title: ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.
abstract: Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Edgardo R
authors.initials: ER
authors.lastname: Parrilla Castellar
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD;
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA;
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.affiliation: Division of Hematopathology, University of Pittsburgh Medical Center, Pittsburgh, PA;
authors.forename: Steven H
authors.initials: SH
authors.lastname: Swerdlow
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Department of Pathology and Laboratory Medicine, United Health Services Hospitals, Johnson City/Binghamton, NY;
authors.forename: Jagmohan S
authors.initials: JS
authors.lastname: Sidhu
authors.affiliation: Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH;
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.affiliation: Department of Pathology and Laboratory Medicine, Centrex Clinical Laboratories, Utica, NY;
authors.forename: Shridevi
authors.initials: S
authors.lastname: Karikehalli
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL;
authors.forename: Liuyan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Center for Individualized Medicine.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Division of Hematopathology, University of Pittsburgh Medical Center, Pittsburgh, PA;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gibson
authors.affiliation: Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH;
authors.forename: Sarah
authors.initials: S
authors.lastname: Ondrejka
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD;
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolae
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Karen L
authors.initials: KL
authors.lastname: Grogg
authors.affiliation: Department of Health Sciences Research, and.
authors.forename: Cristine
authors.initials: C
authors.lastname: Allmer
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN; and.
authors.forename: Kay M
authors.initials: KM
authors.lastname: Ristow
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: William R
authors.initials: WR
authors.lastname: Macon
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Mark E
authors.initials: ME
authors.lastname: Law
authors.affiliation: Department of Health Sciences Research, and.
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN; and.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN; and.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: Department of Health Sciences Research, and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Andrew L
authors.identifier: http://orcid.org/0000-0001-5009-4808
authors.initials: AL
authors.lastname: Feldman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002648:Child; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D050835:Interferon Regulatory Factors / Q000235:genetics; D053208:Kaplan-Meier Estimate; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult; D000099218:Interferon Regulatory Factor-4
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor; D054637:Dual-Specificity Phosphatases; D050835:Interferon Regulatory Factors; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4; C115051:TP63 protein, human; C000626173:ALK protein, human; C442824:DUSP22 protein, human