CASE REPORT

Non-enhancing relapse of a primary CNS lymphoma with multiplediffusion-restricted lesions

Lars Fischer • Arend Koch • Uwe Schlegel •

Hans-Christian Koch • Rudiger Wenzel •

Nicolas Schroder • Eckhard Thiel • Agnieszka Korfel

Received: 29 January 2010 / Accepted: 21 June 2010 / Published online: 3 July 2010

� Springer Science+Business Media, LLC. 2010

Abstract Primary CNS lymphoma (PCNSL) and its vari-

ant primary intraocular lymphoma (PIOL) are rare forms of

extranodal non-Hodgkin’s lymphoma confined to the CNS

including the retina and the optical nerve; histologically,

most cases are diffuse large B cell lymphomas. PCNSL in

immunocompetent patients display typical radiological

features on MRI, i.e. intensely and homogeneously enhanc-

ing lesions with moderate edema. Here, we report a 52-year-

old male with a history of a PIOL and two consecutive

intracerebral relapses who presented with dysarthria, dys-

phagia, and gait ataxia. Gadolinium-enhanced T1 scans were

unremarkable but multiple lesions with restricted water

diffusivity were seen on diffusion-weighted imaging.

Relapse of his PCNSL was secured histologically only on

autopsy. The possible etiology of the diffusion-restricted

lesions is discussed.

Keywords Diffuse large B cell lymphoma �Primary CNS lymphoma � Diffusion weighed imaging �Non-enhancing

Case

A 52-year-old male with a history of primary intraocular

lymphoma (PIOL) and two consecutive intracerebral

relapses presented in November 2008 with rapidly pro-

gressive cerebellar dysarthria, dysphagia for solid food,

gait ataxia and a continuous rhythmic twitching of the soft

palate, suggestive of palatal myoclonus, not involving

other oromandibular or oculomotor muscles.

In October 2004, a PIOL of the right eye (high-grade B

cell non-Hodgkin’s lymphoma) was established by vitrec-

tomy. No further CNS or systemic lymphoma manifestations

were detected on cranial MRI (cMRI), in cerebrospinal fluid

(CSF), on chest and abdomen computed tomography (CT) or

in bone marrow. A complete remission (CR) was achieved in

February 2005 after six courses of intravenous ifosfamide. In

June 2006, the patient presented with dysarthria, right-sided

ataxia and facial nerve palsy due to an isolated cerebellar

relapse with a single right cerebellar lesion moderately

enhancing on T1-weighted MRI scans (Fig. 1a). Five cour-

ses of intravenous high-dose methotrexate (HD-MTX) (4 g/

m2/day 1) and ifosfamide (2.0 g/m2/day/days 3–5) were

given (with collection of peripheral blood stem cells after

course 3) resulting in a CR. In May 2008, ataxia, dysarthria

and paresis with hypesthesia of the left leg developed. Cra-

nial MRI showed a singular, intensely enhancing lesion in

the right semioval centre (Fig. 1b). No ocular or systemic

manifestations were detected. The patient was treated with

four cycles of HD-MTX (2 g/m2 due to renal insufficiency)

L. Fischer (&) � E. Thiel � A. Korfel

Department of Hematology and Oncology, Charite

Universitatsmedizin, Campus Benjamin Franklin,

Hindenburgdamm 30, 12200 Berlin, Germany

e-mail: lars.fischer@charite.de

A. Koch � N. Schroder

Department of Neuropathology, Charite Universitatsmedizin,

Campus Mitte, Berlin, Germany

U. Schlegel

Department of Neurology, Knappschaftskrankenhaus,

University of Bochum, Bochum, Germany

H.-C. Koch

Department of Neuroradiology, Charite Universitatsmedizin,

Campus Benjamin Franklin, Berlin, Germany

R. Wenzel

Department of Neurology, Charite Universitatsmedizin,

Campus Benjamin Franklin, Berlin, Germany

123

J Neurooncol (2011) 102:163–166

DOI 10.1007/s11060-010-0287-5

and myeloablative chemotherapy (carmustin 400 mg/m2

and thiotepa 4 9 5 mg/kg) followed by autologous stem cell

transplantation resulting in a CR.

In November 2008, the patient presented with the initially

described symptoms. On cMRI, multiple supratentorial white

matter lesions were visible on T2 and particularly on FLAIR

scans, but T1 scans were unremarkable and no gadolinium

enhancement was seen. Diffusion-weighted scans revealed

several small hyperintense lesions, some with corresponding

signal reduction on ADC mapping (Fig. 2). In the CSF, no

lymphoma cells were detected by cytomorphologic, im-

munocytologic or PCR evaluation, and PCR for HSV and JC

virus DNA was negative. A duodenal biopsy was negative

for Trophyrema whippeli. The patient declined another brain

biopsy and was temporarily treated with dexamethasone,

aciclovir, ceftriaxon and trimethoprim/sulfamethoxazole

with no clinical effect, but there was progression of the

multiple non-enhancing lesions on FLAIR and diffusion

weighed imaging (DWI) scans, both of periventricular and

peripheral location. His condition deteriorated and he died

shortly afterwards from central respiratory depression.

Post-mortem examination revealed an extensive infiltra-

tion of the brain with a diffuse large B cell lymphoma with a

typical perivascular accumulation (Fig. 3); an intravascular

lymphoma growth was not visible. In most brain specimens,

lymphoma cellular density was rather low or moderate.

Lymphoma diagnosis was further verified by PCR demon-

strating a clonal immunoglobulin rearrangement. The his-

tological examination of spleen, liver and bone marrow did

not yield any signs of lymphoma infiltration.

Discussion

The vast majority of immunocompetent primary CNS

lymphoma (PCNSL) patients exhibit characteristic MRI

features with intensely and homogeneously enhancing

lesions and moderate edema [1]. Very few PCNSL cases

lacking contrast enhancement have been reported, several

only at relapse despite characteristic MRI appearance at

first presentation [2–5]. In contrast to the rather dense focal

tumor cell infiltration in typical PCNSL, most of these

cases exhibited a diffuse brain infiltration with lymphoma

Fig. 1 MRI images of the two precedent intracerebral relapses with

a radiomorphologic appearance characteristic for PCNSL (T1,

gadolinium)

Fig. 2 Representative MR images: FLAIR scan shows periventric-

ular and peripheral hyperintensities (a) but without detectable contrast

medium uptake on the gadolinium-enhanced T1 scan (b). Diffusion-

weighted imaging (DWI) reveals several hyperintense lesions (c, e)

with corresponding signal reduction on apparent diffusion coefficient

(ADC) maps (d, f)

164 J Neurooncol (2011) 102:163–166

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cells obviously not resulting in a significant disruption of

the blood–brain barrier. Thus, the term ‘‘lymphomatosis

cerebri’’ has been suggested to best describe this form of

PCNSL [6, 7].

Non-enhancing CNS lesions can frequently be found in

intravascular or angiotropic lymphoma (IVL), a rare variant

of aggressive (usually B cell) non-Hodgkin’s lymphoma

with selective growth of neoplastic cells within blood vessel

lumina [8]. It is a systemically disseminated lymphoma

with a high propensity for CNS and cutaneous lesions and

often infiltrating liver, spleen or bone marrow, but usually

sparing lymph nodes; patients often present with elevated

LDH, anemia and B symptoms [9]. CNS IVL may present

with infarct-like lesions and a rather ‘‘encephalopathic’’

syndrome due to intravascular lymphoma growth leading to

occlusion of many cerebral blood vessels [10–13].

PIOL is regarded a subtype of PCNSL which may occur

concomitantly with the cerebral manifestations or as an

ocular relapse of cerebral lymphoma. A small proportion of

patients (\20%) present initially with isolated intraocular

lymphoma; over 80% of these patients develop an intrace-

rebral relapse. Thus, the case presented here is typical for its

clinical course, also in terms of the subsequent remitting-

relapsing PCNSL [14]. However, our case is unique for its

combination of neuroradiologic features of lymphomatosis

cerebri (lack of gadolinium enhancement) and lesions

compatible with small infarctions (restricted water diffu-

sivity); moreover, those atypical features appeared only in

the third relapse. Due to the lack of enhancing lesions,

PCNSL relapse was not regarded as the preferred differen-

tial diagnosis. Although the progression of numerous

hyperintensities on T2 and FLAIR scans was suspicious,

they were not easily distinguishable from toxic leukoen-

cephalopathy [15].

The etiology of the various diffusion-restricted lesions

remains speculative. One explanation might be the pres-

ence of regional intravascular lymphoma growth causing

multiple small ischaemic lesions. However, no histologic

correlate for the infarct-like lesions could be found on the

brain autopsy specimens examined. On the other hand,

interspersed nodules with very dense lymphoma growth

may be responsible for the reduced water diffusion

observed, as markedly reduced ADC values have been

reported for PCNSL, especially in areas of dense cellularity

[16–18].

According to IPCG criteria lack of contrast-enhancing

lesions in the absence of other lymphoma manifestations is

regarded as CR in PCNSL [19]. However, as illustrated by

this case, the MRI appearance of a PCNSL relapse can

be atypical. In these patients, a brain biopsy should be

considered to secure the right diagnosis.

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