Development of primary central nervous system lymphoma in a systemic lupus erythematosus patient after treatment with mycophenolate mofetil and review of the literature

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma (NHL), which affects the brain, spinal cord, leptomeninges and eyes, with no systemic symptoms. A study showed that the risk of developing lymphoma is increased in those with autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, Sjogren syndrome and systemic lupus erythematosus (SLE), who receive immunosupressive treatment. ¹ We present the case of our patient with SLE and lupus nephritis, who developed PCNSL after using mycophenolate mofetil (MMF). We also summarize all patients with MMF-related PCNSL in the literature (Table 1).

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Table 1

Review of the literature.

Study	Ethnicity	Year	Age/sex	Diagnosis	Duration of exposure to MMF	Pathology
Dasgupta et al. 4	Korean	2005	58/F	SLE and focal proliferative and membranous lupus nephritis	2 g/day 1 year	EBV-positive diffuse large B-cell lymphoma
Finelli et al. 5	African-American	2006	42/F	SLE and lupus nephritis	1 g/day 6 years	The neoplastic cells were positive for the B-cell antigen, CD20, and many were positive for EBV-LMP, and morphologically diagnostic of diffuse large B-cell lymphoma
Tsang et al. 6	Chinese	2010	43/F	SLE and class IV lupus nephritis	1 g/day 8 years	Strong membranous expression of CD20 on the tumour cells, EBV-encoded RNA showed a strong positive
Lai et al. 7	Singapore	2013	20/F	SLE and lupus nephritis	NA	NA
Our case	Turkish	2016	56/F	SLE and class IV lupus nephritis	2 g/day 2 years	CD20(+), vimentin(+), scarcely CD3(+), CD5(–), actin(–), Bcl2 (+)

A 56-year-old female patient with type 2 diabetes mellitus, hypertension and a history of coronary artery bypass graft operation was referred to our department in 2008 with symmetrical polyarthritis, oral aphthae, malar rash, photosensitivity and pleuritis. She had leukopenia (1490/mm³), lymphopenia (240/mm³), ANA (1/1280 homogeneous pattern), Crithidia anti-dsDNA and anti-histone positivity, low complement levels and polymerase chain reaction for Epstein–Barr virus (EBV) was negative. She was diagnosed with SLE and was started on hydroxychloroquine and prednisolone. In 2012, active urinary sediment and 12 g/day proteinuria per day were detected; therefore, a renal biopsy was performed which showed class 4 lupus nephritis. MMF 2 g/day was added to the therapy. In 2014, the patient was admitted with severe headache and difficulty in walking. Neurological examination showed 4/5 hemiparesis of the right upper extremity. Cranial MRI showed a left parietal lobe lesion of 47 × 57 mm with haemorrhagic borders and content spreading into cortex white matter and causing diffuse vasogenic oedema and subfalcine shift; post-contrast images showed peripheral irregular contrasting increasing with time on the dural surface and surface facing white matter, and in diffusion-weighted images there were mixed signals (Figure 1).

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Figure 1

(a) Diffusion-weighted image sequence, diffusion restriction areas were seen hyperintense in the mass at the left pariatel lobe. (b) Diffuse vasogenic oedema and midline shift, which belong to the mass are seen in axial fluid-attenuated inversion recovery (FLAIR) image. (c) In precontrast axial T1-weighted image, haemorrhagic materials in the border of the mass are seen hyperintense. (d) In postcontrast axial T1-weighted image pathological curvilinear contrast enhancements are seen in the border of the white matter and posterior dura.

Treatment with MMF was discontinued. The biopsy revealed a tumour mass with diffuse necrosis. The viable areas of the tumour were composed of tumour cells with enlarged nuclei and scanty cytoplasm, showing centroblastic and immunoblastic lymphoid features. Immunohistochemically there was diffuse positivity for CD20, Bcl2 and vimentin and scant positivity for CD3, while CD5, CD10, CD23, CD30, Bcl6, CD138, smooth muscle actin, EBV and pankeratin were all negative. The Ki67 index was over 60% (Figure 2). She was diagnosed with diffuse large B-cell lymphoma (DLBCL). Bone marrow biopsy showed no infiltration. Positron emission tomography/computed tomography showed increased activity in the area of the cranial lesion. She was transferred to the haematology department and given methotrexate 4000 mg/m², rituximab 375 mg/m² and temozolomide 170 mg/m². Starting from the second week, filgrastim prophylaxis was used. Pseudomonas aeruginosa sepsis occurred after chemotherapy then the patient died as a result of cardiac arrest.

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Figure 2

(a) Perivascular lymphoid infiltration around the large vessels (HE × 20). (b) Reactive brain tissue infiltrated with atypical lymphocytes (right and left upper) (HE × 40). (c) Cytoplasmic enlargement, nuclear pleomorphism and nucleoli clarify in the atypical lymphocyte, which does not create pronounced patterns and demonstrating diffuse distribution (HE × 400). (d) Diffuse CD20 positivity in the lymphocyte cytoplasm and cell membrane (IHK × 200).

Although SLE patients have no increase in the risk of malignancy-related deaths, ² DLBCL is frequently found among them. ³ SLE patients receiving immunosuppressive treatment have a higher risk of NHL. It is not clear whether immunosuppressive agents cause lymphoid malignancy. Our patient used no cyclophosphamide or azathioprine; therefore, the association between MMF and PCNSL becomes stronger.

The first case of PCNSL in SLE was a 58-year-old Korean woman who was diagnosed with a combination of focal proliferative (WHO class III) and membranous (WHO class V) lupus nephritis. She was successfully treated with MMF at 1 g by mouth twice daily with initial high doses of steroids. In the context of tapering the corticosteroid dose to 5 mg/day, her urine protein-to-creatinine ratio had decreased from 9 mg protein/mg creatinine (proteinuria approximately 9 g/24 hours) in November 2003, to 0.3 mg protein/mg creatinine in September 2004. In October 2004, she was admitted to hospital with an acute change in mental status. A diagnosis of DLBCL was made with brain biopsy. Five days after the brain biopsy, she was started on a course of chemotherapy. ⁴

The second case was a 42-year-old African-American woman who had a 13-year diagnosis of SLE and 9-year lupus nephropathy. She was treated with low-dose prednisone and azathioprine for 6 years followed by 1 year of cyclophosphamide prior to being changed to low-dose prednisone and 1000 mg/day of MMF for 6 years up until admission. She was admitted to the hospital with a 1 month history of persistent vertigo and a several day history of left-sided weakness and double vision. The patient underwent a stereotactic biopsy for multiple ring-enhancing lesions. The postoperative course was complicated by cerebellar haemorrhage and life support was withdrawn on hospital day 51. ⁵

The third case was a 43-year-old Chinese woman who was diagnosed with SLE in 1992. She was given low-dose prednisolone with satisfactory control of her symptoms until she presented with proteinuria of 3.8 g/day in June 2000 with biopsy confirmed active lupus nephritis of WHO class IV. She was treated with prednisolone 50 mg and MMF 1 g daily. She achieved a partial response with residual proteinuria in the range of 0.6–0.9 g/day. The patient developed DLBCL of the central nervous system after almost 8 years of treatment with MMF in 2008. There was complete remission of the lymphoma after chemotherapy. ⁶

The fourth case was 20-year-old woman with a history of lupus nephritis on MMF who presented following a seizure. She was diagnosed with stage 1 PCNSL and treated with chemotherapy. ⁷

Our SLE patient who developed PCNSL after 2 years of treatment with MMF is the fifth case in the literature. Large-scale studies are needed to clarify any association between MMF usage in SLE and PCNSL.