Bone Marrow Infiltration of Angioimmunoblastic T-Cell Lymphoma Identification and Prognostic Impact of Histologic Patterns and Diagnostic Application of Ancillary Phenotypic and Molecular Analyses Magdalena M. Gerlach, MD; Darius Juskevicius, PhD; Visar Vela, MSc; Stefan Dirnhofer, MD; Alexandar Tzankov, MD  Context.—Angioimmunoblastic T-cell lymphomas origi- nate from T follicular helper cells and express respective markers (BCL6, CD10, CXCL13, ICOS, and PD-1). Al- though commonly present, bone marrow involvement by angioimmunoblastic T-cell lymphoma can be diagnostical- ly challenging. Additionally, only little is known about the distribution of T follicular helper cells in healthy and reactively changed bone marrows or in samples affected by other lymphomas. Objective.—To establish a diagnostic approach to reliably identify bone marrow infiltration of angioimmu- noblastic T-cell lymphoma. Design.—We analyzed the morphologic infiltration pattern and the expression of T follicular helper-cell markers in 42 matched paired lymph node and bone marrow samples and applied comparative clonality testing. Furthermore, we studied the expression of BCL6 and PD-1 in a control cohort of healthy, reactively changed, and otherwise affected bone marrows. Results.—We identified 3 different bone marrow infil- tration patterns correlating with overall survival (intersti- tial/micronodular infiltration with or without eosinophilia and diffuse infiltration with eosinophilia). The matched pairs showed a consistent (co)expression of PD-1 and BCL6 with a generally weaker expression in the bone marrow than in the lymph nodes. Comparative clonality testing was helpful in only a minority of cases. Infiltrates of the most important differential diagnoses contained either PD-1– or BCL6-positive tumor-infiltrating cells, but no coexpressing cells. Conclusions.—Bone marrow infiltration by angioimmu- noblastic T-cell lymphoma displays 3 different patterns that correlate with prognosis. BCL6 and PD-1 can be reliably used to identify lymphoma infiltrates and to help rule out several differential diagnoses. Comparative clonality testing rarely provides additional value and cannot replace morphologic and phenotypic analyses. (Arch Pathol Lab Med. 2020;144:602–611; doi: 10.5858/ arpa.2019-0007-OA) A ngioimmunoblastic T-cell lymphoma (AITL) is the most common noncutaneous T-cell neoplasm in the West- ern world. 1 It is currently defined by the World Health Organization as a neoplasm of mature T follicular helper cells (TFHs) characterized by systemic disease and a polymorphous infiltrate involving lymph nodes (LNs), with a prominent proliferation of high endothelial venules and follicular dendritic cells. 2 Already in 1968, Lennert and Mestdagh 3 suggested that AITL is a supposed special form of Hodgkin lymphoma, accompanied by massive occurrence of epithelial cells in affected LNs, generalized lymphade- nopathy, and skin symptoms. In 1974, it was described by Frizzera et al 4 as a ‘‘lymphoma-like clinical presentation and a specific histological picture’’ accompanied by an acute onset of general symptoms; erroneously, it was considered as a nonneoplastic process very similar to graft-versus-host reactions and therefore named angioimmunoblastic lymph- adenopathy with dysproteinemia (AILD). Shortly thereafter, Lukes and Tindle 5 published their data on a case series of 32 patients, emphasizing the clinical and morphologic resem- blance to Hodgkin lymphoma, apart from the absence of diagnostic Reed-Sternberg cells, proposing an underlying hyperproliferation of B cells. Nathwani et al 6 showed that there were no histopathologic features to predict the clinical course of patients with AILD, who later on either did or did not develop what had been called at that time ‘‘progression to immunoblastic lymphoma’’; they noticed that the most important prognostic factor in either case was achieving complete remission, emphasizing that no sharp line can be drawn between ‘‘benign’’ and ‘‘malignant’’ AILD lesions. 6 On the other side of the Atlantic Ocean, Radaszkiewcz and Lennert 7 published another 50 cases of so-called lympho- granulomatosis X, a term synonymously used for AILD, and elucidated its clinical features, response to treatment, and its prognosis. For the first time, the updated Kiel classification Accepted for publication July 11, 2019. Published online September 26, 2019. From the Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Alexandar Tzankov, MD, Medical Genetics and Pathology, University Hospital Basel, Schoenbeinstr. 40, Basel, BS 4031, Switzerland (email: alexandar.tzankov@usb.ch). 602 Arch Pathol Lab Med—Vol 144, May 2020 Angioimmunoblastic T-Cell Lymphoma in Bone Marrow—Gerlach et al