title: Paediatric nodal marginal zone B-cell lymphadenopathy of the neck: a Haemophilus influenzae-driven immune disorder?
abstract: Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kluin
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Microbiology and Infection Control, Zorggroep Twente, Hengelo, The Netherlands.|Laboratory for Microbiology, Twente Achterhoek, Hengelo, The Netherlands.
authors.forename: Jannetta
authors.initials: J
authors.lastname: Beverdam-Vincent
authors.affiliation: Department of Pathology, Erasmus Medical Centre Rotterdam, EMCR, Rotterdam, The Netherlands.
authors.forename: Willemina R R
authors.initials: WR
authors.lastname: Geurts-Giele
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Lydia
authors.initials: L
authors.lastname: Visser
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Bea
authors.initials: B
authors.lastname: Rutgers
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ed
authors.initials: E
authors.lastname: Schuuring
authors.affiliation: Department of Pathology, LABPON, Hengelo, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: Van Baarlen
authors.affiliation: Department of Pathology, Erasmus Medical Centre Rotterdam, EMCR, Rotterdam, The Netherlands.
authors.forename: King H
authors.initials: KH
authors.lastname: Lam
authors.affiliation: Department of Pathology, St Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Seldenrijk
authors.affiliation: Department of Pathology, Pathologie Friesland, Leeuwarden, The Netherlands.
authors.forename: Robby E
authors.initials: RE
authors.lastname: Kibbelaar
authors.affiliation: Department of Pathology, Amphia Hospital, Breda, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Wit
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Diepstra
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rosati
authors.affiliation: Department of Oncology and Hematology, Sophia Children Hospital, Rotterdam, The Netherlands.
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.affiliation: Department of Oncology and Hematology, Sophia Children Hospital, Rotterdam, The Netherlands.
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Department of Internal Medicine, St Antonius Ziekenhuis, Nieuwegein, The Netherlands.
authors.forename: Jarmo C B
authors.initials: JC
authors.lastname: Hunting
authors.affiliation: Department of Internal Medicine, Medisch Centrum Leeuwarden, The Netherlands.
authors.forename: Mels
authors.initials: M
authors.lastname: Hoogendoorn
authors.affiliation: Department of Pediatrics, Zorggroep Twente, Hengelo, The Netherlands.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: van der Gaag
authors.affiliation: Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands.
authors.forename: Joost W J
authors.initials: JW
authors.lastname: van Esser
authors.affiliation: Department of Pediatric Oncology & Hematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Eveline
authors.initials: E
authors.lastname: de Bont
authors.affiliation: Department of Hematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.affiliation: Department of Medical Microbiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Rik H
authors.initials: RH
authors.lastname: Winter
authors.affiliation: Department of Medical Microbiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jerome R
authors.initials: JR
authors.lastname: Lo Ten Foe
authors.affiliation: Microbiology and Infection Control, Zorggroep Twente, Hengelo, The Netherlands.|Laboratory for Microbiology, Twente Achterhoek, Hengelo, The Netherlands.
authors.forename: Adri G M
authors.initials: AG
authors.lastname: van der Zanden
mesh_terms: D000293:Adolescent; D000907:Antibodies, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000382:microbiology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D018858:Germinal Center / Q000382:microbiology / Q000473:pathology; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D059785:Karyotype; D008198:Lymph Nodes / Q000382:microbiology / Q000473:pathology; D008206:Lymphatic Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D008297:Male; D010950:Plasma Cells / Q000382:microbiology / Q000473:pathology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial
keywords: Haemophilus influenzae; IgD; hyperplasia; infection; lymphadenopathy; malignant lymphoma; marginal zone; paediatric