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A central nervous system B-cell lymphoma arising two years after initialdiagnosis of CLIPPERS

Guillaume Taieb, Emmanuelle Uro-Coste, Michel Clanet, Hans Lass-mann, Alexandra Benouaich-Amiel, Camille Laurent, Marie-BernadetteDelisle, Pierre Labauge, David Brassat

PII: S0022-510X(14)00385-2DOI: doi: 10.1016/j.jns.2014.06.015Reference: JNS 13258

To appear in: Journal of the Neurological Sciences

Received date: 28 March 2014Revised date: 12 May 2014Accepted date: 9 June 2014

Please cite this article as: Taieb Guillaume, Uro-Coste Emmanuelle, Clanet Michel, Lass-mann Hans, Benouaich-Amiel Alexandra, Laurent Camille, Delisle Marie-Bernadette,Labauge Pierre, Brassat David, A central nervous system B-cell lymphoma arising twoyears after initial diagnosis of CLIPPERS, Journal of the Neurological Sciences (2014), doi:10.1016/j.jns.2014.06.015

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Title: A central nervous system B-cell lymphoma arising two years after initial diagnosis of

CLIPPERS

Running title: CNS B-cell Lymphoma and CLIPPERS

Authors:

Guillaume Taieb, MD,1,† Emmanuelle Uro-Coste, MD, PhD,2,† Michel Clanet, MD,

PhD,3 Hans Lassmann, MD, PhD,4 Alexandra Benouaich-Amiel, MD,3 Camille Laurent,

MD,2 Marie-Bernadette Delisle, MD, PhD,2 Pierre Labauge, MD, PhD,5 David Brassat, MD,

PhD 3

Affiliations:

1. Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4, France

2. Department of Pathology

Hôpital de Rangueil

1, avenue du Professeur Jean Poulhès

31059 Toulouse cedex 9, France

3. Pole des Neurosciences and INSERM UMR1043

Université Toulouse III

CHU Toulouse, Hôpital Purpan

Place du Docteur Baylac

31059 Toulouse cedex 9, France

4. Center for Brain Research

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Medical University of Vienna

Spitalgasse 4

A-1090 Vienna, Austria

5. Department of Neurology

CHU Montpellier, Hôpital Gui de Chauliac

34295 Montpellier Cedex 5, France

Corresponding Author: Guillaume Taieb Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4 France E-mail: taiebguillaume@gmail.com Phone: (33) 4 66 68 32 61 Fax: (33) 4 66 68 40 16

Highlights:

- CLIPPERS is a recently described relapsing-remitting brainstem disease of unknown origin

- Sentinel lesions of primary CNS lymphoma could fit all features of CLIPPERS

- Including our patient, three cases of CLIPPERS progressed to CNS B-cell lymphoma

- CLIPPERS and CNS lymphoma are two distinct diseases or belong to the same disorder?

- Further investigations are needed to determine the pathophysiology of CLIPPERS

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Type of submission: Letter to the Editor Disclosure: We have no conflict of interest to declare and no financial disclosure to make. Word count text: 1051 Word count abstract: 0 Number of figures: 2 Number of References: 10 Keywords: Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement

Responsive to Steroids, Primary CNS lymphoma, Primary CNS lymphomatoid

granulomatosis, Sentinel lesions, Pathophysiology, Autoimmune disorder.

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Text:

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to

Steroids (CLIPPERS) is a steroid-responsive and steroid-dependent relapsing-remitting

disease, combining clinical brainstem attacks, characteristic punctate and curvilinear

enhancing lesions involving the pons and/or the middle cerebellar peduncles, and the presence

of perivascular lymphoreticular infiltrations (with mainly CD4-cells) on brain biopsy.1,2,3

Among the 12 CLIPPERS patients of the 2012 French cohort, one ultimately developed a

central nervous system (CNS) B-cell lymphoma.3 The case is presented here.

A 58-year-old man, without medical history, developed ataxia and diplopia within two

months. Clinical examination showed cerebellar ataxia in all four limbs, horizontal

bidirectional conjugate nystagmus, and left-sided peripheral facial nerve palsy. Brain

magnetic resonance imaging (MRI) showed punctate and curvilinear enhancing lesions

involving the entire brainstem and the right internal capsule (MRI-figure [A, B]) matching

with hyperintensities on T2-weighted images. Spinal cord MRI was normal. Cerebrospinal

fluid (CSF) analysis showed elevated levels of proteins (99mg/dl, normal < 46 mg/dl),

lymphocytic pleocytosis (19/mm3, normal < 3/mm3), without malignant cells and absence of

oligoclonal bands. CSF flow cytometry was not performed. Extensive serological analyses for

infectious (including HIV), autoimmune, and paraneoplastic disorders were negative.3 Whole-

body 18-fluorodeoxyglucose positron emission tomography scan was normal. A cerebellar

brain biopsy revealed perivascular lymphohistiocytic infiltrates, including mainly CD4-cells,

with parenchymal extension. CD8-cells were scarce with very low levels of granzyme B.

Axonal swelling and torpedoes were observed in the vicinity of inflammatory perivascular

lesions. Necrotizing vasculitis, demyelination and granulomatous lesions were absent.

Hybridization analysis to detect the EBV-RNA was negative. Intravenous pulses of

methylprednisolone (1g daily for 5 days) were started, leading to marked clinical and

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radiological improvement (MRI-figure [C,D]). Subsequently daily doses of 80 mg of oral

prednisolone were introduced and tapered progressively to 40 mg per day. Eighteen months

after the onset of symptoms, the patient experienced a relapse with gait ataxia and diplopia

accompanied by recurrence of initial enhancing lesions on brain MRI. Azathioprine (150 mg

daily) was added to the prednisolone (40 mg daily), leading to moderate clinical and

radiological improvement. Six months after the second attack, the patient relapsed again and

became bedridden. Brain MRI showed recurrence of initial enhancing lesions, becoming

confluent, associated with new large lesions with homogenous enhancement (MRI-figure

[E,F]). A left frontal lobe brain biopsy revealed central necrotic tissue with numerous necrotic

B-cells, negative for EBV-encoded RNA, together with perivascular T-cell infiltrates at the

margins of the tumour (Histological-figure [A-L]). Polymerase chain reaction analysis of the

BCR and TCR genes led to a technical failure, probably because of necrotic DNA

fragmentation. Given the radiological and histological features, the diagnosis of CNS B-cell

lymphoma was considered. The patient refused chemotherapy and died 37 months after the

disease onset. Autopsy was not performed.

One case of primary CNS lymphoma (PCNSL) 4 and one case of primary CNS lymphomatoid

granulomatosis (PCNS-LYG), 5 both presenting initially with all CLIPPERS features,

challenge the underlying CLIPPERS pathophysiology as an autoimmune disorder.

Lymphomatoid granulomatosis (LYG) mainly affects middle-aged adults and primarily

involves the lungs, and less frequently the skin and the CNS. Histological features of LYG are

characterized by an angiocentric infiltrate, including a varying number of B-cells within a

background of T-cells (mainly CD4-cells), often associated with necrosis due to intravascular

infiltration. The disease extends from an indolent process when no atypical B-cell was found

(grade I), to an aggressive B-cell lymphoma (grade III). 6 Unlike systemic LYG with CNS

localization, PCNS-LYG is not systematically associated with EBV. 7 Considering that

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PCNSL is also an angiocentric B-cell proliferation, negative for EBV (in immunocompetent

patient), with sometimes intratumoral necrosis and reactive perivascular T-cell infiltrates, 8

the diagnosis between PCNSL and PCNS-LYG grade III is challenging. In our case, since the

necrosis is intratumoral (as opposed to necrosis related to intravascular thrombosis seen in

PCNS-LYG), PCNLS remains the most likely diagnosis. The first biopsy in our patient

(performed before steroid therapy) showing perivascular CD4-cell infiltrates could be

interpreted as sentinel lesions of PCNSL. Sentinel lesions are considered as a host immune

response fighting against the emergence of PCNSL, and could recede spontaneously or after

steroid therapy. In the initial description, sentinel lesions have been described as a transient

symptomatic contrast enhancing mass that preceded the emergence of PCNSL within 12

months. 9 In our patient, the sentinel lesions of PCNSL matched with all CLIPPERS findings.

Then, we reported the third case presenting initially with all CLIPPERS features progressed

eventually to CNS B-cell lymphoma. In all of these three patients, some unusual or atypical

findings could challenge the diagnosis of CLIPPERS before the emergence of CNS

lymphoma. Remnant (even mild) gadolinium enhancement after steroid therapy (as seen in

our case), or the presence of asymmetrical involvement of the brainstem (as in the patient

progressed to PCNS-LYG),5 could be considered as unusual. Indeed, even described in the

first description by Pittock et al.,1 these two radiological findings have been rarely reported

thereafter. In addition, as opposed to the persistent steroid sensitivity observed in

CLIPPERS,1,2,3 after the first typical brainstem attack (observed in all of the three patients),

the further relapses became less sensitive (or resistant) to intravenous boluses of

methylprednisolone and/or occurred while the daily dose of steroid was above 20 mg. In the

reported case by Limousin et al.,4 the magnetic resonance spectroscopy (MRS) suggested an

arising tumour at the second relapse (occurring under 30 mg/day of prednisolone) before the

final diagnosis of PCNSL. However, whether MRS (or another sequences such as diffusion

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and perfusion) could distinguish CLIPPERS from PCNSL remained unknown and should be

evaluated.

In the light of our observation and the review of the literature, three different hypotheses

could be proposed about the underlying origin of CLIPPERS. First, CLIPPERS is a pre

lymphoma state, 10 and represents an effective host immune response (i.e. sentinel lesion in

PCNSL or PCNS-LYG grade I in LYG) preventing a clonal proliferation of B-cells. When

this immune response becomes too weak, B-cell lymphoma (i.e. PCNSL or PCNS-LYG grade

III) could emerge. In the second issue, as suggested Pittock et al., 1 CLIPPERS might be an

autoimmune disorder triggered by an unknown perivascular antigen. Then in some

CLIPPERS patients, chronic antigenic stimulation might lead to malignant transformation of

B-cells targeting this antigen. Finally, CLIPPERS could be a syndrome rather than a single

disease, including initial stage of CNS B-cell lymphoma, CLIPPERS disease, and maybe

another disorders.

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References

1. Pittock SJ, Debruyne J, Krecke KN, et al. Chronic lymphocytic inflammation with pontine

perivascular enhancement responsive to steroids (CLIPPERS). Brain. 2010;133:2626-2634.

2. Simon NG, Parratt JD, Barnett MH, et al. Expanding the clinical, radiological and

neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular

enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry.

2012 ;83:15-22.

3. Taieb G, Duflos C, Renard D, et al. Long-term outcomes of CLIPPERS (chronic

lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a

consecutive series of 12 patients. Arch Neurol. 2012;69:847-855.

4. Limousin N, Praline J, Motica O, et al. Brain biopsy is required in steroid-resistant patients

with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to

steroids (CLIPPERS). J Neurooncol. 2012;107:223-224.

5. De Graaff HJ, Wattjes MP, Rozemuller-Kwakkel AJ, Petzold A, Killestein J. Fatal B-cell

Lymphoma Following Chronic Lymphocytic Inflammation With Pontine Perivascular

Enhancement Responsive to Steroids. JAMA Neurol. 2013;70:915-918

6. Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained

over 4 decades. Am J Surg Pathol. 2010;34:e35-48.

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7. Lucantoni C, De Bonis P, Doglietto F, et al. Primary cerebral lymphomatoid

granulomatosis: report of four cases and literature review. J Neurooncol. 2009;94:235-242.

8. Ponzoni M, Berger F, Chassagne-Clement C, et al. Reactive perivascular T-cell infiltrate

predicts survival in primary central nervous system B-cell lymphomas.

Br J Haematol. 2007;138:316-323.

9. Alderson L, Fetell MR, Sisti M, Hochberg F, Cohen M, Louis DN. Sentinel lesions of

primary CNS lymphoma. J Neurol Neurosurg Psychiatry. 1996;60:102-105.

10. Taieb G, Renard D, Labauge P. Should CLIPPERS be considered a Prelymphoma state or

a new Inflammatory disease? JAMA Neurol. 2013;70:1200-1201.

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Figure legends MRI-figure At the first attack, gadolinium-injected T1-weighted images showed punctate and curvilinear

enhancing lesions involving the pons, the middle cerebellar peduncles, the cerebellum, (A)

and the right internal capsule (B). After steroid therapy, enhanced lesions decreased in the

brainstem and disappeared in the right internal capsule (C,D). At the third relapse, recurrence

of punctate enhancing lesions involving the brainstem became confluent (E), and large lesions

with homogenous enhancement appeared in the left thalamus, the splenium and the genu of

the corpus callosum and spreading along the frontal horn of the left lateral ventricle (F).

Histological-figure

Central massive necrosis (x400) contained cellular ghosts (A) with few CD3+ T-cells (D) and

a huge population of CD20+ B-cells (G) and numerous macrophage CD68+ cells (J).

In necrotic tissue (x200) cellular and vascular ghosts were visualized with some fragmented

nuclei (B). Few CD3+ T-cells (E) were present. Numerous CD20+ necrotic cells (H) and

CD68+ cells (K) were localized in the perivascular area.

Tumour margin (x400) shows small, regular lymphocytes in the perivascular space with some

aggressivity towards the vascular wall (C). CD3+ T-cells (F) are prominent in this infiltrate.

CD20+ B-cells (I) are very scarce. CD68+ cells are present almost outside the perivascular

area (L).

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MRI-figure Histological-figure

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Highlights:

- CLIPPERS is a recently described relapsing-remitting brainstem disease of unknown origin

- Sentinel lesions of primary CNS lymphoma could fit all features of CLIPPERS

- Including our patient, three cases of CLIPPERS progressed to CNS B-cell lymphoma

- CLIPPERS and CNS lymphoma are two distinct diseases or belong to the same disorder?

- Further investigations are needed to determine the pathophysiology of CLIPPERS