Clinicopathological Study of Methotrexate-Associated Lymphoproliferative Disorders in Rheumatoid Arthritis Patients: Histological Classification and Predictive Factors for Disease Progression

Introduction: Rheumatoid arthritis (RA) patients treated with methotrexate (MTX) may develop lymphoproliferative disorders (LPD), and MTX-associated LPD (MTX-LPD) are recognized as iatrogenic immunodeficiency-associated LPDs. However, the clinicopathological features of MTX-LPD have not been well documented, and distinct diagnostic criteria have not been established. This study analyzed clinicopathological features of MTX-LPD to clarify its characteristics.

Methods: Between 2004 and 2015, 193 patients with RA were diagnosed with MTX-LPD at Kurume University. Lesions were classified into the following 4 diagnostic categories: (1) reactive hyperplasia (RH) - lesions with lymphoid proliferation characterized by retention of architecture; (2) polymorphic LPD (Poly-LPD) - diffuse and destructive lesions composed of plasma cells, immunoblasts, and variably-sized lymphocytes, with lesions not fulfilling criteria for lymphoid neoplasms in immunocompetent hosts; (3) diffuse, large B-cell lymphoma (DLBCL) type - fulfilling criteria for immunocompetent hosts; (4) classic Hodgkin lymphoma (CHL) type - fulfilling morphologic and immunophenotypic criteria of CHL. Low grade B-cell lymphoma and peripheral T-cell lymphoma were excluded from this study.

Results: All 193 patients received low-dose MTX; and the patients were classified as having RH (n=28), Poly-LPD (n=33), DLBCL type (n=107), and CHL type (n=25) lesions. The clinical features of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions were as follows: median age, 62 (range, 26-81 years), 68 (42-83 years), 69 (39-88 years), and 66 (46-85 years); extra-nodal involvement, 11% (3/28), 36% (12/33), 70% (73/105), and 16% (4/25); multiple involved sites, 46% (12/26), 48% (16/33), 62% (64/104), and 48% (12/25), respectively. Of the patients who discontinued MTX without concurrent chemotherapy or surgery at the time of diagnosis, 100% (14/14), 73% (22/30), 49% (34/70), and 11% (2/19) of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions had spontaneous regression. Among those who received chemotherapy, 78% (7/9), 72% (48/67), and 70% (14/20) of patients with Poly-LPD, DLBCL-type, and CHL-type lesions had complete remission. One, 17, and 2 patients with Poly-LPD, DLBCL-type, and CHL-type lesions had disease- or treatment-related death during the follow-up period (median, 25 months; range, 1-143 months).

Respective histological features of RH, Poly-LPD, DLBCL-type, and CHL-type lesions were as follows: necrosis - 0% (0/27), 48% (16/33), 34% (36/107), 16% (4/25); angioinvasion - 0% (0/27), 9% (3/33), 14% (15/106), 4% (1/25); epithelioid clusters - 0% (0/27), 9% (3/32), 0% (0/105), 24% (6/25). Hodgkin/Reed-Sternberg-like cells were observed in 15% (4/27), 48% (14/29), and 25% (25/100) of patients with RH, Poly-LPD, and DLBCL-type lesions, respectively. Epstein-Barr virus-encoded RNA (EBER)-positive lymphocytes/neoplastic cells were observed in 64% (18/28), 75% (24/32), 54% (56/104), and 84% (21/25) of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions, respectively. On immunohistochemical analysis, neoplastic cells, detected in patients with DLBCL-type and CHL-type lesions, were positive for each antibody as follows: CD20 - 98% (104/106), 0% (0/25); CD30 - 43% (40/93), 100% (25/25); CD15 - 6% (4/63), 48% (12/25); LMP-1 - 59% (43/73), 72% (18/25); EBNA-2 - 23% (15/65), 0% (0/22), respectively.

Among patients who discontinued MTX without concurrent chemotherapy at diagnosis, RH and Poly-LPD patients had significant favorable chemotherapy-free survival (CFS) (p<0.0001, p=0.0120), while CHL patients had unfavorable CFS (p=0.0344) compared to DLBCL patients (Figure 1). Moreover, EBER-positive DLBCL patients had significantly favorable CFS compared to negative DLBCL patients (p=0.0046), although there were no significant differences in other categorized groups. Overall survival was not significantly different between any categorized groups; however, DLBCL patients with high risk according to the international prognostic index had unfavorable prognoses (p<0.0001).

Conclusions: MTX-LPD patients of histological type RH and Poly-LPD lesions had favorable clinical outcomes, while CHL patients had significantly unfavorable clinical outcomes, compared to patients with DLBCL. Histological classification may help predict disease progression in patients with MTX-LPD.

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