Vincent Allain1,2, Virginie Grandin3, Véronique Meignin4, Rémi Bertinchamp2, David Boutboul1,2,5, Claire Fieschi1,2,5, Lionel Galicier2,5, Laurence Gérard2,5, Marion Malphettes2,5, Jacinta Bustamante1,3,5,6,7, Mathieu Fusaro1,3, Nathalie Lambert3, Jérémie Rosain1,3, Christelle Lenoir1,8, Sven Kracker1,9, Frédéric Rieux-Laucat1,10, Sylvain Latour1,8, Jean-Pierre de Villartay1,11, Capucine Picard1,3,5,8,12, Eric Oksenhendler13,14,15. 1. University of Paris, Paris, France. 2. Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, 1 avenue Claude Vellefaux, 75010, Paris, France. 3. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France. 4. Department of Pathology, Saint-Louis Hospital, AP-HP, Paris, France. 5. Centre de Référence Des Déficits Immunitaires Héréditaires (CEREDIH), Paris, France. 6. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France. 7. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. 8. Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Imagine Institute, Paris, France. 9. Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France. 10. Imagine Institute, INSERM UMR 1163, Paris, France. 11. Laboratory "Genome Dynamics in the Immune System," INSERM UMR 1163, Imagine Institute, Paris, France. 12. Immuno-Hematology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France. 13. University of Paris, Paris, France. eric.oksenhendler@aphp.fr. 14. Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, 1 avenue Claude Vellefaux, 75010, Paris, France. eric.oksenhendler@aphp.fr. 15. Centre de Référence Des Déficits Immunitaires Héréditaires (CEREDIH), Paris, France. eric.oksenhendler@aphp.fr.
Abstract
PURPOSE: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. METHODS: Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. RESULTS: A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. CONCLUSION: Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.
PURPOSE: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. METHODS: Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. RESULTS: A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. CONCLUSION: Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.
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