Evolution of the cancer stem cell model. Cell Stem Cell 2014;14:275-291.
Swerdllow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, ed 4. Lyon, IARC Press, 2008.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-2390.
Aguiar-Bujanda D, Blanco-Sanchez MJ, Jimenez-Gallego P, Mori-De Santiago M, Hernandez-Sosa M, Galvan-Ruiz S, Hernandez-Sarmiento S, Saura-Grau S, Bohn-Sarmiento U: Therapeutic approaches in patients with newly diagnosed follicular lymphoma. Future Oncol 2014;10:1967-1980.
Kumar A, Sundararajan S, Puvvada S, Persky DO: Limited stage aggressive non-Hodgkin lymphoma: what is optimal therapy? Curr Treat Options Oncol 2016;17:45.
Gribben JG: How I treat CLL up front. Blood 2010;115:187-197.
Armitage JO: How I treat patients with diffuse large B-cell lymphoma. Blood 2007;110:29-36.
Brudno J, Tadmor T, Pittaluga S, Nicolae A, Polliack A, Dunleavy K: Discordant bone marrow involvement in non-Hodgkin lymphoma. Blood 2016;127:965-970.
Agbay RL, Loghavi S, Medeiros LJ, Khoury JD: High-grade transformation of low-grade B-cell lymphoma: pathology and molecular pathogenesis. Am J Surg Pathol 2016;40:e1-e16.
Parikh SA, Kay NE, Shanafelt TD: How we treat Richter syndrome. Blood 2014;123:1647-1657.
Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ: Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2008;26:196-203.
Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K, Arcaini L, Lucioni M, Rocque GB, Xu-Monette ZY, Visco C, Chang J, Chigrinova E, Forconi F, Marasca R, Besson C, Papadaki T, Paulli M, Larocca LM, Pileri SA, Gattei V, Bertoni F, Foa R, Young KH, Gaidano G: The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 2011;117:3391-3401.
Mao Z, Quintanilla-Martinez L, Raffeld M, Richter M, Krugmann J, Burek C, Hartmann E, Rudiger T, Jaffe ES, Muller-Hermelink HK, Ott G, Fend F, Rosenwald A: IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol 2007;31:1605-1614.
Ohno T, Smir BN, Weisenburger DD, Gascoyne RD, Hinrichs SD, Chan WC: Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with “Hodgkin's transformation”. Blood 1998;91:1757-1761.
Tsimberidou AM, O'Brien S, Kantarjian HM, Koller C, Hagemeister FB, Fayad L, Lerner S, Bueso-Ramos CE, Keating MJ: Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer 2006;107:1294-1302.
Montoto S, Fitzgibbon J: Transformation of indolent B-cell lymphomas. J Clin Oncol 2011;29:1827-1834.
Chung R, Lai R, Wei P, Lee J, Hanson J, Belch AR, Turner AR, Reiman T: Concordant but not discordant bone marrow involvement in diffuse large B-cell lymphoma predicts a poor clinical outcome independent of the International Prognostic Index. Blood 2007;110:1278-1282.
Sehn LH, Scott DW, Chhanabhai M, Berry B, Ruskova A, Berkahn L, Connors JM, Gascoyne RD: Impact of concordant and discordant bone marrow involvement on outcome in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 2011;29:1452-1457.
Shim H, Oh JI, Park SH, Jang S, Park CJ, Huh J, Suh C, Chi HS: Prognostic impact of concordant and discordant cytomorphology of bone marrow involvement in patients with diffuse, large, B-cell lymphoma treated with R-CHOP. J Clin Pathol 2013;66:420-425.
Kremer M, Spitzer M, Mandl-Weber S, Stecker K, Schmidt B, Hofler H, Quintanilla-Martinez L, Fend F: Discordant bone marrow involvement in diffuse large B-cell lymphoma: comparative molecular analysis reveals a heterogeneous group of disorders. Lab Invest 2003;83:107-114.
Küppers R, Duhrsen U, Hansmann ML: Pathogenesis, diagnosis, and treatment of composite lymphomas. Lancet Oncol 2014;15:e435-e446.
Fend F, Quintanilla-Martinez L, Kumar S, Beaty MW, Blum L, Sorbara L, Jaffe ES, Raffeld M: Composite low grade B-cell lymphomas with two immunophenotypically distinct cell populations are true biclonal lymphomas: a molecular analysis using laser capture microdissection. Am J Pathol 1999;154:1857-1866.
Jaffe ES, Zarate-Osorno A, Kingma DW, Raffeld M, Medeiros LJ: The interrelationship between Hodgkin's disease and non-Hodgkin's lymphomas. Ann Oncol 1994;5(suppl 1):7-11.
Hoeller S, Copie-Bergman C: Grey zone lymphomas: lymphomas with intermediate features. Adv Hematol 2012;2012:460801.
Ejegod D, Sorensen KD, Mossbrugger I, Quintanilla-Martinez L, Schmidt J, Pedersen FS: Control of pathogenicity and disease specificity of a T-lymphomagenic gammaretrovirus by E-box motifs but not by an overlapping glucocorticoid response element. J Virol 2009;83:336-346.
Dogan A, Bagdi E, Munson P, Isaacson PG: CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. Am J Surg Pathol 2000;24:846-852.
Eshoa C, Perkins S, Kampalath B, Shidham V, Juckett M, Chang CC: Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas. Am J Clin Pathol 2001;115:862-867.
Kampalath B, Barcos MP, Stewart C: Phenotypic heterogeneity of B cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Clin Pathol 2003;119:824-832.
Bilalovic N, Blystad AK, Golouh R, Nesland JM, Selak I, Trinh D, Torlakovic E: Expression of bcl-6 and CD10 protein is associated with longer overall survival and time to treatment failure in follicular lymphoma. Am J Clin Pathol 2004;121:34-42.
Soma LA, Craig FE, Swerdlow SH: The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol 2006;37:152-159.
Remstein ED, Hanson CA, Kyle RA, Hodnefield JM, Kurtin PJ: Despite apparent morphologic and immunophenotypic heterogeneity, Waldenstrom's macroglobulinemia is consistently composed of cells along a morphologic continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. Semin Oncol 2003;30:182-186.
Goteri G, Olivieri A, Ranaldi R, Lucesole M, Filosa A, Capretti R, Pieramici T, Leoni P, Rubini C, Fabris G, Lo Muzio L: Bone marrow histopathological and molecular changes of small B-cell lymphomas after rituximab therapy: comparison with clinical response and patients outcome. Int J Immunopathol Pharmacol 2006;19:421-431.
Seliem RM, Freeman JK, Steingart RH, Hasserjian RP: Immunophenotypic changes and clinical outcome in B-cell lymphomas treated with rituximab. Appl Immunohistochem Mol Morphol 2006;14:18-23.
Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S: From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010;10:37-50.
Parikh SA, Shanafelt TD: Prognostic factors and risk stratification in chronic lymphocytic leukemia. Semin Oncol 2016;43:233-240.
Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, Kluth S, Bozic I, Lawrence M, Bottcher S, Carter SL, Cibulskis K, Mertens D, Sougnez CL, Rosenberg M, Hess JM, Edelmann J, Kless S, Kneba M, Ritgen M, Fink A, Fischer K, Gabriel S, Lander ES, Nowak MA, Dohner H, Hallek M, Neuberg D, Getz G, Stilgenbauer S, Wu CJ: Mutations driving CLL and their evolution in progression and relapse. Nature 2015;526:525-530.
Chigrinova E, Rinaldi A, Kwee I, Rossi D, Rancoita PM, Strefford JC, Oscier D, Stamatopoulos K, Papadaki T, Berger F, Young KH, Murray F, Rosenquist R, Greiner TC, Chan WC, Orlandi EM, Lucioni M, Marasca R, Inghirami G, Ladetto M, Forconi F, Cogliatti S, Votavova H, Swerdlow SH, Stilgenbauer S, Piris MA, Matolcsy A, Spagnolo D, Nikitin E, Zamo A, Gattei V, Bhagat G, Ott G, Zucca E, Gaidano G, Bertoni F: Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 2013;122:2673-2682.
Fabbri G, Khiabanian H, Holmes AB, Wang J, Messina M, Mullighan CG, Pasqualucci L, Rabadan R, Dalla-Favera R: Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med 2013;210:2273-2288.
Okosun J, Bodor C, Wang J, Araf S, Yang CY, Pan C, Boller S, Cittaro D, Bozek M, Iqbal S, Matthews J, Wrench D, Marzec J, Tawana K, Popov N, O'Riain C, O'Shea D, Carlotti E, Davies A, Lawrie CH, Matolcsy A, Calaminici M, Norton A, Byers RJ, Mein C, Stupka E, Lister TA, Lenz G, Montoto S, Gribben JG, Fan Y, Grosschedl R, Chelala C, Fitzgibbon J: Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014;46:176-181.
Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, Ouillette P, Trifonov V, Rossi D, Tabbo F, Ponzoni M, Chadburn A, Murty VV, Bhagat G, Gaidano G, Inghirami G, Malek SN, Rabadan R, Dalla-Favera R: Genetics of follicular lymphoma transformation. Cell Rep 2014;6:130-140.
Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, Kela I, Hopmans ES, Myklebust JH, Ji H, Plevritis SK, Levy R, Alizadeh AA: Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 2013;121:1604-1611.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-511.
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, Montserrat E, Campo E, Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B, Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES, Wilson WH, Chan WC, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project: Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313-2323.
O'Malley DP, Auerbach A, Weiss LM: Practical applications in immunohistochemistry: evaluation of diffuse large B-cell lymphoma and related large B-cell lymphomas. Arch Pathol Lab Med 2015;139:1094-1107.
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: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275-282.
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: Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 2014;123:1214-1217.
Quintanilla-Martinez L: IX. Is it only about MYC? How to approach the diagnosis of diffuse large B-cell lymphomas. Hematol Oncol 2015;33(suppl 1):50-55.
Jiang P, Wang H, Li W, Zang C, Li B, Wong YJ, Meyer C, Liu JS, Aster JC, Liu XS: Network analysis of gene essentiality in functional genomics experiments. Genome Biol 2015;16:239.
Juskevicius D, Lorber T, Gsponer J, Perrina V, Ruiz C, Stenner-Liewen F, Dirnhofer S, Tzankov A: Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis. Leukemia 2016;30:2385-2395.
Shaknovich R, Melnick A: Epigenetics and B-cell lymphoma. Curr Opin Hematol 2011;18:293-299.
Pan H, Jiang Y, Boi M, Tabbo F, Redmond D, Nie K, Ladetto M, Chiappella A, Cerchietti L, Shaknovich R, Melnick AM, Inghirami GG, Tam W, Elemento O: Epigenomic evolution in diffuse large B-cell lymphomas. Nat Commun 2015;6:6921.
Stoecker MM, Wang E: Histiocytic/dendritic cell transformation of B-cell neoplasms: pathologic evidence of lineage conversion in differentiated hematolymphoid malignancies. Arch Pathol Lab Med 2013;137:865-870.
Feldman AL, Minniti C, Santi M, Downing JR, Raffeld M, Jaffe ES: Histiocytic sarcoma after acute lymphoblastic leukaemia: a common clonal origin. Lancet Oncol 2004;5:248-250.
Feldman AL, Berthold F, Arceci RJ, Abramowsky C, Shehata BM, Mann KP, Lauer SJ, Pritchard J, Raffeld M, Jaffe ES: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 2005;6:435-437.
Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL: Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 2003;21:759-806.
Xie H, Ye M, Feng R, Graf T: Stepwise reprogramming of B cells into macrophages. Cell 2004;117:663-676.
Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T: Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity 2006;25:731-744.
Rapino F, Robles EF, Richter-Larrea JA, Kallin EM, Martinez-Climent JA, Graf T: C/EBPα induces highly efficient macrophage transdifferentiation of B lymphoma and leukemia cell lines and impairs their tumorigenicity. Cell Rep 2013;3:1153-1163.
Wang E, Hutchinson CB, Huang Q, Sebastian S, Rehder C, Kanaly A, Moore J, Datto M: Histiocytic sarcoma arising in indolent small B-cell lymphoma: report of two cases with molecular/genetic evidence suggestive of a “transdifferentiation” during the clonal evolution. Leuk Lymphoma 2010;51:802-812.
Wang E, Papalas J, Hutchinson CB, Kulbacki E, Huang Q, Sebastian S, Rehder C, Silbermins D, Moore J, Datto M: Sequential development of histiocytic sarcoma and diffuse large b-cell lymphoma in a patient with a remote history of follicular lymphoma with genotypic evidence of a clonal relationship: a divergent (bilineal) neoplastic transformation of an indolent B-cell lymphoma in a single individual. Am J Surg Pathol 2011;35:457-463.
Feldman AL, Arber DA, Pittaluga S, Martinez A, Burke JS, Raffeld M, Camos M, Warnke R, Jaffe ES: Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood 2008;111:5433-5439.
Buser L, Bihl M, Rufle A, Mickys U, Tavoriene I, Griskevicius L, Tzankov A: Unique composite hematolymphoid tumor consisting of a pro-T lymphoblastic lymphoma and an indeterminate dendritic cell tumor: evidence for divergent common progenitor cell differentiation. Pathobiology 2014;81:199-205.
Zhang D, McGuirk J, Ganguly S, Persons DL: Histiocytic/dendritic cell sarcoma arising from follicular lymphoma involving the bone: a case report and review of literature. Int J Hematol 2009;89:529-532.
Brunner P, Rufle A, Dirnhofer S, Lohri A, Willi N, Cathomas G, Tzankov A, Juskevicius D: Follicular lymphoma transformation into histiocytic sarcoma: indications for a common neoplastic progenitor. Leukemia 2014;28:1937-1940.
Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Sehn LH, Shenkier TN, Gascoyne RD, Connors JM: Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol 2008;26:5165-5169.
Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP, Schwartz LH, Zucca E, Fisher RI, Trotman J, Hoekstra OS, Hicks RJ, O'Doherty MJ, Hustinx R, Biggi A, Cheson BD: Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014;32:3048-3058.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance AL, Lymphoma G; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Óseañ German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.
Bodet-Milin C, Kraeber-Bodere F, Moreau P, Campion L, Dupas B, Le Gouill S: Investigation of FDG-PET/CT imaging to guide biopsies in the detection of histological transformation of indolent lymphoma. Haematologica 2008;93:471-472.
Noy A, Schoder H, Gonen M, Weissler M, Ertelt K, Cohler C, Portlock C, Hamlin P, Yeung HW: The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL). Ann Oncol 2009;20:508-512.
Casulo C, Burack WR, Friedberg JW: Transformed follicular non-Hodgkin lymphoma. Blood 2015;125:40-47.
Sun R, Medeiros LJ, Young KH: Diagnostic and predictive biomarkers for lymphoma diagnosis and treatment in the era of precision medicine. Mod Pathol 2016;29:1118-1142.
Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K, Buhler A, Bottcher S, Ritgen M, Kneba M, Winkler D, Tausch E, Hoth P, Edelmann J, Mertens D, Bullinger L, Bergmann M, Kless S, Mack S, Jager U, Patten N, Wu L, Wenger MK, Fingerle-Rowson G, Lichter P, Cazzola M, Wendtner CM, Fink AM, Fischer K, Busch R, Hallek M, Dohner H: Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123:3247-3254.
Montserrat E, Dreger P: Treatment of chronic lymphocytic leukemia with del(17p)/TP53 mutation: allogeneic hematopoietic stem cell transplantation or BCR-signaling inhibitors? Clin Lymphoma Myeloma Leuk 2016;16:S74-S81.
Wang D, Bodovitz S: Single cell analysis: the new frontier in “omics”. Trends Biotechnol 2010;28:281-290.
Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, Andrews SR, Stegle O, Reik W, Kelsey G: Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods 2014;11:817-820.
Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, Li F, Tsang S, Wu K, Wu H, He W, Zeng L, Xing M, Wu R, Jiang H, Liu X, Cao D, Guo G, Hu X, Gui Y, Li Z, Xie W, Sun X, Shi M, Cai Z, Wang B, Zhong M, Li J, Lu Z, Gu N, Zhang X, Goodman L, Bolund L, Wang J, Yang H, Kristiansen K, Dean M, Li Y, Wang J: Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 2012;148:886-895.
Tang F, Lao K, Surani MA: Development and applications of single-cell transcriptome analysis. Nat Methods 2011;8:S6-S11.
Bendall SC, Nolan GP: From single cells to deep phenotypes in cancer. Nature Biotechnol 2012;30:639-647.
Spitzer MH, Nolan GP: Mass cytometry: single cells, many features. Cell 2016;165:780-791.
Rubakhin SS, Lanni EJ, Sweedler JV: Progress toward single cell metabolomics. Curr Opin Biotechnol 2013;24:95-104.
Navin N, Hicks J: Future medical applications of single-cell sequencing in cancer. Genome Med 2011;3:31.
Shapiro E, Biezuner T, Linnarsson S: Single-cell sequencing-based technologies will revolutionize whole-organism science. Nat Rev Genet 2013;14:618-630.
Schubert W, Bonnekoh B, Pommer AJ, Philipsen L, Bockelmann R, Malykh Y, Gollnick H, Friedenberger M, Bode M, Dress AW: Analyzing proteome topology and function by automated multidimensional fluorescence microscopy. Nat Biotechnol 2006;24:1270-1278.
Gerdes MJ, Sevinsky CJ, Sood A, Adak S, Bello MO, Bordwell A, Can A, Corwin A, Dinn S, Filkins RJ, Hollman D, Kamath V, Kaanumalle S, Kenny K, Larsen M, Lazare M, Li Q, Lowes C, McCulloch CC, McDonough E, Montalto MC, Pang Z, Rittscher J, Santamaria-Pang A, Sarachan BD, Seel ML, Seppo A, Shaikh K, Sui Y, Zhang J, Ginty F: Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. Proc Natl Acad Sci USA 2013;110:11982-11987.
Giesen C, Wang HA, Schapiro D, Zivanovic N, Jacobs A, Hattendorf B, Schuffler PJ, Grolimund D, Buhmann JM, Brandt S, Varga Z, Wild PJ, Gunther D, Bodenmiller B: Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods 2014;11:417-422.
Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, Levenson RM, Lowe JB, Liu SD, Zhao S, Natkunam Y, Nolan GP: Multiplexed ion beam imaging of human breast tumors. Nat Med 2014;20:436-442.
Rimm DL: Next-gen immunohistochemistry. Nat Methods 2014;11:381-383.
Zbuk KM, Eng C: Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 2007;7:35-45.
Houle D, Govindaraju DR, Omholt S: Phenomics: the next challenge. Nat Rev Genet 2010;11:855-866.
Bassarova A, Troen G, Fossa A, Ikonomou IM, Beiske K, Nesland JM, Delabie J: Transformation of B cell lymphoma to histiocytic sarcoma: somatic mutations of PAX-5 gene with loss of expression cannot explain transdifferentiation. J Hematop 2009;2:135-141.
Zeng W, Meck J, Cheson BD, Ozdemirli M: Histiocytic sarcoma transdifferentiated from follicular lymphoma presenting as a cutaneous tumor. J Cutan Pathol 2011;38:999-1003.
Fraser CR, Wang W, Gomez M, Zhang T, Mathew S, Furman RR, Knowles DM, Orazi A, Tam W: Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma to interdigitating dendritic cell sarcoma: evidence for transdifferentiation of the lymphoma clone. Am J Clin Pathol 2009;132:928-939.
Shao H, Xi L, Raffeld M, Feldman AL, Ketterling RP, Knudson R, Rodriguez-Canales J, Hanson J, Pittaluga S, Jaffe ES: Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases. Mod Pathol 2011;24:1421-1432.
West DS, Dogan A, Quint PS, Tricker-Klar ML, Porcher JC, Ketterling RP, Law ME, McPhail ED, Viswanatha DS, Kurtin PJ, Dao LN, Ritzer RD, Nowakowski GS, Feldman AL: Clonally related follicular lymphomas and Langerhans cell neoplasms: expanding the spectrum of transdifferentiation. Am J Surg Pathol 2013;37:978-986.
Ambrosio MR, De Falco G, Rocca BJ, Barone A, Amato T, Bellan C, Lazzi S, Leoncini L: Langerhans cell sarcoma following marginal zone lymphoma: expanding the knowledge on mature B cell plasticity. Virchows Arch 2015;467:471-480.
Chen W, Jaffe R, Zhang L, Hill C, Block AM, Sait S, Song B, Liu Y, Cai D: Langerhans cell sarcoma arising from chronic lymphocytic lymphoma/small lymphocytic leukemia: lineage analysis and BRAF V600E mutation study. N Am J Med Sci 2013;5:386-391.
Fernandez-Pol S, Bangs CD, Cherry A, Arber DA, Gratzinger D: Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma. Hum Pathol 2016;55:39-43.
Hure MC, Elco CP, Ward D, Hutchinson L, Meng X, Dorfman DM, Yu H: Histiocytic sarcoma arising from clonally related mantle cell lymphoma. J Clin Oncol 2012;30:e49-e53.
Michonneau D, Kaltenbach S, Derrieux C, Trinquand A, Brouzes C, Gibault L, North MO, Delarue R, Varet B, Emile JF, Brousse N, Hermine O: BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia. J Clin Oncol 2014;32:e117-e121.
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