title: Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma.
abstract: Primary cutaneous large B-cell lymphoma, leg type has been individualized from nodal diffuse large B-cell lymphoma. The objective of this study was to screen primary cutaneous large B-cell lymphoma, leg type for genetic alterations recently described in nodal diffuse large B-cell lymphoma. Skin biopsies from 23 patients were analyzed for IRF4, BCL2, BCL6, and MYC expression. FISH testing was performed for BCL2, BCL6, MYC with separation probes and for CDKN2A and PRDM1/BLIMP1 deletion. Multiple sequential FISH analyses with up to six probes were performed to define samples with multiple cytogenetic alterations. MYD88 mutations were studied by Sanger sequencing. All cases but one displayed at least one genetic alteration (96%). Nine patients exhibited a single genetic mutation and 12 combined several alterations (52%). We observed a split for BCL2, BCL6, or MYC in 1/23, 6/23, and 3/23 of cases, respectively. No double-hit lymphoma was observed. CDKN2A deletion was detected by FISH in only 5/23 cases. BLIMP1 and/or 6q deletion was observed at a higher rate in 10/20 of cases. No correlation between rearrangement and immunohistochemical expression was found for BCL2 or MYC. FISH tracking of sequential hybridizations showed that several alterations were carried by the same nuclei. The p.L265P MYD88 mutation was found in 11/18 (61%) of cases. Contrary to most cutaneous lymphomas that rarely harbor primary genetic alteration of their nodal histological equivalent, primary cutaneous large B-cell lymphoma, leg type seems to be a 'cutaneous counterpart' of activated B-cell-like diffuse large B-cell lymphoma with a similar cytogenetic profile and a high rate of MYD88 oncogenic L265P mutation. This also suggests a common lymphomagenesis with NF-κB activation, strong IRF4 expression and terminal B-cell differentiation blockage. Our data support the use of therapies targeting NF-κB, as most patients displayed disease progression and resistance to conventional therapies.
authors.affiliation: 1] EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France [2] Dermatology Department, CHU Bordeaux, Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pham-Ledard
authors.affiliation: EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France.
authors.forename: Martina
authors.initials: M
authors.lastname: Prochazkova-Carlotti
authors.affiliation: EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Andrique
authors.affiliation: 1] EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France [2] Tumor Bank and Tumor Biology Laboratory, CHU Bordeaux, Bordeaux, France.
authors.forename: David
authors.initials: D
authors.lastname: Cappellen
authors.affiliation: Pathology Department, CHU Bordeaux, Bordeaux, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Vergier
authors.affiliation: Tumor Bank and Tumor Biology Laboratory, CHU Bordeaux, Bordeaux, France.
authors.forename: Fabian
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Dermatology Department, CHU Reims, Reims, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Grange
authors.affiliation: Pathology Department, CHU Dijon, Dijon, France.
authors.forename: Tony
authors.initials: T
authors.lastname: Petrella
authors.affiliation: 1] EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France [2] Dermatology Department, CHU Bordeaux, Bordeaux, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Beylot-Barry
authors.affiliation: 1] EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, Bordeaux, France [2] Tumor Bank and Tumor Biology Laboratory, CHU Bordeaux, Bordeaux, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D007866:Leg / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*