Abstract
Chronic lymphocytic leukemia (CLL) is an indolent mature B-cell lymphoproliferative disorder that often presents with bone marrow and peripheral blood involvement. Lymphadenopathy and proliferation in extramedullary tissues are often seen. The key to the precise diagnosis of CLL begins with assessment of the cytomorphology of the neoplastic cells, often from peripheral blood, but also the architectural patterns of involvement from tissue sections in bone marrow and lymph node biopsies. Although not 100% sensitive and specific, these morphologic features are strong clues in the broad differential diagnosis. Immunophenotyping complements and aids the morphologic impressions. Although often an indolent disease, some patients tend to have progressive disease and an aggressive clinical course. Staining for CD38 and 70 kD zeta-associated protein (ZAP-70) helps to prognosticate the patient’s disease and predict the tumor’s mutational status for the immunoglobulin heavy-chain, variable region (IGHV). Since defining the disease in the mid-nineteenth century, the workup of CLL now combines multiple disciplines, from basic characterization of morphology to immunophenotyping, and now molecular genetics that all aid in arriving at a precise diagnosis and help to choose the proper therapies for affected patients. In this section, the morphology and immunophenotype of CLL are discussed, with special emphasis on differential diagnosis and transformation (Richter syndrome). The issue of monoclonal B-cell lymphocytosis is also addressed, the criteria and description of which have recently been modified in the new 2016 WHO revision.
References
Muller-Hermelink H, Montserrat E, Catovsky D. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer Press; 2008. p. 180–2.
Minot B, Issacs R. Lymphatic leukemia: age, incidence, duration and benefit derived from irradiation. Boston Med Surg J. 1924;1:1–9.
Rai KR. Progress in chronic lymphocytic leukaemia: a historical perspective. Baillieres Clin Haematol. 1993;6:757–65.
Scarfò L, Ghia P. What does it mean I have a monoclonal B-cell lymphocytosis? Recent insights and new challenges. Semin Oncol. 2016;43:201–8.
Omoti CE, Omoti AE. Richter syndrome: a review of clinical, ocular, neurological and other manifestations. Br J Haematol. 2008;142:709–16.
Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2008;142:202–15.
Rossi D, Gaidano G. Richter syndrome: pathogenesis and management. Semin Oncol. 2016;43:311–9.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.
Romano C, Sellitto A, Chiurazzi F, Simeone L, De Fanis U, Raia M, et al. Clinical and phenotypic features of CD5-negative B cell chronic lymphoproliferative disease resembling chronic lymphocytic leukemia. Int J Hematol. 2015;101:67–74.
Marti GE, Rawstron AC, Ghia P, Hillmen P, Houlston RS, Kay N, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130:325–32.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.
Rawstron AC, Bennett FL, O’Connor SJM, Kwok M, Fenton JAL, Plummer M, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575–83.
Rawstron AC, Shanafelt T, Lanasa MC, Landgren O, Hanson C, Orfao A, et al. Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). Cytometry B Clin Cytom. 2010;78(Suppl 1):S19–23.
Gibson SE, Swerdlow SH, Ferry JA, Surti U, Dal Cin P, Harris NL, et al. Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis. Haematologica. 2011;96:1144–52.
Ghia P. Another piece of the puzzle: is there a “nodal” monoclonal B-cell lymphocytosis? Haematologica. 2011;96:1089–91.
Vardi A, Dagklis A, Scarfò L, Jelinek D, Newton D, Bennett F, et al. Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL. Blood. 2013;121:4521–8.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.
Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24:512–20.
Nieto WG, Teodosio C, López A, Rodríguez-Caballero A, Romero A, Bárcena P, et al. Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics. Cytometry B Clin Cytom. 2010;78(Suppl 1):S24–34.
Nieto WG, Almeida J, Romero A, Teodosio C, López A, Henriques AF, et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood. 2009;114:33–7.
Shanafelt TD, Kay NE, Rabe KG, Call TG, Zent CS, Maddocks K, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009;27:3959–63.
Morabito F, Mosca L, Cutrona G, Agnelli L, Tuana G, Ferracin M, et al. Clinical monoclonal B lymphocytosis versus Rai 0 chronic lymphocytic leukemia: a comparison of cellular, cytogenetic, molecular, and clinical features. Clin Cancer Res. 2013;19:5890–900.
Ferrajoli A, Shanafelt TD, Ivan C, Shimizu M, Rabe KG, Nouraee N, et al. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. Blood. 2013;122:1891–9.
Xochelli A, Kalpadakis C, Gardiner A, Baliakas P, Vassilakopoulos TP, Mould S, et al. Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity? Blood. 2014;123:1199–206.
National Cancer Institute. SEER stat fact sheets: Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html.
Ng D, Toure O, Wei M-H, Arthur DC, Abbasi F, Fontaine L, et al. Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia. Blood. 2007;109:916–25.
Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052–7.
Montserrat E, Moreno C. Chronic lymphocytic leukaemia: a short overview. Ann Oncol. 2008;19(Suppl 7):vii320–5.
Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica. 2011;96:752–61.
Weir EG, Epstein JI. Incidental small lymphocytic lymphoma/chronic lymphocytic leukemia in pelvic lymph nodes excised at radical prostatectomy. Arch Pathol Lab Med. 2003;127:567–72.
Baumhoer D, Tzankov A, Dirnhofer S, Tornillo L, Terracciano LM. Patterns of liver infiltration in lymphoproliferative disease. Histopathology. 2008;53:81–90.
Cerroni L, Zenahlik P, Höfler G, Kaddu S, Smolle J, Kerl H. Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients. Am J Surg Pathol. 1996;20:1000–10.
Graff-Baker A, Sosa JA, Roman SA. Primary thyroid lymphoma: a review of recent developments in diagnosis and histology-driven treatment. Curr Opin Oncol. 2010;22:17–22.
Vega F, Padula A, Valbuena JR, Stancu M, Jones D, Medeiros LJ. Lymphomas involving the pleura: a clinicopathologic study of 34 cases diagnosed by pleural biopsy. Arch Pathol Lab Med. 2006;130:1497–502.
Benekli M, Büyükaşik Y, Haznedaroğlu IC, Savaş MC, Ozcebe OI. Chronic lymphocytic leukemia presenting as acute urinary retention due to leukemic infiltration of the prostate. Ann Hematol. 1996;73:143–4.
Trisolini R, Lazzari Agli L, Poletti V. Bronchiolocentric pulmonary involvement due to chronic lymphocytic leukemia. Haematologica. 2000;85:1097.
Garofalo M, Murali R, Halperin I, Magardician K, Moussouris HF, Masdeu JC. Chronic lymphocytic leukemia with hypothalamic invasion. Cancer. 1989;64:1714–6.
Morrison C, Shah S, Flinn IW. Leptomeningeal involvement in chronic lymphocytic leukemia. Cancer Pract. 1998;6:223–8.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.
Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–15.
Liang X, Moseman EA, Farrar MA, Bachanova V, Weisdorf DJ, Blazar BR, et al. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood. 2010;115:5041–52.
Grandjenette C, Kennel A, Faure GC, Béné MC, Feugier P. Expression of functional toll-like receptors by B-chronic lymphocytic leukemia cells. Haematologica. 2007;92:1279–81.
Wagner M, Oelsner M, Moore A, Götte F, Kuhn P-H, Haferlach T, et al. Integration of innate into adaptive immune responses in ZAP-70-positive chronic lymphocytic leukemia. Blood. 2016;127:436–48.
Colombo M, Cutrona G, Reverberi D, Fabris S, Neri A, Fabbi M, et al. Intraclonal cell expansion and selection driven by B cell receptor in chronic lymphocytic leukemia. Mol Med. 2011;17:834–9.
Ghiotto F, Fais F, Valetto A, Albesiano E, Hashimoto S, Dono M, et al. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest. 2004;113:1008–16.
Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200:519–25.
Schwartz RS, Stollar BD. Heavy-chain directed B-cell maturation: continuous clonal selection beginning at the pre-B cell stage. Immunol Today. 1994;15:27–32.
Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194:1625–38.
Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194:1639–47.
Kikushige Y, Ishikawa F, Miyamoto T, Shima T, Urata S, Yoshimoto G, et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell. 2011;20:246–59.
den Ottolander GJ, Brederoo P, Schuurman RK, Teeuwsen VJ, Schuit HR, van der Meulen J, et al. Intracellular immunoglobulin G “pseudocrystals” in a patient with chronic B-cell leukemia. Cancer. 1986;58:43–51.
Lunning MA, Zenger VE, Dreyfuss R, Stetler-Stevenson M, Rick ME, White TA, et al. Albumin enhanced morphometric image analysis in CLL. Cytometry B Clin Cytom. 2004;57:7–14.
Oscier D, Else M, Matutes E, Morilla R, Strefford JC, Catovsky D. The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial. Br J Haematol. 2016;174(5):767–75.
Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol. 1996;92:382–8.
Cordone I, Matutes E, Catovsky D. Monoclonal antibody Ki-67 identifies B and T cells in cycle in chronic lymphocytic leukemia: correlation with disease activity. Leukemia. 1992;6:902–6.
Criel A, Wlodarska I, Meeus P, Stul M, Louwagie A, Van Hoof A, et al. Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias. Br J Haematol. 1994;87:523–8.
Lin P, Hao S, Handy BC, Bueso-Ramos CE, Medeiros LJ. Lymphoid neoplasms associated with IgM paraprotein: a study of 382 patients. Am J Clin Pathol. 2005;123:200–5.
Offit K, Louie DC, Parsa NZ, Noy A, Chaganti RS. Del (7)(q32) is associated with a subset of small lymphocytic lymphoma with plasmacytoid features. Blood. 1995;86:2365–70.
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;91:1757–61.
Friedman DR, Sibley AB, Owzar K, Chaffee KG, Slager S, Kay NE, et al. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study. Am J Hematol. 2016;91:687–91.
Oscier DG, Matutes E, Copplestone A, Pickering RM, Chapman R, Gillingham R, et al. Atypical lymphocyte morphology: an adverse prognostic factor for disease progression in stage A CLL independent of trisomy 12. Br J Haematol. 1997;98:934–9.
Frater JL, McCarron KF, Hammel JP, Shapiro JL, Miller ML, Tubbs RR, et al. Typical and atypical chronic lymphocytic leukemia differ clinically and immunophenotypically. Am J Clin Pathol. 2001;116:655–64.
Montserrat E, Villamor N, Reverter JC, Brugués RM, Tàssies D, Bosch F, et al. Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients. Br J Haematol. 1996;93:111–6.
Kim YS, Ford RJ, Faber JA, Bell RH, Elenitoba-Johnson KS, Medeiros LJ. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma involving bone marrow with an interfollicular pattern. Am J Clin Pathol. 2000;114:41–6.
Schade U, Bock O, Vornhusen S, Jäger A, Büsche G, Lehmann U, et al. Bone marrow infiltration pattern in B-cell chronic lymphocytic leukemia is related to immunoglobulin heavy-chain variable region mutation status and expression of 70-kd zeta-associated protein (ZAP-70). Hum Pathol. 2006;37:1153–61.
Zanotti R, Ambrosetti A, Lestani M, Ghia P, Pattaro C, Remo A, et al. ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor. Leukemia. 2007;21:102–9.
Randen U, Tierens AM, Tjønnfjord GE, Delabie J. Bone marrow histology in monoclonal B-cell lymphocytosis shows various B-cell infiltration patterns. Am J Clin Pathol. 2013;139:390–5.
Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood. 1993;81:2475–87.
Yoo D, Pierce LE, Lessin LS. Acquired pure red cell aplasia associated with chronic lymphocytic leukemia. Cancer. 1983;51:844–50.
Schmid C, Isaacson PG. Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology. 1994;24:445–51.
Gradowski JF, Sargent RL, Craig FE, Cieply K, Fuhrer K, Sherer C, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression. Am J Clin Pathol. 2012;138:132–9.
Gupta D, Lim MS, Medeiros LJ, Elenitoba-Johnson KS. Small lymphocytic lymphoma with perifollicular, marginal zone, or interfollicular distribution. Mod Pathol. 2000;13:1161–6.
Narang S, Wolf BC, Neiman RS. Malignant lymphoma presenting with prominent splenomegaly. A clinicopathologic study with special reference to intermediate cell lymphoma. Cancer. 1985;55:1948–57.
Edelman M, Evans L, Zee S, Gnass R, Ratech H. Splenic micro-anatomical localization of small lymphocytic lymphoma/chronic lymphocytic leukemia using a novel combined silver nitrate and immunoperoxidase technique. Am J Surg Pathol. 1997;21:445–52.
Arber DA, Rappaport H, Weiss LM. Non-Hodgkin’s lymphoproliferative disorders involving the spleen. Mod Pathol. 1997;10:18–32.
Schwartz JB, Shamsuddin AM. The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia. Hum Pathol. 1981;12:432–40.
Garicochea B, Cliquet MG, Melo N, del Giglio A, Dorlhiac-Llacer PE, Chamone DA. Leptomeningeal involvement in chronic lymphocytic leukemia identified by polymerase chain reaction in stored slides: a case report. Mod Pathol. 1997;10:500–3.
Kuse R, Lueb H. Gastrointestinal involvement in patients with chronic lymphocytic leukemia. Leukemia. 1997;11(Suppl 2):S50–1.
Elliott MA, Letendre L, Li CY, Hoyer JD, Hammack JE. Chronic lymphocytic leukaemia with symptomatic diffuse central nervous system infiltration responding to therapy with systemic fludarabine. Br J Haematol. 1999;104:689–94.
Mhawech-Fauceglia P, Saxena R, Zhang S, Terracciano L, Sauter G, Chadhuri A, et al. Pax-5 immunoexpression in various types of benign and malignant tumours: a high-throughput tissue microarray analysis. J Clin Pathol. 2007;60:709–14.
Vuillier F, Dumas G, Magnac C, Prevost M-C, Lalanne AI, Oppezzo P, et al. Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the mu and CD79a chains. Blood. 2005;105:2933–40.
Bomberger C, Singh-Jairam M, Rodey G, Guerriero A, Yeager AM, Fleming WH, et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood. 1998;91:2588–600.
Bennett F, Rawstron A, Plummer M, de Tute R, Moreton P, Jack A, et al. B-cell chronic lymphocytic leukaemia cells show specific changes in membrane protein expression during different stages of cell cycle. Br J Haematol. 2007;139:600–4.
Asplund SL, McKenna RW, Doolittle JE, Kroft SH. CD5-positive B-cell neoplasms of indeterminate immunophenotype: a clinicopathologic analysis of 26 cases. Appl Immunohistochem Mol Morphol. 2005;13:311–7.
Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111:3941–67.
Papageorgiou SG, Kontos CK, Pappa V, Thomadaki H, Kontsioti F, Dervenoulas J, et al. The novel member of the BCL2 gene family, BCL2L12, is substantially elevated in chronic lymphocytic leukemia patients, supporting its value as a significant biomarker. Oncologist. 2011;16:1280–91.
Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82:1820–8.
Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism. Blood. 2016;127(25):3215–24.
Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22.
Marotta G, Raspadori D, Sestigiani C, Scalia G, Bigazzi C, Lauria F. Expression of the CD11c antigen in B-cell chronic lymphoproliferative disorders. Leuk Lymphoma. 2000;37:145–9.
Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88:841–86.
Ghia P, Guida G, Stella S, Gottardi D, Geuna M, Strola G, et al. The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Blood. 2003;101:1262–9.
Jelinek DF, Tschumper RC, Geyer SM, Bone ND, Dewald GW, Hanson CA, et al. Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br J Haematol. 2001;115:854–61.
Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK, et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood. 2002;99:1023–9.
Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764–75.
Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105–11.
Wilhelm C, Neubauer A, Brendel C. Discordant results of flow cytometric ZAP-70 expression status in B-CLL samples if different gating strategies are applied. Cytometry B Clin Cytom. 2006;70:242–50.
Schroers R, Griesinger F, Trümper L, Haase D, Kulle B, Klein-Hitpass L, et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia. 2005;19:750–8.
D’Arena G, Tarnani M, Rumi C, Vaisitti T, Aydin S, De Filippi R, et al. Prognostic significance of combined analysis of ZAP-70 and CD38 in chronic lymphocytic leukemia. Am J Hematol. 2007;82:787–91.
Buggins AGS, Levi A, Gohil S, Fishlock K, Patten PEM, Calle Y, et al. Evidence for a macromolecular complex in poor prognosis CLL that contains CD38, CD49d, CD44 and MMP-9. Br J Haematol. 2011;154:216–22.
Ho AK, Hill S, Preobrazhensky SN, Miller ME, Chen Z, Bahler DW. Small B-cell neoplasms with typical mantle cell lymphoma immunophenotypes often include chronic lymphocytic leukemias. Am J Clin Pathol. 2009;131:27–32.
Tam CS, Otero-Palacios J, Abruzzo LV, Jorgensen JL, Ferrajoli A, Wierda WG, et al. Chronic lymphocytic leukaemia CD20 expression is dependent on the genetic subtype: a study of quantitative flow cytometry and fluorescent in-situ hybridization in 510 patients. Br J Haematol. 2008;141:36–40.
Huang JC, Finn WG, Goolsby CL, Variakojis D, Peterson LC. CD5- small B-cell leukemias are rarely classifiable as chronic lymphocytic leukemia. Am J Clin Pathol. 1999;111:123–30.
Schlette E, Fu K, Medeiros LJ. CD23 expression in mantle cell lymphoma: clinicopathologic features of 18 cases. Am J Clin Pathol. 2003;120:760–6.
Matutes E, Polliack A. Morphological and immunophenotypic features of chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2000;4:22–47.
Dronca RS, Jevremovic D, Hanson CA, Rabe KG, Shanafelt TD, Morice WG, et al. CD5-positive chronic B-cell lymphoproliferative disorders: diagnosis and prognosis of a heterogeneous disease entity. Cytometry B Clin Cytom. 2010;78(Suppl 1):S35–41.
Palumbo GA, Parrinello N, Fargione G, Cardillo K, Chiarenza A, Berretta S, et al. CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Leuk Res. 2009;33:1212–6.
Miao Y, Fan L, Wu Y-J, Xia Y, Qiao C, Wang Y, et al. Low expression of CD200 predicts shorter time-to-treatment in chronic lymphocytic leukemia. Oncotarget. 2016;7:13551–62.
Gutierrez A, Tschumper RC, Wu X, Shanafelt TD, Eckel-Passow J, Huddleston PM, et al. LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis. Blood. 2010;116:2975–83.
Amador-Ortiz C, Goolsby CL, Peterson LC, Wolniak KL, McLaughlin JL, Gao J, et al. Flow cytometric analysis of lymphoid enhancer-binding factor 1 in diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Clin Pathol. 2015;143:214–22.
Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol. 2015;68:473–8.
Wu W, Zhu H, Fu Y, Shen W, Miao K, Hong M, et al. High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid. Oncotarget. 2016;7(16):21631–43.
Ahmad E, Steinberg SM, Goldin L, Hess CJ, Caporaso N, Kreitman RJ, et al. Immunophenotypic features distinguishing familial chronic lymphocytic leukemia from sporadic chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2008;74:221–6.
Ghia P, Prato G, Stella S, Scielzo C, Geuna M, Caligaris-Cappio F. Age-dependent accumulation of monoclonal CD4+CD8+ double positive T lymphocytes in the peripheral blood of the elderly. Br J Haematol. 2007;139:780–90.
Fazi C, Scarfò L, Pecciarini L, Cottini F, Dagklis A, Janus A, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118:6618–25.
Lortholary P, Ripault M, Boiron M. Richter’s syndrome. Nouv Rev Fr Hematol. 1964;4:456–7.
Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990;93:333–9.
Parikh SA, Habermann TM, Chaffee KG, Call TG, Ding W, Leis JF, et al. Hodgkin transformation of chronic lymphocytic leukemia: incidence, outcomes, and comparison to de novo Hodgkin lymphoma. Am J Hematol. 2015;90:334–8.
Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162:774–82.
Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–401.
Aydin S, Rossi D, Bergui L, D’Arena G, Ferrero E, Bonello L, et al. CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome? Blood. 2008;111:5646–53.
Rossi D, Spina V, Cerri M, Rasi S, Deambrogi C, De Paoli L, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15:4415–22.
Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391–401.
Giné E, Martinez A, Villamor N, López-Guillermo A, Camos M, Martinez D, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95:1526–33.
Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012;119:5104–10.
Janssens A, Berth M, De Paepe P, Verhasselt B, Van Roy N, Noens L, et al. EBV negative Richter’s syndrome from a coexistent clone after salvage treatment with alemtuzumab in a CLL patient. Am J Hematol. 2006;81:706–12.
Martinez D, Valera A, Perez NS, Sua Villegas LF, Gonzalez-Farre B, Sole C, et al. Plasmablastic transformation of low-grade B-cell lymphomas: report on 6 cases. Am J Surg Pathol. 2013;37:272–81.
Robak T, Urbańska-Ryś H, Strzelecka B, Krykowski E, Bartkowiak J, Bĺoński JZ, et al. Plasmablastic lymphoma in a patient with chronic lymphocytic leukemia heavily pretreated with cladribine (2-CdA): an unusual variant of Richter’s syndrome. Eur J Haematol. 2001;67:322–7.
Hsi ED, Lorsbach RB, Fend F, Dogan A. Plasmablastic lymphoma and related disorders. Am J Clin Pathol. 2011;136:183–94.
Mao Z, Quintanilla-Martinez L, Raffeld M, Richter M, Krugmann J, Burek C, et al. 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;31:1605–14.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937–47.
Berglund M, Thunberg U, Amini R-M, Book M, Roos G, Erlanson M, et al. Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis. Mod Pathol. 2005;18:1113–20.
Chigrinova E, Rinaldi A, Kwee I, Rossi D, Rancoita PMV, Strefford JC, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013;122:2673–82.
Yamaguchi M, Seto M, Okamoto M, Ichinohasama R, Nakamura N, Yoshino T, et al. De novo CD5+ diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients. Blood. 2002;99:815–21.
Nakamura N, Nakamura S, Yamaguchi M, Ichinohasama R, Yoshino T, Kuze T, et al. CD5+ diffuse large B-cell lymphoma consists of germline cases and hypermutated cases in the immunoglobulin heavy chain gene variable region. Int J Hematol. 2005;81:58–61.
Taniguchi M, Oka K, Hiasa A, Yamaguchi M, Ohno T, Kita K, et al. De novo CD5+ diffuse large B-cell lymphomas express VH genes with somatic mutation. Blood. 1998;91:1145–51.
Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30.
Put N, Van Roosbroeck K, Konings P, Meeus P, Brusselmans C, Rack K, et al. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course. Ann Hematol. 2012;91:863–73.
Li Y, Hu S, Wang SA, Li S, Huh YO, Tang Z, et al. The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia. Mod Pathol. 2016;29:444–51.
Tsimberidou A-M, O’Brien S, Kantarjian HM, Koller C, Hagemeister FB, Fayad L, et al. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer. 2006;107:1294–302.
Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012;156:50–66.
Jamroziak K, Tadmor T, Robak T, Polliack A. Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy. Leuk Lymphoma. 2015;56:1949–58.
Pescarmona E, Pignoloni P, Mauro FR, Cerretti R, Anselmo AP, Mandelli F, et al. Hodgkin/Reed-Sternberg cells and Hodgkin’s disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background. Virchows Arch. 2000;437:129–32.
de Leval L, Vivario M, De Prijck B, Zhou Y, Boniver J, Harris NL, et al. Distinct clonal origin in two cases of Hodgkin’s lymphoma variant of Richter’s syndrome associated with EBV infection. Am J Surg Pathol. 2004;28:679–86.
Xiao W, Chen WW, Sorbara L, Davies-Hill T, Pittaluga S, Raffeld M, et al. Hodgkin lymphoma variant of Richter transformation: morphology, EBV status, clonality and survival analysis-with comparison to Hodgkin-like Lesion. Hum Pathol. 2016;55:108–16.
Tzankov A, Fong D. Hodgkin’s disease variant of Richter’s syndrome clonally related to chronic lymphocytic leukemia arises in ZAP-70 negative mutated CLL. Med Hypotheses. 2006;66:577–9.
Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127:279–86.
Vuillier F, Claisse JF, Vandenvelde C, Travade P, Magnac C, Chevret S, et al. Evaluation of residual disease in B-cell chronic lymphocytic leukemia patients in clinical and bone-marrow remission using CD5-CD19 markers and PCR study of gene rearrangements. Leuk Lymphoma. 1992;7:195–204.
Maloum K, Sutton L, Baudet S, Laurent C, Bonnemye P, Magnac C, et al. Novel flow-cytometric analysis based on BCD5+ subpopulations for the evaluation of minimal residual disease in chronic lymphocytic leukaemia. Br J Haematol. 2002;119:970–5.
Gupta R, Jain P, Deo SVS, Sharma A. Flow cytometric analysis of CD5+ B cells: a frame of reference for minimal residual disease analysis in chronic lymphocytic leukemia. Am J Clin Pathol. 2004;121:368–72.
Hillmen P. MRD in CLL. Clin Adv Hematol Oncol. 2006;4:6–7; discussion 10; suppl 12.
Rawstron AC, Villamor N, Ritgen M, Böttcher S, Ghia P, Zehnder JL, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007;21:956–64.
Rawstron AC, Böttcher S, Letestu R, Villamor N, Fazi C, Kartsios H, et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia. 2013;27:142–9.
Dowling AK, Liptrot SD, O’Brien D, Vandenberghe E. Optimization and validation of an 8-color single-tube assay for the sensitive detection of minimal residual disease in B-cell chronic lymphocytic leukemia detected via flow cytometry. Lab Med. 2016;47:103–11.
Delage R, Jacques L, Massinga-Loembe M, Poulin J, Bilodeau D, Mignault C, et al. Persistent polyclonal B-cell lymphocytosis: further evidence for a genetic disorder associated with B-cell abnormalities. Br J Haematol. 2001;114:666–70.
Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia. 1994;8:1640–5.
Ferrer A, Salaverria I, Bosch F, Villamor N, Rozman M, Beà S, et al. Leukemic involvement is a common feature in mantle cell lymphoma. Cancer. 2007;109:2473–80.
Salaverria I, Royo C, Carvajal-Cuenca A, Clot G, Navarro A, Valera A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. Blood. 2013;121:1394–402.
Fernàndez V, Salamero O, Espinet B, Solé F, Royo C, Navarro A, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408–18.
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826–33.
Baseggio L, Traverse-Glehen A, Petinataud F, Callet-Bauchu E, Berger F, French M, et al. CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases. Haematologica. 2010;95:604–12.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Alikhan, M.B., Venkataraman, G. (2018). Morphology and Immunophenotype of Chronic Lymphocytic Leukemia. In: Wiernik, P., Dutcher, J., Gertz, M. (eds) Neoplastic Diseases of the Blood. Springer, Cham. https://doi.org/10.1007/978-3-319-64263-5_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-64263-5_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-64262-8
Online ISBN: 978-3-319-64263-5
eBook Packages: MedicineMedicine (R0)