EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate

doi:10.1016/j.prp.2008.08.006

Pathology - Research and Practice

Volume 205, Issue 1, 15 January 2009, Pages 43-49

https://doi.org/10.1016/j.prp.2008.08.006 Get rights and content

Abstract

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein–Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation.

Introduction

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is typically administered for treating autoimmune diseases [9]. Eighty-five percent of these tumors affect patients with rheumatoid arthritis (RA), and 6% occur in patients with psoriasis and dermatomyositis [9], [17]. The association of MTX with the development of lymphoma in psoriatics is controversial. Some authors reported no association, while others revealed an increased risk of lymphoma, especially in cases with severe psoriasis [14], [8], [11], [6], [18]. Only in two single-case reports have the clinicopathological features of MTX-LPD been described to date, and both tumors were positive for EBV by in situ hybridization [15], [19], as compared with 30–44% in RA patients with MTX-LPD [17], [12], [10]. Here, we report the detailed clinicopathological features of a patient with severe psoriasis who developed MTX-LPD.

Section snippets

Case report

The patient was a 50-year-old male with a tender and firm left neck mass that had lasted for 1 month and mild dysphagia lasting for 1 week. He presented in September 2006. There was no fever, weight loss, or night sweating. Tracing back his history, he had severe psoriasis with continuing MTX treatment (7.5–22.5 mg/week) for 8 years since 1998. Physical examination revealed a 6-cm left submandibular lymph node and necrosis over nasopharynx. Incisional biopsy of the cervical node and debridement

Histopathology and immunohistochemistry

The surgical specimens were fixed in buffered formalin and embedded in paraffin, and sections of 3 μm thickness were stained with hematoxylin and eosin. Immunohistochemical stains were performed in an autostainer (Bond MAX, Vision BioSystems Ltd., Mount Waverley, Australia) using a polymer detection system (Bond™ Polymer Refine Detection, Vision BioSystems Ltd.), and an antigen-retrieval technique was applied as needed for each specific antibody. The antibodies used were CD3, CD20, CD30, CD79a,

Histopathology and immunohistochemistry

The histopathology of the three specimens from left submandibular lymph node, nasopharynx, and pre-vertebral fascia, carried out in September 2006, shared similar pathological features. The normal architecture was totally effaced by diffuse atypical lymphocytic infiltration with tumor necrosis (Fig. 1a). The lymphoid infiltrate was polymorphic with a predominance of immunoblasts and plasmablasts characterized by a large, vesicular nucleus and a prominent central nucleolus and eosinophilic to

Discussion

In 2001 WHO classification of lymphoid neoplasm, MTX-LPD is defined as a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is typically administered for treating autoimmune diseases, possibly resembling DLBCL, Hodgkin lymphoma, or polymorphous post-transplant lymphoproliferative disorders [9]. In most studies, the risk of lymphoma in RA patients was reported to be increased [7], [13]. In 1991, Ellman et al. reported the first case of a lymphoma developing in a RA

Acknowledgement

This work was supported by research grant CMFHR9743 from Chi-Mei Medical Center.

References (22)

A. Hannuksela-Svahn et al.
Psoriasis, its treatment, and cancer in a cohort of Finnish patients
J. Invest. Dermatol.
(2000)
M. Kojima et al.
Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases
Pathol. Res. Pract.
(2006)
X. Mariette et al.
Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France
Blood
(2002)
L. Mellemkjaer et al.
Rheumatoid arthritis and cancer risk
Eur. J. Cancer
(1996)
S.A. Rezk et al.
Epstein–Barr virus-associated lymphoproliferative disorders
Hum. Pathol.
(2007)
A.A.T.P. Brink et al.
Presence of Epstein–Barr virus latency type III at the single cell level in post-transplantation lymphoproliferative disorders and AIDS related lymphomas
J. Clin. Pathol.
(1997)
S.S. Chuang et al.
Sporadic paediatric and adult Burkitt lymphomas share similar phenotypic and genotypic features
Histopathology
(2008)
L. Colomo et al.
Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities
Am. J. Surg. Pathol.
(2004)
M.H. Ellman et al.
Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate
J. Rheumatol.
(1991)
W.H. Feng et al.
Reactivation of latent Epstein–Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas
J. Natl. Cancer Inst.
(2004)

J.M. Gelfand et al.

Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom

Arch. Dermatol.

(2003)

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Epstein Barr virus (EBV)-associated primary central nervous system lymphoma (ePCNSL) is increasingly recognized in immunocompromised subjects, including patients receiving systemic immunosuppressive therapy. Here, we report the first case of primary CNS lymphoma associated with EBV in a patient with diffuse cutaneous systemic sclerosis (dcSSc) receiving long-term mycophenolate mofetil (MMF).
A 51-year-old female with dcSSc had been on MMF 2 grams daily, which was initiated for a rapidly rising modified Rodnan skin score (mRSS), severe pruritus, and progressive joint contractures. She had an impressive response to this therapy with a significant decrease in her mRSS. Her condition remained stable for the next five years, after which she developed worsening headaches for 2–3 weeks, associated with dizziness, gait instability, and left homonymous hemianopia. MRI scan of the brain revealed a solitary 2.4 cm peripherally enhancing right parietal lobe mass. Excised tissue from the right parietal lobe mass showed EBV-associated diffuse large B cell lymphoma. She received four cycles of chemotherapy (high dose methotrexate and rituximab). Currently, her condition is being monitored. Her left homonymous hemianopia persists.
Because of a favorable toxicity profile, MMF is increasingly being used as long-term immunomodulatory therapy for a wide variety of autoimmune disorders. Nevertheless, patients on long-term MMF should still undergo regular CNS surveillance, not only for opportunistic infections but also for opportunistic malignancies such as PCNSL. Progressive focal or non-focal neurological deficits should always raise the alarm. Prompt evaluation and management can prevent irreversible neurological sequelae.
EBV-induced lymphoproliferative disorders in rheumatic patients: A systematic review of the literature
2018, Joint Bone Spine
Citation Excerpt :
Iatrogenic immunosuppression plays a central role in the development of EBV-associated LPDs, since IST could impair T-cell-mediated immune reactions to latently-infected B lymphocytes, eventually promoting their transformation in malignant cells and the subsequent development of latent EBV-associated lymphomas [7,10]. Besides immune suppression, persistent antigenic stimulation and chronic inflammation seem to promote both virus reactivation and expansion of EBV infected B-cells [10,11]. Overall, available data regarding EBV-induced LPDs in rheumatic patients are lacking and heterogeneous, deriving only from case reports and small case series, thus resulting unuseful to support the decision-making processes of clinicians.
Epstein-Barr virus (EBV) is involved in the pathogenesis of approximately 40% of lymphoproliferative disorders (LPDs) arising in patients receiving immunosuppressive treatment (IST) for rheumatic diseases, but data from large cohorts are still not available. We aimed to identify clinicopathological features, management and outcome of this condition.
We reviewed all published cases of EBV-encoded RNA (EBER)-positive LPDs and included in our analysis one unpublished patient diagnosed in our Hospital. We excluded those cases without an underling rheumatic condition, a specific IST or not reporting univocal data.
In the cumulative cohort of 159 patients, most were affected by rheumatoid arthritis (83.0%) and treated with methotrexate (75.4%). 68.5% of LPDs developed between the age of 40 and 70 years, after 13.3 ± 9.6 years from rheumatic disease onset and 58.7 ± 47.0 months of IST. LPDs were mostly B-cell lineage derived (39.0%), Ann Arbor disease's stage I (38.3%) and presented with extra-nodal involvement in 63.1%, which was most frequently represented by central nervous system (17.6%). The most common approach was IST withdrawal (93.3%), variably associated with radiotherapy(RT)/chemotherapy(CT) in 38.3% of cases. Overall, 61.7% of patients achieved a complete remission (CR; 30.2 ± 24.0 months). Among published cases of patients that only suspended IS as first line treatment approach, 67.2% achieved CR. No significant demographic, clinical and histological differences between patients who achieved CR and who did not, and between who achieved CR by IST withdrawal alone and who did not were observed (P > 0.05 in all comparison).
The current study reviews all the published evidences of EBV-induced LPDs in patients receiving IST treatment for rheumatic conditions.
EBV-induced lymphoproliferative disorders in rheumatic patients: A systematic review of the literature
2017, Revue du Rhumatisme (Edition Francaise)
Le virus Epstein-Barr (EBV) joue un rôle dans la pathogenèse d’environ 40 % des syndromes lymphoprolifératifs (SLP) qui surviennent chez des patients sous traitement immunosuppresseur (TIS) pour une maladie rhumatismale, mais il n’y a pas encore de données issues de grandes cohortes. Nous avons souhaité identifier les caractéristiques clinicopathologiques, la prise en charge et les résultats de cette affection.
Nous avons passé en revue tous les cas publiés de SLP positifs pour l’ARN encodé de l’EBV (EBER), incluant dans notre analyse un patient dont le cas n’avait pas été publié mais dont le diagnostic avait été établi dans notre hôpital. Nous avons exclu les cas ne présentant pas d’affection rhumatismale sous-jacente, sans TIS spécifique ou pour lesquels il n’existait pas de données univoques.
La majorité des 159 patients cumulés de notre cohorte présentaient une polyarthrite rhumatoïde (83 %) et recevaient du méthotrexate (75,4 %). Chez 68,5 % des patients, le SLP est apparu entre 40 et 70 ans, après une période de 13,3 ± 9,6 ans depuis l’apparition de la maladie rhumatismale et après 58,7 ± 47 mois de TIS. Les SLP étaient majoritairement dérivés de la lignée B (39 %), de stade I dans la classification d’Ann Arbor (38,3 %) et présentaient dans 63,1 % des cas une atteinte extranodale touchant principalement le système nerveux central (17,6 %). L’approche la plus fréquemment adoptée a été l’arrêt du TIS (93,3 %) associé, dans 38,3 % des cas, à une radiothérapie (RT) ou une chimiothérapie (CT). Au total, une rémission complète a été obtenue chez 61,7 % des patients (RC ; 30,2 ± 24,0 mois). Parmi les cas publiés de patients pour lesquels l’approche de première instance a consisté en l’arrêt seul du TIS, une RC a été obtenue dans 67,2 % des cas. Aucune différence démographique, clinique ou histologique significative n’a été observée entre les patients ayant obtenu une RC et les autres, ni entre ceux ayant atteint la RC par arrêt seul du TIS et les autres (p > 0,05 pour toutes les comparaisons).
Cette étude examine toutes les preuves publiées relatives à des SLP induits par l’EBV chez des patients recevant un TIS pour une affection rhumatismale.
Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis
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Citation Excerpt :
Histopathologically, DLBCL, classic Hodgkin lymphoma, and follicular lymphoma account for 35% to 60%, 12% to 25%, and 5% to 10%, respectively, of cases of the disorder. The interval from starting treatment of RA to onset of MTX-LPD is 3 years (0.5-5 years), and the disorder shows EBV positivity.7-10 Kojima et al.15 and Hosida et al.9 found rates of EBV positivity of 54% (7 of 13) and 27% (13 of 48), respectively.
We report an extremely rare case of massive methotrexate-associated lymphoproliferative disorder (MTX-LPD) arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. The patient was a 75-year-old woman who was referred to our department because of severe pain associated with a unilateral ulcer on the left retromolar triangle. The tumor had an extranodal location in the retromolar triangle and in the right lung. A clinicopathologic examination found a lymphocytic infiltrate with increasingly atypical histopathologic features. Atypical large cells were strongly positive in Epstein-Barr virus–encoded small RNA in situ hybridization and in staining with CD20 antibodies. MTX-LPD was diagnosed based on the medical history and histopathologic results. The lesion responded well to withdrawal of MTX followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. There have been no signs of recurrence for 4 years since withdrawal of MTX.
Methotrexate-associated lymphoproliferative disorder complicated by bisphosphonate-related osteonecrosis of the jaw arising in a female rheumatoid arthritis patient: Report of a case
2014, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in an immunosuppressed patient administered with MTX. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition characterized by bone exposure in the oromaxillofacial region of the patients administered with BPs. Here, we report a case of MTX-LPD complicated by BRONJ occurred in a 67-year-old Japanese woman with RA, who received MTX and alendronate sodium hydrate for several years. She had a mass with ulcer formation in the area of hard palate. Histopathologically, large atypical lymphoid cells were found to infiltrate into granulation tissue in the ulcerative oral mucosa. Immunohistochemistry showed that the large atypical lymphoid cells were positive for Ki-67, CD3, CD30, and CD79a and negative for CD15, ALK1, and AE1/AE3. Withdrawal of MTX therapy led to complete remission within 4 weeks. However, 9 weeks later, necrotic bone was formed on hard palate and sequestrectomy was performed twice. Thereafter, the operation for closing naso-oral fistula was performed. The patient has been free of recurrence for 1 year since fistula closure. This is a very rare case in which the oral cavity was the initial site of manifestation of MTX-LPD followed by BRONJ in the patient with RA.
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TEACHING CASESEBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate

Abstract

Introduction

Section snippets

Case report

Histopathology and immunohistochemistry

Histopathology and immunohistochemistry

Discussion

Acknowledgement

J. Invest. Dermatol.

Pathol. Res. Pract.

Blood

Eur. J. Cancer

Hum. Pathol.

Presence of Epstein–Barr virus latency type III at the single cell level in post-transplantation lymphoproliferative disorders and AIDS related lymphomas

J. Clin. Pathol.

Sporadic paediatric and adult Burkitt lymphomas share similar phenotypic and genotypic features

Histopathology

Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities

Am. J. Surg. Pathol.

Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate

J. Rheumatol.

Reactivation of latent Epstein–Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas

J. Natl. Cancer Inst.

Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom

Arch. Dermatol.

TEACHING CASES
EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate