Lupus (2010) 19, 330–333
http://lup.sagepub.com
CASE REPORT
Diffuse large B-cell lymphoma of the central nervous system
in mycophenolate mofetil-treated patients with systemic
lupus erythematosus
HHL Tsang1, NJ Trendell-Smith2, AKP Wu3 and MY Mok1
1
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; 2Department of Pathology,
Queen Mary Hospital, The University of Hong Kong, Hong Kong; and 3Department of Radiology, Queen Mary Hospital,
The University of Hong Kong, Hong Kong
Patients with systemic lupus erythematosus (SLE) are susceptible to the development of
lymphoproliferative disorders and postulated causes include intrinsic defects in immune
surveillance and iatrogenic administration of immunosuppressants. Since the introduction
of mycophenolate mofetil (MMF) to the immunosuppressive regimen for the management
of post-organ transplantation, there have been reports of primary lymphoma of the central
nervous system (PCNSL). MMF has been widely used to treat active SLE patients with Class
IV lupus nephritis. In addition to two previously reported cases of PCNSL among SLE
patients on long-term MMF, we report a third patient who has been on treatment with
MMF for 8 years. The histology showed features compatible with diffuse large B-cell
lymphoma with strong immunohistochemical staining for CD20 and positive signal for
Epstein–Barr virus (EBV)-encoded RNA by in-situ hybridization that is similar to other
case reports, suggesting EBV driven B-cell lymphoproliferative disease. The patient responded
to withdrawal of MMF, intravenous methotrexate, rituximab and whole brain radiotherapy.
With the increasing use of MMF in active renal as well as non-renal exacerbations of SLE,
PCNSL should be included in the differential diagnosis in patients who present with gradual
onset of focal neurological deficit. Lupus (2010) 19, 330–333.
Key words: Epstein–Barr virus; immunosuppression; lymphoma; mycophenolate mofetil;
systemic lupus erythematosus
Case report
Correspondence to: Dr Mo Yin MOK, FRCP, Division of
Rheumatology and Immunology, Department of Medicine, Queen
Mary Hospital, The University of Hong Kong, Hong Kong.
Email: [email protected]
Received 28 June 2009; accepted 13 August 2009
DNA antibodies. She was given low-dose prednisolone with satisfactory control of her symptoms
until she presented with proteinuria of 3.8 g per
day in June 2000 with biopsy proven active lupus
nephritis of WHO Class IV. She was treated with
prednisolone 50 mg and MMF 1 g daily. She failed
to tolerate a higher dose of MMF with significant
diarrhoea. She achieved a partial response with
residual proteinuria in the range of 0.6 to 0.9 g
per day. MMF was tailed down to 500 mg daily
and concomitant azathioprine 50 mg daily was
then added as a steroid sparing agent since July
2002.
The patient was alert and oriented upon admission. She was afebrile and her blood pressure was
170/103 mmHg with a regular heart rate of 90 beats
per minute. Physical examination showed left upper
motor neuron type facial weakness and left hemiparesis with grade 3 limb power associated with
! The Author(s) 2010 Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
10.1177/0961203309347921
We report the case of a patient with known history
of systemic lupus erythematosus (SLE) who developed diffuse large B-cell lymphoma of the central
nervous system after almost 8 years of treatment with mycophenolate mofetil (MMF). A 43year-old Chinese woman was admitted in April
2008 for gradual onset of left-sided weakness for
1 week. She was diagnosed to have SLE in
1992 when she presented with malar rash, migratory arthralgia, early morning stiffness, elevated
anti-nuclear and anti-double stranded (ds)
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hyperreflexia and an extensor plantar response over
the left side. There was no gross sensory deficit,
no nystagmus or cerebellar signs. There was
no rash, no palpable lymphadenopathy and no
hepatosplenomegaly. Complete blood picture
showed normal white blood cell count of 4.4
(normal (N) 4.4–10.1) 109/l with a differential
neutrophil count of 3.6 (N 2.2–6.7) 109/l and lymphocyte count of 0.2 (N 1.2–3.4) 109/l and elevated erythrocyte sedimentation rate (84 mm/h).
She had normal liver and renal function and
normal lactate dehydrogenase (183 (N 107–
218) U/L). Serology revealed slightly elevated antidsDNA antibody level (63 (N 0–35) IU/ml),
depressed C3 level (36 (N 76–150) mg/dl) and
normal C4 level (13 (N 9–35) mg/dl) which had
been stable compared with the last check 1 month
ago. The patient’s serum C3 level had been low
since the onset of disease and she was believed
to have genetic C3 deficiency. The level of C-reactive protein was below the detectable limit
(<0.35 mg/dl). Blood culture showed no growth.
Standby computed tomography (CT) scan of the
brain showed no obvious mass or hydrocephalus.
Magnetic resonance imaging (MRI) of the brain
demonstrated a focal mass 1.5 1.4 1.6 cm3 in
the subcortical part of the right high parietal
region, located within the right precentral gyrus
with perifocal oedema. The lesion was isointense
to grey matter on both T1- and T2-weighted
images and was associated with rim enhancement
after gadolinium administration (Figure 1A and B).
Isointensity on the T2-weighted image favoured high
cellularity lesions such as lymphoma. Cerebrospinal
fluid (CSF) analysis showed no pleiocytosis, normal
CSF levels of protein (0.35 (N 0.12–0.60) g/l) and
glucose (2.9 (N 2.2–3.9) mmol/l). Bacterial and
viral cultures of the CSF showed no growth and
cytology was negative for malignant cells.
Serology for human immunodeficiency virus
(HIV) was negative.
Craniotomy with excision of the entire supratentorial mass was performed. Intraoperative brain
biopsy was not diagnostic but showed extensive
necrosis with foci of increased cellularity and some
cytological atypia only. Paraffin material later
revealed diffuse sheets of large lymphoid cells in
which many ‘immunoblast-like’ cells were noted
(Figure 2A). Immunohistochemistry demonstrated
strong membranous expression of CD20 on the
tumour cells (Figure 2B). The tumour was negative
for cytokeratin markers MNF116, AE1/3 and S100.
In-situ hybridization (ISH) studies for Epstein–Barr
virus (EBV)-encoded RNA (EBER) showed a
strong positive signal in the large B-cell population
(A)
(B)
Figure 1 Magnetic resonance imaging scan of the brain.
(A) T2-weighted image showing isointensity of the lesion to
grey matter. (B) Rim enhancement after administration of
gadolinium contrast with significant perifocal oedema.
(Figure 2C). The patient was diagnosed to have
EBV driven large B-cell lymphoproliferative disease. Haematologists were consulted and azathioprine and MMF were stopped. PET-CT scan and
bone marrow for staging showed no evidence of
lymphoma elsewhere. She was treated with highdose intravenous methotrexate 3 g every 3–4 weeks
for three times and whole brain radiotherapy.
Experimental use of intrathecal rituximab 25 mg
was also given monthly on two occasions. There
was complete remission of the lymphoma and the
patient showed gradual improvement in her limb
power with residual mild hemiparesis of grade 4.
Her serum C3 level remained low (41 mg/dl).
Lupus
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332
Discussion
(A)
(B)
(C)
Figure 2 Epstein–Barr virus (EBV)-positive diffuse large
B-cell lymphoma of the central nervous system (CNS).
(A) Photomicrograph showing CNS lymphoproliferative
lesion composed of a diffuse infiltrate of large ‘immunoblast-like’ cells arranged in a typical perivascular distribution
(H&E 200). (B) Photomicrograph showing strong membranous expression of the B-cell marker CD20 in the lymphoid
tumour cells by immunohistochemistry (100). (C) In-situ
hybridization demonstrating a strong positive signal for
EBV-encoded small RNAs (EBER) in tumour cells.
Lymphoproliferative disorders including primary
lymphoma of the central nervous system
(PCNSL) are a well-recognized complication of systemic immunosuppression following organ transplantation and HIV infection.1 PCNSL is not
common and accounts for only 2–3% of nonHodgkin lymphoma (NHL) cases. The first case
of lupus-associated PCNSL related to MMF use
involved a Korean patient with active lupus nephritis treated with MMF 2 g daily for 1 year.2 Another
case of PCNSL occurred in an African-American
lupus patient treated with MMF 1 g daily for lupus
nephritis for 6 years3 compared with MMF in use
for 8 years in our patient. As in our case, both
patients later developed diffuse large B-cell lymphoma of the CNS in which tumour cells showed
a positive signal for EBER by ISH. PCNSL have
also been reported in patients suffering from other
autoimmune conditions including myasthenia
gravis, CNS vasculitis, relapsing polychondritis
and dermatomyositis, treated with MMF 2 g daily
for a variable period of 8–46 months.4 All of these
patients responded to withdrawal of MMF and
treatment by rituximab but spontaneous resolution
of PCNSL upon discontinuation of MMF and concomitant methotrexate has also been described for
a patient with dermatomyositis.
While these case reports suggested a possible
association of PCNSL with MMF, SLE patients
may be predisposed to the development of lymphoma regardless of immunosuppressant use. A
meta-analysis involving over 8700 SLE patients
from six cohorts found that NHL was more
common in SLE patients with a standardized incidence rate ranging from 5.2 to 44.4.5 A proportion
of these patients had not been treated by immunosuppressive medications6 implying that development of lymphoma in some patients may not be
related to the use of immunosuppressants.
Furthermore, the link between MMF and PCNSL
and other lymphoproliferative disorders has been
reflected in recent decades when MMF has been
more widely used and replaced azathioprine in the
therapeutic regimen for organ transplant recipients.
PCNSL was not uncommonly reported in patients
with MMF treated renal transplant recipients with
the development of these lesions at a median of 14
months after switching from azathioprine to
MMF.7
Thus, the development of PCNSL in SLE
patients may occur as a result of impaired
immune surveillance and compromised T-cell
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Diffuse large B-cell lymphoma of the central nervous system
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activity resulting from the immunosuppressant
leading to persistence of EBV, an important aetiological agent for B-cell malignancy, dysregulated
apoptosis related to over-expression of oncogenes
such as Bcl-2 and malignant transformation from
hyperactive B- and T-cells from the underlying
lupus. Furthermore, low serum complement profile
(C3, C4 and CH50) has been described to be associated with lymphoma in patients with primary
Sjogren’s syndrome, although only low C4 levels
were found to be an independent significant variable in multivariate analysis.8
Our patient who developed PCNSL after treatment with MMF for almost 8 years provides a third
case of possible MMF-associated PCNSL in SLE
patients. While our patient was also put on lowdose azathioprine for 6 years, we cannot delineate
the risk posed by specific immunosuppressive
agents when these were used in combination.
Indeed, the Collaborative Transplant Study database showed that azathioprine in combination with
corticosteroids predisposed to development of
post-transplant lymphoproliferative disease with a
relative risk of 12.7 among 6283 cadaveric kidney
recipients.9 However, the association of azathioprine with EBV-related lymphoma in SLE patients is
rare.10 With the more frequent use of MMF clinically in lupus nephritis owing to its efficacy to sideeffect profile compared with cyclophosphamide,
and its growing use in non-renal manifestations of
SLE, the link between MMF use and the development of lymphoproliferative disorders has yet to be
elucidated from surveillance in a large scale. The
approach in the management of this condition
would include withdrawal of MMF with close
monitoring of the lupus disease and judicious use
of immunosuppressive agents if necessary.
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