Iatrogenic immunodeficiency-associated lymphoproliferative disorders of B-cell type that develop in patients receiving immunosuppressive drugs other than in the post-transplant setting

Abstract

In the current revised 4th edition of the World Health Organization (WHO) classification, 'other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs)' is listed in the last section in the chapter on immunodeficiency-associated lymphoproliferative disorders. Oii-LPDs cover a broad spectrum from benign lesions to lymphoma, and correspond to one of the subtypes in the WHO classification for immunocompetent patients.The WHO classification does not clearly indicate the histological subtype of this disease category; however, the framework of subtype classification is similar to the classification of post-transplant lymphoproliferative disorders, and recent studies have attempted to subcategorize Oii-LPDs that fit this unique disease type. In this review, we provide an overview of B-cell-type Oii-LPDs regarding their histopathology and immunophenotype, genetics and clinical behaviors.

Keywords: Epstein-Barr virus; immunodeficiency; lymphoproliferative disorder; methotrexate.

Fig. 1

(A) Frequency of subtypes in 281 MTX-LPD cases from studies that included non-lymphomatous lesions^,. (B) Histological subtypes of large B-cell lymphoma-type MTX-LPDs indicated in Figure 1A. (C) Frequency of EBV positivity in LBCL-type LPD cases and latency of EBV infection^,,-,-. Outer circle indicates positivity or negativity for EBV. Inner circle indicates latency of EBV infection. LBCL, Large B-cell lymphoma; RH, reactive hyperplasia; P-LPD, polymorphic-lymphoproliferative disorder; CHL, Classical Hodgkin lymphoma; BCL, B-cell lymphoma; DLBCL, NOS, diffuse large B-cell lymphoma, not otherwise specified; THRLBCL, T-cell/histiocyte-rich large B-cell lymphoma; GZL, gray zone lymphoma (B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma); EBV, Epstein-Barr virus; NA, not applicable/available. (D) Frequency of lymphoma subtypes in 334 MTX-LPD cases with details described in series reports^,,,-.

Fig. 2

Reactive hyperplasia in a patient with Oii-LPD. (A) Preserved architecture of lymph node tissue and scattered epithelioid cell granulomas were seen in interfollicular regions. (B) EBV-infected cells detected by EBER in situ hybridization were observed in the interfollicular area.

Fig. 3

B-cell lymphoproliferative disorder in a patient with Oii-LPD. Surgically resected specimens of the spleen were evaluated. (A) The architecture of the spleen was destroyed by infiltration of a variety of lymphoid cells from small mature lymphocytes and plasma cells to large atypical B-cells. (B) Scattered atypical “Hodgkin-like” cells were seen. (C) Immunostaining for CD20 demonstrated marked B-cell infiltration. (D) EBV-infected cells were detected by EBER in situ hybridization.

Fig. 4

EBV-positive DLBCL-type Oii-LPD. ( EBV-positive DLBCL-type Oii-LPD. (A) Marked infiltration of large atypical cells was seen in a lymph node. The atypical cells were positive for CD20 (B), positive for EBV on EBER in situ hybridization (C) and partially positive for CD30 (D).

Fig. 5

Classic Hodgkin lymphoma-type Oii-LPD. (A) Typical Hodgkin/Reed-Sternberg (H/RS) cells were surrounded by prominent inflammatory cells (eosinophils, small lymphocytes, histiocytes, endothelial cells, etc.) in a lymph node. HRS cells were negative for CD20 (B), weakly positive for PAX5 (C), and positive for CD30 (D), CD15 (E) and EBV on EBER in situ hybridization (F).