Original ArticlesThe Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell LymphomaMorichika, Kazuho MD, PhD*; Karube, Kennosuke MD, PhD†; Sakihama, Shugo PhD†; Watanabe, Risa MD‡; Kawaki, Mamoru MD‡; Nishi, Yukiko MD, PhD*; Nakachi, Sawako MD, PhD*; Okamoto, Shiki VMD, PhD*; Takahara, Taishi MD, PhD§; Satou, Akira MD, PhD§; Shimada, Satoko MD, PhD∥; Shimada, Kazuyuki MD, PhD¶; Tsuzuki, Toyonori MD, PhD§; Fukushima, Takuya MD, PhD#; Morishima, Satoko MD, PhD*; Masuzaki, Hiroaki MD, PhD* Author Information *Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine) †Department of Pathology and Cell Biology, Graduate School of Medicine ‡Faculty of Medicine #Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan §Department of Surgical Pathology, Aichi Medical University Hospital Departments of ∥Pathology and Clinical Laboratories ¶Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan K.M. and K.K.: conception and design. K.M., K.K., S. Sakihama: development of methodology. K.M., K.K., S. Sakihama, R.W., M.K., Y.N., S.N., S.O., T. Takahara, A.S., S. Shimada, K.S., T. Tsuzuki, T.F., S.M., H.M.: acquisition of data. K.M., K.K., S. Sakihama, R.W., M.K.: analysis and interpretation of data. K.M., K.K., S. Sakihama, R.W., M.K., Y.N., S.N., S.O., T. Takahara, A.S., S. Shimada, K.S., T. Tsuzuki, T.F., S.M., H.M.: writing, review, and/or revision of the manuscript. K.M., K.K., S.M., H.M.: administrative, technical, or material support. K.K. and H.M. are co-corresponding authors. Conflicts of Interest and Source of Funding: Supported by the Spatiotemporal Genomics Project promoted by the University of the Ryukyus; Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K08371 and 19K07438 to K.K., 19K17862 to K.M., 19K17835 to S. Sakihama, 18K15104 to A.S.), Okinawa prefecture (to K.K.), Ichiro Kanehara Foundation (to K.K.), Yasuda Medical Foundation (to K.K.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.K.), Japan Leukemia Research Fund (to K.K.), a Japanese Society of Hematology research grant (to K.K.), Okinawa Internal Medicine Research Promotion Society (to K.K.), Takeda Science Foundation (to K.K.), Life Medicine Research Promotion Foundation (to K.K.), The Shinnihon Foundation of Advanced Medical Treatment Research (to K.K.), and Okinawa Medical Science Research Foundation (to K.M.). For the remaining authors none were declared. Correspondence: Kennosuke Karube, MD, PhD, Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan (e-mail: [email protected]). The American Journal of Surgical Pathology 45(6):p 832-840, June 2021. | DOI: 10.1097/PAS.0000000000001691 Buy SDC Metrics Abstract On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.