Original ArticlesLymphadenopathy Associated With Neutralizing Anti-interferon-gamma Autoantibodies Could Have Monoclonal T-cell Proliferation Indistinguishable From Malignant Lymphoma and Treatable by Antibiotics A Clinicopathologic StudyYuan, Chang-Tsu MD*,†,‡; Wang, Jann-Tay MD, PhD§; Sheng, Wang-Huei MD, PhD§; Cheng, Pei-Yuan MS∥; Kao, Chein-Jun MS¶; Wang, Jann-Yuan MD, PhD§; Chen, Chien-Yuan MD, PhD§; Liau, Jau-Yu MD†,∥; Tsai, Jia-Huei MD†,∥; Lin, Yi-Jyun MS†; Chen, Chung-Chung MS†; Chen, Yee-Chun MD, PhD§,#; Chang, Shan-Chwen MD, PhD§; Wu, Un-In MD§,**Author Information *Graduate Institute of Clinical Medicine ∥Graduate Institute of Pathology, National Taiwan University Departments of †Pathology §Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine Departments of ‡Pathology **Medicine, National Taiwan University Cancer Center ¶Department of Laboratory Medicine #Center of Infection Control, National Taiwan University Hospital, Taipei, Taiwan C.-T.Y. and U.-I.W.: conception and design. C.-T.Y., J.-T.W., W.-H.S., P.-Y.C., C.-J.K., J.-Y.W., C.-Y.C., J.-Y.L., J.-H.T., Y.-J.L., C.-C.C., and U.-I.W.: performed experiment and analysis. C.-T.Y. and U.-I.W.: wrote the paper. J.-Y.W., Y.-C.C., S.-C.C., and U.-I.W.: critical revision of the paper. Conflicts of Interest and Source of Funding: Supported by the Ministry of Science and Technology (MOST 106-2314-B-002-214, MOST 107-2314-B-002-209-MY3, MOST 108-2314-B-002-218-MY2). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Un-In Wu, MD, Department of Medicine, National Taiwan University Cancer Center, No. 57, Lane 155, Sec. 3, Keelung Road, Da’an District, Taipei City 10106, Taiwan (e-mail: [email protected]). The American Journal of Surgical Pathology: August 2021 - Volume 45 - Issue 8 - p 1138-1150 doi: 10.1097/PAS.0000000000001731 Buy SDC Metrics Abstract Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.