title: Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry.
abstract: OBJECTIVE
  According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases.
  
  
  METHODS
  We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry.
  
  
  RESULTS
  We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification.
  
  
  CONCLUSIONS
  We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.
authors.affiliation: Authors' Affiliations: Servei de Patologia, Servei d'Hematologia, Hospital del Mar; Programa de Recerca en Càncer, Servei d'Anàlisi de Microarrays, Institut Català de Recerca i Estudis Avançats (ICREA), Research Programme on Biomedical Informatics (GRIB), IMIM, Universitat Pompeu Fabra, PRBB; Servei d'Hematología, ICO-Hospital Germans Trias i Pujol; Servei d'Hematologia, IDIBELL-Hospital de Bellvitge, L'Hospitalet de Llobregat; Servei d'Hematologia, Hospital Universitari Vall d'Hebron; Centre de Regulació Genòmica, Barcelona; Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo; Servicio de Hematología, Hospital General Universitario de Valencia, Valencia; Laboratorio de Citometría de Flujo, Servicio de Hematología, Fundación Jiménez Díaz, Madrid; Servicio General de Citometría, Centro de Investigación del Cáncer (IBMCC-CSIC/USAL and IBSAL) and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York; and Universitat Autònoma de Barcelona.
authors.forename: Blanca
authors.initials: B
authors.lastname: Espinet
authors.forename: Ana
authors.initials: A
authors.lastname: Ferrer
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.forename: Lara
authors.initials: L
authors.lastname: Nonell
authors.forename: Antonio
authors.initials: A
authors.lastname: Salar
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández-Rodríguez
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Puigdecanet
authors.forename: Javier
authors.initials: J
authors.lastname: Gimeno
authors.forename: Mar
authors.initials: M
authors.lastname: Garcia-Garcia
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Vela
authors.forename: Elisa
authors.initials: E
authors.lastname: Luño
authors.forename: Rosa
authors.initials: R
authors.lastname: Collado
authors.forename: José Tomás
authors.initials: JT
authors.lastname: Navarro
authors.forename: Esmeralda
authors.initials: E
authors.lastname: de la Banda
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.forename: Leonor
authors.initials: L
authors.lastname: Arenillas
authors.forename: Cristina
authors.initials: C
authors.lastname: Serrano
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Belén
authors.initials: B
authors.lastname: Miñana
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.forename: Lourdes
authors.initials: L
authors.lastname: Florensa
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: Francesc
authors.initials: F
authors.lastname: Solé
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.forename: Sergio
authors.initials: S
authors.lastname: Serrano
mesh_terms: D058070:Asymptomatic Diseases; D001402:B-Lymphocytes / Q000502:physiology*; D016022:Case-Control Studies; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D003937:Diagnosis, Differential; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008218:Lymphocytosis / Q000175:diagnosis* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: C530104:CCND1 protein, human; D019938:Cyclin D1