Immunodeficiency-associated Lymphoproliferative Disorders Research Articles

A case of methotrexate-related lymphoproliferative disease showing multiple liver lesions in a patient with rheumatoid arthritis

A 66-year-old woman with rheumatoid arthritis (RA) who had been receiving methotrexate (MTX) for 2 years presented with tarry stools. Contrast-enhanced computed tomography (CT) of the abdomen revealed irregular wall thickening in the ileocecal region and multiple low-contrast masses in both lobes of the liver. Lower gastrointestinal endoscopy revealed a type 2 tumor in the ileocecal region with a semi-peripheral ulcer. Histological examination of liver and colon biopsies showed other iatrogenic immunodeficiency-associated lymphoproliferative disorder (Oi-LPD), diffuse large B-cell lymphoma type, with positivity for Epstein-Barr virus DNA. After withdrawal of MTX, the LPD lesions disappeared and the patient achieved remission. We considered this to be a sporadic case of Oi-LPD, diffuse large B-cell lymphoma type, in the liver and colon due to treatment with MTX. There has been no previous report of this condition with simultaneous hepatic and colonic lesions, and the present case is thought to be highly informative in relation to the pathogenesis.

The incidence and prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of the lung related to methotrexate: A retrospective study

Background and objectiveOther iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are rare but well-known diseases that manifest during or after methotrexate (MTX) administration. Limited information is available on the clinical characteristics of OIIA-LPD of the lung because only a few cases have been reported. Thus, we aimed to assess the incidence and prognosis of patients with OIIA-LPD of the lung. MethodsPatients with OIIA-LPD of the lung treated at our institution between January 2008 and July 2020 were retrospectively analysed. ResultsAmong the 51 patients with OIIA-LPD, 16 (31.3%, 7 men, 9 women) had OIIA-LPD of the lung (median age, 69 [range, 63–82] years). Peripheral lesions were observed in 10 (62.5%), central lesions in two (12.5%), and both lesions in four (25.0%) patients. Nine of the 16 patients underwent bronchoscopic biopsy, seven were diagnosed (diagnostic yield, 77.8%) and, re-biopsy was performed in 2 patients. Eight (50.0%) patients had LPD and six (37.5%) had diffuse large B-cell lymphoma. In the 14 patients with confirmed treatment efficacy, the overall response rate to MTX withdrawal was 71.4%. However, chemotherapy was required in case of larger lesions (three patients). Death related to OIIA-LPD occurred in only one patient, and 11 of the 14 patients were alive during the study period (median follow-up time, 53.7 [range, 4.3–84.2] months). ConclusionThe incidence of OIIA-LPD of the lung is 31.3% and higher than that reported previously. The treatment effect of MTX withdrawal seems to be sufficient; however, in some cases, chemotherapy may be required from the beginning.

Epstein-Barr Virus-Associated Lymphomatoid Papules: A Sign of Immunosuppression Resembling Lymphomatoid Papulosis.

Epstein-Barr virus (EBV)-positive lymphoproliferative disorders associated with immunodeficiency constitute a spectrum of lymphoid and plasma cell proliferations that vary in cytomorphology, immunophenotype, and clinical behavior. CD30-positive cutaneous lymphocytic infiltrates with EBV expression and lymphomatoid papulosis-like presentations have been rarely reported. This retrospective study assessed the clinical and histopathological characteristics of EBV-positive cases with papulonodular morphologies and CD30 positivity seen by Northwestern Medicine Dermatopathology. Twelve patients (7M:5F, mean age 69 years) were presented with papular cutaneous lesions without antecedent patch/plaque disease. Nine cases were associated with known immunosuppression in the setting of transplant-related therapies (n = 4), hematopoietic malignancy (n = 2), post-transplant hematopoietic malignancy (n = 1), and autoimmune disease treatment (n = 2). Two patients had age-related immunosenescence. Four patients demonstrated EBV viremia; for 2 patients, this finding comprised the first sign of immunosuppression. Workup was negative for systemic lymphoma in all patients. Various treatment strategies were used, including observation (n = 3), discontinuation/reduction of immunosuppression (n = 3), rituximab (n = 4), and steroids (n = 4). At mean 30-month follow-up, 4 patients (33.3%) were alive, 3 with and 1 without disease. Eight patients (67.6%) had died, 3 after lesional resolution and 5 with recurrent disease. Biopsies revealed mixed lymphoid infiltrates composed of atypical CD30-positive T cells (n = 5) or B cells (n = 7) with variable EBV-encoded small RNA expression. These cases suggest clinicopathologic presentations resembling lymphomatoid papulosis with atypical, large CD30-positive, EBV-positive cells could comprise first sign of potentially serious immunodeficiency and should prompt evaluation for EBV viremia. These cases also broaden the current picture of immunodeficiency-associated lymphoproliferative disorders to include lymphomatoid papulosis-like clinical presentations.

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study

AbstractLymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B–non-Hodgkin lymphoma [B-NHL], [n = 10]; T-cell/natural killer cell-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For T-cell/natural killer cell-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges

BackgroundLymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described.Case presentationA patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD.ConclusionsThis is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Natalizumab was associated with EBV negative tumors (P=.023), and EBV positive tumors were associated with improved outcomes (P=.016). Surgical resection was associated with improved outcomes (P=.032), although limited by potential confounding effect. Antiviral treatment (P=.095), rituximab (P=.111), and stem cell transplant (SCT) (P=.198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

MO12-4 Clinical management of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

Other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) is known to develop during the use of immunosuppressive drugs (ISDs). Since lesions may regress spontaneously after discontinuation of ISDs, four-week follow-up is recommended after cessation of ISDs. However, it was not clear whether chemotherapy should be given promptly to patients who did not resolve spontaneously within 4 weeks.

Intracerebral manifestation of iatrogenic, immunodeficiency-associated polymorphic B-LPD with morphology mimicking Hodgkin lymphoma: a case report and literature review

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (IA-LPD) may arise in patients treated with immunosuppressive drugs for autoimmune disease or other conditions. Polymorphic EBV-positive B-lymphoproliferations often have features mimicking Hodgkin lymphoma and typically a self-limited, indolent course. We present an unusual case with isolated, intracerebral manifestation of polymorphic B-LPD with features of classic Hodgkin-lymphoma in an immunosuppressed patient treated with methotrexate and infliximab, including clinical-radiological features and a detailed description of morphological findings, together with a literature review on reported cases of primary CNS manifestation of cHL and IA-LPD with Hodgkin-like morphology. The patient achieved complete remission following neurosurgery with gross total tumor resection and drug withdrawal without any additional treatment. Post-operative staging revealed no evidence for focal relapse or systemic disease during the 18 months follow-up period. Among the previously reported 24 cases of primary, isolated Hodgkin lymphoma in the central nervous system, three similar cases of iatrogenic, IA-LPDs were identified and are discussed here. Polymorphic B-LPD are destructive lesions with a range of morphologic features and disease manifestations. It is clinically important to recognize the spectrum of proliferations with features of classic Hodgkin lymphoma in immunodeficiency, iatrogenic settings, because they are likely to impact the choice of treatment strategies.

A Case of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Induced by Methotrexate with Extensive Tracheobronchial Involvement

A Case of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Induced by Methotrexate with Extensive Tracheobronchial Involvement

The case study of other iatrogenic immunodeficiency-associated lymphoproliferative disorders among the patients during the course of rheumatoid arthritis

The case study of other iatrogenic immunodeficiency-associated lymphoproliferative disorders among the patients during the course of rheumatoid arthritis

Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment

Objectives Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. Methods We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. Results LPD patients were categorized into two groups: patients who regressed spontaneously (n = 19) and those who needed chemotherapy (n = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. Conclusions Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.

Retrospective analyses of other iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with rheumatic diseases.

SummaryOther iatrogenic immunodeficiency‐associated lymphoproliferative disorders (OIIA‐LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA‐LPDs, including 36 with diffuse large B‐cell lymphoma (DLBCL)‐type and 19 with Hodgkin lymphoma (HL)‐type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein–Barr virus positivity in DLBCL‐type (P = 0·013). The 2‐year overall survival and progression‐free survival (PFS) at a median follow‐up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2‐year PFS was seen between patients with DLBCL‐type and HL‐type OIIA‐LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour‐derived DNA from 20 DLBCL‐type OIIA‐LPD samples, histone‐lysine N‐methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha‐induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL‐type OIIA‐LPD. Cases with DLBCL‐type OIIA‐LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA‐LPDs, especially DLBCL‐types, showed favourable prognoses.

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 2).

Simple SummaryEpstein–Barr virus (EBV)-associated lymphoproliferative disorders have been garnering attention in recent years. EBV infects people primarily in their first years of life. The viral genome is maintained in a latent phase within the host cells, usually B-lymphocytes. The immunosuppression of different origins alters homeostasis between the virus and the host, enabling EBV-linked lymphoproliferative disorders to appear. Entities with different biological behaviors often share some morphological and phenotypic features, making the diagnosis complicated. Nodal and extra-nodal sites, including the gastrointestinal tract may be involved. This review, divided into three parts, aims to summarize the available clinical, pathological, molecular and therapeutic data on EBV-associated lymphoproliferative disorders involving the gastrointestinal tract. In this part of the review, we discuss plasmablastic lymphoma, extra-cavitary primary effusion lymphoma and Burkitt lymphoma.Epstein–Barr virus (EBV) is a common pathogen infecting people primarily early in life. The virus has the ability to persist throughout a person’s life, usually in B lymphocytes. Conditions of immunodeficiency as well as the introduction of immunosuppressive therapies and the advent of transplant technologies has brought immunodeficiency-associated lymphoproliferative disorders into view, which are often driven by EBV. The group of EBV-associated lymphoproliferative disorders includes different entities, with distinct biological features, ranging from indolent disorders, which may even spontaneously regress, to aggressive lymphomas requiring prompt and adequate treatment. These disorders are often diagnostically challenging due to their overlapping morphology and immunophenotype. Both nodal and extra-nodal sites, including the gastrointestinal tract, may be involved. This review, divided in three parts, summarizes the clinical, pathological, molecular features and treatment strategies of EBV-related lymphoproliferative disorders occurring in the gastrointestinal tract and critically analyzes the major issues in the differential diagnosis. In this part of the review, we discuss plasmablastic lymphoma, extra-cavitary primary effusion lymphoma and Burkitt lymphoma.

Epstein-Barr virus-associated lymphoproliferative disorders in immunosuppressed patients

: A diverse range of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) arise in the context of immunodeficiency. Post-transplant lymphoproliferative disease (PTLD) encompasses multiple disease entities which develop due to iatrogenic immunosuppression necessary for organ transplantation, and are frequently EBV-positive. A similar spectrum of lymphoproliferative pathologies, many of which are EBV-associated, occur in non-transplant immunodeficiency states, including those secondary to disease-modifying agents, human immunodeficiency virus (HIV) infection, age-associated immunosenescence, and a wide array of primary immune conditions. Common to each of these disease settings is disruption of the normal immune responses that exert control over EBV, permitting the virus to contribute to tumourigenesis. In this review, we provide an overview of the classification of EBV-positive immunodeficiency-associated LPDs, highlighting the strengths and weaknesses of systems provided by the World Health Organisation (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues in comparison to the Society for Hematopathology (SH) and the European Association for Haematopathology (EAH). As an exemplar of EBV-associated LPD, we then undertake a detailed review of the pathophysiology and management of PTLD. This includes a discussion of prophylactic, pre-emptive and therapeutic approaches, recognising important differences in the management of PTLD arising after haematopoietic stem cell and solid organ transplantation. We summarise recent published clinical data guiding the use of conventional chemo-immunotherapy, and cover the role of cellular and novel drug therapies. Thereafter, we provide focused reviews on a selection of other noteworthy EBV-positive LPD entities, highlighting current and emerging strategies for their management: EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma and lymphomatoid granulomatosis.

P13-8 A retrospective analysis on the prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

P13-8 A retrospective analysis on the prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

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. [Display omitted] DisclosuresTamaru:Takeda Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nichirei Biosciences Inc.: Research Funding. Tokuhira:Ezai: Honoraria.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders in the oral cavity: a clinicopathologic study of 4 cases and literature review

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OI-LPD) have been reported as one of the adverse effects of immunosuppressive therapy. The aim of this study was to describe the clinicopathologic and immunohistochemical features of OI-LPD in the oral cavity. Immunohistochemistry was performed to describe the immunohistochemical features in our 4 cases. The results were analyzed along with 62 cases of oral OI-LPD in the English and Japanese literature to define clinical and pathologic characteristic features. In our immunohistochemical analysis, Epstein-Barr virus (EBV)-positive OI-LPD showed a higher percentage of mouse double minute 2-positive cells than EBV-negative samples. A literature survey revealed that OI-LPD (including the present cases) arises primarily in the gingiva, followed by the tongue, and usually occurs with a male-to-female ratio of 1:1.9. The rate of EBV positivity was 93.8%. Further, 31 of 66 patients had osteonecrosis of the jaw and 24 of 31 patients had taken multiple immunosuppressive drugs in combination. We can therefore conclude that the overexpression of mouse double minute 2 in OI-LPD is associated with EBV infection, and the combination of multiple immunosuppressive drugs may be a risk factor for osteonecrosis of the jaw.

Disappearance of bilateral adrenal tumours: immunodeficiency-associated lymphoproliferative disorder in a patient with rheumatoid arthritis

Disappearance of bilateral adrenal tumours: immunodeficiency-associated lymphoproliferative disorder in a patient with rheumatoid arthritis

Characteristics of rheumatoid arthritis with immunodeficiency-associated lymphoproliferative disorders to regress spontaneously by the withdrawal of methotrexate and their clinical course: A retrospective, multicenter, case-control study.

To investigate clinical characteristics and time course of lymphoproliferative disorders (LPDs) in rheumatoid arthritis (RA) patients after methotrexate (MTX) discontinuation, in those who achieved spontaneous regression (SR). We retrospectively reviewed clinical data from RA patients with LPDs obtained from eight institutions between 2000 and 2017 and compared clinical and pathological findings between SR and non-SR groups. Among 232 RA patients with LPDs, 216 were treated with MTX at the onset of LPD and 144 (66.7%) achieved SR after MTX discontinuation. Higher MTX doses, high titers of anti-CCP antibodies (>13.5 U/mL), and lower LDH and soluble IL-2 receptor levels were associated with SR. Lymphocyte count was decreased at LPD onset and increased at 2 weeks after MTX discontinuation in the SR group. Epstein-Barr virus-positive mucocutaneous ulcer, reactive lymphoid hyperplasia and unclassifiable B-cell lymphoma, were more frequent in the SR than in the non-SR group. In multivariable analysis, diffuse large B-cell lymphomas was an independent predictive factor for non-SR. In the patients with SR, 73.9% achieved partial or complete regression as early as 2 weeks after MTX discontinuation. SR and non-SR in RA patients with LPDs after MTX discontinuation were associated with certain clinical characteristics.