Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases

• Published in: Modern pathology Vol. 32; no. 8; pp. 1135 - 1146
• Main Authors: Satou, Akira, Tabata, Tetsuya, Miyoshi, Hiroaki, Kohno, Kei, Suzuki, Yuka, Yamashita, Daisuke, Shimada, Kazuyuki, Kawasaki, Tomonori, Sato, Yasuharu, Yoshino, Tadashi, Ohshima, Koichi, Takahara, Taishi, Tsuzuki, Toyonori, Nakamura, Shigeo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2019; Elsevier Limited
• Subjects: 631/67/1990/291/1621/1916; 692/699/67/1990/291/1621/1916; Aged; Aged, 80 and over; CD8 antigen; Cell Proliferation - drug effects; Cytotoxicity; Epstein-Barr virus; Female; Herpesvirus 4, Human - isolation & purification; Hodgkin's lymphoma; Humans; Immunoblastic Lymphadenopathy - chemically induced; Immunoblastic Lymphadenopathy - immunology; Immunoblastic Lymphadenopathy - pathology; Immunodeficiency; Immunoproliferative diseases; Immunosuppressive Agents - adverse effects; Interferon; Laboratory Medicine; Lymphatic diseases; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, T-Cell, Peripheral - chemically induced; Lymphoma, T-Cell, Peripheral - immunology; Lymphoma, T-Cell, Peripheral - pathology; Lymphoproliferative Disorders - chemically induced; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - pathology; Lymphoproliferative Disorders - virology; Male; Medicine; Medicine & Public Health; Methotrexate; Methotrexate - adverse effects; Middle Aged; Pathology; Phenotype; Phenotypes; Prognosis; Retrospective Studies; T-cell lymphoma; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - pathology; T-Lymphocyte Subsets - virology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; Tumor cells
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-019-0264-2

Methotrexate-associated lymphoproliferative disorders are categorized as “other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4–8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma ( n  = 19), peripheral T-cell lymphoma, NOS ( n  = 6), and CD8 + cytotoxic T-cell lymphoma ( n  = 3). Among the 28 cases, only one CD8 + cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males ( p  = 0.035) and presence of B-symptoms ( p  = 0.036), and lower proportion of Epstein-Barr virus + tumor cells ( p  < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression ( p  = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8 + cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.