[en] Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.
Disciplines :
Hematology
Author, co-author :
Veloza, Luis; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
Cavalieri, Doriane; Department of Hematology, University Hospital of Clermont-Ferrand, Clermont-Ferrand
Missiaglia, Edoardo; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
Ledoux-Pilon, Albane; Department of Pathology, University Hospital of Clermont-Ferrand, Clermont-Ferrand
Bisig, Bettina; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
Pereira, Bruno; Clinical Research Direction, University Hospital of Clermont-Ferrand, Clermont-Ferrand
Bonnet, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Poullot, Elsa; AP-HP, Henri Mondor Hospital, Pathology Department, F-94010 Créteil
Quintanilla-Martinez, Leticia; Institute of Pathology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen
Dubois, Romain; Department of Pathology, University Hospital of Lille, Lille
Llamas-Gutierrez, Francisco; Department of Pathology, University Centre Hospital, Rennes
Bossard, Céline; Department of Pathology, CHU de Nantes
De Wind, Roland; Department of Pathology, Institute Jules Bordet, Bruxelles
Drieux, Fanny; Centre Henri Becquerel, Service of Anatomical and Cytological Pathology, Centre Henri Becquerel Rouen, France, Rouen
Fontaine, Juliette; Multisite pathology Institute, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite
Parrens, Marie; Department of Pathology, CHU de Bordeaux, University of Bordeaux, Bordeaux
Sandrini, Jeremy; Department of Pathology, Le Mans Hospital Center, 72000 Le Mans
Fataccioli, Virginie; AP-HP, Henri Mondor Hospital, Pathology Department, F-94010 Créteil, France, University Paris Est Créteil, INSERM, IMRB, F-94010 Créteil
Delfau-Larue, Marie-Hélène; University Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France, Department of Immunobiology and Inserm U955, Henri Mondor University Hospital, Créteil
Daniel, Adrien; Department of Hematology, University Hospital of Lille, Lille
Lhomme, Faustine; Department of Hematology, University Hospital of Rennes, Hospital Pontchaillou, Rennes
Clément-Filliatre, Lauriane; Department of Oncology, Louis Pasteur clinic, Essey-Lès-Nancy
Lemonnier, François; University Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France, AP-HP, Henri Mondor Hospital, Lymphoid malignancies unit, F-94010 Créteil
Cairoli, Anne; Service of Hematology, Department of Oncology, Lausanne University, Hospital and Lausanne University, Lausanne
Morel, Pierre; Department of Hematology, Hospital of Lens, Lens, France and Department of Hematology, University Hospital of Amiens, Amiens
Glaisner, Sylvie; Department of Hematology, Institute Curie, Hospital Rene Huguenin, Saint-Cloud
Joly, Bertrand; Department of Hematology, Sud-Francilien Hospital Centre, Corbeil-Essonnes
El Yamani, Abderrazak; Department of Hematology, Hospital Centre of Blois, Blois
Laribi, Kamel; Department of Hematology, Hospital Centre Le Mans, Le Mans
Bachy, Emmanuel; Department of Hematology, Centre Hospitalier Lyon Sud and Inserm U1111, Pierre Bénite
Siebert, Reiner; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
Vallois, David; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
Gaulard, Philippe; AP-HP, Henri Mondor Hospital, Pathology Department, F-94010 Créteil, France, University Paris Est Créteil, INSERM, IMRB, F-94010 Créteil
Tournilhac, Olivier; Department of Hematology, University Hospital of Clermont-Ferrand, Clermont-Ferrand
De Leval, Laurence; Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne. Laurence.deleval@chuv.ch
The work developed at the Institute of Pathology of Lausanne, was supported by the histopathology, immunopathology and molecular pathology facilities, and the digital pathology platform of the Institute. The authors would like to thank Dr Nathalie Piazzon and Mr Jean-Daniel Roman for assistance with data management, Mrs Catherine Chapuis for technical assistance, Dr Justine Bouilly and Dr Audrey Letourneau for analysis and interpretation of TDS data and Mrs Cloé Bregnard and Mónica Esteves De Azevedo for performing the FISH studies. They also thank Dr Amedeo Sciarra for his contribution to data coding, Dr Adamantia Kapopoulou and Mr Vimel Rattina for their contribution in whole exome analysis and Mr Venkatesh Kacherla in the preparation of Figure 4 panels. The authors are indebted to Mrs Julien Marquis and Johann Weber from the Lausanne Genomic Technologies Facility, Center for Integrative Genomics of Lausanne University where whole-exome sequencing was performed. The authors would like to thank Drs Patrick Bruandet and Jacques Akpo-Allavo (Service de Pathologie CH Blois), Drs Florence Bloget and Damienne Declerck (Medipath, Avon), Drs François Lamarche and Caroline Ghighi (ACP, Abbeville), Drs Pierre Boyer and Jean Kapfer (CAP Orléans), Prof Luc Xerri (Service de Pathologie, IPC Marseille) and Dr Thérèse Rousset (Service de Pathologie, CHU Montpellier) for providing tumor material. Dr Olivier Dubroeucq (Institut Jean Godinot, Reims), Dr Bruno Villemagne (CHD Vendée), Dr Emmanuelle Tchernonog (CHU de Montpellier), Dr Sara Bur-cheri (CH Perpignan), Dr Sophie Rigaudeau (CH de Versailles), Pr Emmanuel Gyan (CHU de Tours), Dr Julie Abraham (CHU de Limoges), Dr Emmanuel Fleck (CH de La Rochelle), Dr Eric Dupont (CH d’Agen), Dr Jean Galtier (CHU de Bordeaux), Dr Thibault Brotelle (CH d’Avignon), Pr Gandhi Damaj (CHU de Caen), Dr Serge Bologna (Centre d’oncologie de Gentilly), Dr Clémentine Sarkozy (Institut Gustave Roussy), Dr Marion Loirat (CH de Saint-Nazaire), Dr Valentin Letailleur (CHU de Nantes), Dr Pierre Englert (Hôpital Erasme, Bruxelles), Romane Muletier (CHU de Clermont-Ferrand), Dr Shota Tsiklauri (CH d’Aubenas), Dr Bernard Drenou (GHR Mulhouse Sud-Alsace), Dr Florian Bouclet (Centre Henri Becquerel, Rouen), Dr Robin Noël (Institut Paoli Calmettes, Marseille), Dr Patrick Mboungou (CH de Boulogne-Sur-Mer), Dr Abdallah Maakaroun (CH de Bourges) and the Hospitals of Dieppe, Mont-de-Marsan, Sud Seine-et-Marne, the Clinique du Saint-Cœur, the Clinique de l’Archette, the Polyclinique du Ternois are acknowledged for providing clinical follow-up. This work was supported by the grants KLS-4293-08-2017R to LDL of the Swiss Cancer Ligue and SNSF – 31BL30_172718 to LDL of the Patholink and the Swiss National Science Foundation.The work developed at the Institute of Pathology of Lausanne, was supported by the histopathology, immunopathology and molecular pathology facilities, and the digital pathology platform of the Institute. The authors would like to thank Dr Nathalie Piazzon and Mr Jean-Daniel Roman for assistance with data management, Mrs Catherine Chapuis for technical assistance, Dr Justine Bouilly and Dr Audrey Letourneau for analysis and interpretation of TDS data and Mrs Cloé Bregnard and Mónica Esteves De Azevedo for performing the FISH studies. They also thank Dr Amedeo Sciarra for his contribution to data coding, Dr Adamantia Kapopoulou and Mr Vimel Rattina for their contribution in whole exome analysis and Mr Venkatesh Ka-cherla in the preparation of Figure 4 panels. The authors are indebted to Mrs Julien Marquis and Johann Weber from the Lausanne Genomic Technologies Facility, Center for Integrative Genomics of Lausanne University where whole-exome sequencing was performed. The authors would like to thank Drs Patrick Bruandet and Jacques Akpo-Allavo (Service de Pathologie CH Blois), Drs Florence Bloget and Damienne Declerck (Medipath, Avon), Drs François Lamarche and Caroline Ghighi (ACP, Abbeville), Drs Pierre Boyer and Jean Kapfer (CAP Orléans), Prof Luc Xerri (Service de Pathologie, IPC Marseille) and Dr Thérèse Rousset (Service de Pathologie, CHU Montpellier) for providing tumor material. Dr Olivier Dubroeucq (Institut Jean Godinot, Reims), Dr Bruno Villemagne (CHD Vendée), Dr Em-manuelle Tchernonog (CHU de Montpellier), Dr Sara Bur-
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