Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders

Abstract

Background: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA).

Methods: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs.

Results: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%).

Conclusions: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Keywords: Epstein–Barr virus; Iatrogenic immunodeficiency; Methotrexate; Rheumatoid arthritis; T cells, NK cells, lymphoproliferative disorders.

Fig. 1

Multiple hepatic nodules were detected in a patient with systemic EBV+ CD8+ TCL (Case No. 13) by computed tomography. The maximum nodule size was 78 mm, and no lymphadenopathy was found in the abdomen

Fig. 2

A: Diffuse invasion by large, atypical lymphocytes in nodal CD4+ TFH+ PTCL (Case No. 1). B: Diffuse infiltrates of small, atypical lymphocytes and plasma cells and moderate vascular reactions were found in nodal CD4+ TFH+ T-LPDs (Case No. 6). C: Diffuse infiltrate of large, atypical lymphocytes with round nuclei and distinct nucleoli in nodal EBER+ CD4+ PTCL-NOS (Case No. 8). Intrahepatic invasion by large, atypical lymphocytes with lobulated nuclei were observed (D), along with bone marrow invasion by medium-sized and large, atypical lymphocytes and two phagocytic macrophages (E) in systemic EBV+ CD8+ TCL (Case Nos. 13 and 14). F: Diffuse monotonous infiltrate of small lymphocytes with mild atypia in nodal CD8+ PTCL-NOS (Case No. 17). HE staining, × 400

Fig. 3

CD4+ (A) and ICOS+ (B) large- or medium-sized lymphocytes were observed in nodal TFH+ PTCL (Case Nos. 3 and 4). C: Many CD30+ (red) and EBER+ (brown) large, atypical lymphocytes were detected in PTCL-NOS (Case No. 8). D: CD8+ large lymphocytes were diffusely found in liver of sEBV+ CD8+ TCL (Case No. 13). E: EBER+ medium- to large-sized lymphocytes were partly clustered in the bone marrow of sEBV+ CD8+ TCL (Case No 14). F: Many p53+ large, atypical lymphocytes were detected in nodal CD8+ sALCL (Case No. 12)

Fig. 4

T-cell receptor (TCR) γ gene analysis by PCR. Clonal peaks (arrows) of the TCRγ gene Vγ and Jγ regions (Tubes A, B) detected by GeneScan analysis in Case Nos. 4 and 21, respectively. The lower marker (LM) and upper marker (UM) were spiked as internal standards

Fig. 5

A: Nine patients with large-cell TNK-LPDs showed significantly worse OS than 12 with small-cell TNK-LPDs (p = 0.008). B: Eight patients with p53+ atypical lymphocytes showed significantly worse OS than 13 with p53− atypical lymphocytes (p = 0.003). C: Five patients with CMYC+ atypical lymphocytes showed significantly worse OS than 16 with CMYC− atypical lymphocytes (p = 0.006). D: Five patients with EBER+ atypical lymphocytes showed a significantly poorer OS than 16 with EBER− atypical lymphocytes (p = 0.043)