ARTICLE
Auteur(s) : Anne-Claude George1, Mahmut
Ozsahin2, Robert Janzer3, Siverio
Agassis4, Reto Meuli5, Audrey S
Baur3, Valérie Frossard1, Serge
Leyvraz1, Nicolas
Ketterer1
1Department of Oncology and Haematology,
Pluridisciplinary Center for Oncology, CHUV, BH-06, 1011 Lausanne,
Switzerland
2Department of Radiotherapy, University Hospital CHUV,
Lausanne, Switzerland
3University Institute of Pathology and Neuropathology,
CHUV, Lausanne, Switzerland
4Department of Neurosurgery, University Hospital CHUV,
Lausanne, Switzerland
5Department of Radiology, University Hospital CHUV,
Lausanne, Switzerland
Primary central nervous system lymphoma (PCNSL) is a rare disease,
and account for less than 1% of all non-Hodgkin’s lymphomas (NHL)
[1]. The PCNSL are typically aggressive, most often of diffuse
large B-cell type, and have a dismal prognosis. Primary
leptomeningeal lymphoma in the absence of brain involvement and
without evidence of systemic disease is an exceedingly rare entity,
representing less than 10% of all the PCNSL. Most of the cases are
aggressive lymphomas with generally poor prognosis [2] but primary
indolent lymphoma involving the dura is also described
[3-6].Recently, few cases of primary indolent lymphoma of the
intracranial dura have been described, with pathological features
and clinical behavior suggesting a lymphoma of mucosa-associated
lymphoid tissue (MALT) type [7]. MALT lymphomas were first
described in 1983 by Isaacson [8], and were secondly recognized in
the REAL as well as in the WHO classification as a distinct entity
among the marginal zone lymphomas (MZL) that includes also splenic
and nodal MZL [9, 10]. MALT lymphomas represent the most common
subset of extranodal lymphomas. They arise frequently from the
stomach, but also from nongastrointestinal sites such as thyroid,
salivary glands, conjonctiva, breast, lung, and skin. They result
of an accumulation of reactive lymphoid tissue due to either
chronic inflammatory disorders such as Helicobacter pylori
infection of the stomach or to an autoimmune disease like Sjögren’s
syndrome of the salivary glands or Hashimoto’s thyroiditis [11]. In
these cases, antigenic stimulation is probably the first step for
development of a lymphoma. MALT lymphomas generally behave as an
indolent disease, remain localized for long periods and have a
favorable outcome although disseminated disease may also be seen at
diagnosis [12].We report here a case of primary dural marginal zone
B-cell lymphoma of MALT type, and review the literature.
Case report
A 75-year-old woman with a history of extra-mammary Paget’s disease
of the perineum treated 3 years before with external beam
radiotherapy (32 Gy) was hospitalized because of blurred vision,
balance disturbance, and recurring falls. She had a 2-year history
of behavior disorders, memory loss, and progressive aphasia. There
were no associated night sweats, weight loss, or fever. On
admission, physical examination, complete blood count, erythrocyte
sedimentation rate, and blood chemistry including LDH and creatinin
levels were all within normal limits. Only serum beta-2
microglobulin levels were high at 3.26 mg/l. Serological tests for
HIV and hepatitis C were negative. Computerized tomography (CT)
scan of the brain showed a bilateral frontal dural mass compressing
the left cerebral hemisphere, suggesting a subacute subdural
effusion. Magnetic resonance imaging (MRI) was performed, and
showed that this subdural lesion had n hypointense T1-weighted
signal and an intermediate T2-weighted signal with an intense and
homogeneous enhancement after gadolinium injection (( figure 1 )A). The mass
infiltrated the frontal circumvolutions and the roof of the left
orbit, suggesting either an inflammatory granulomatous disease or a
neoplastic process.
A craniotomy with a surgical biopsy was performed. The
histological examination revealed a diffuse proliferation by small
lymphocytes with few perivascular plasmocytoid cells. Cytonuclear
abnormalities were rare. Immunohistochemical analysis showed a
large majority of B lymphocytes (CD20 positive) and some reactive T
lymphocytes (CD3 positive) (( figure 2 ) A, B). The
staining for CD10, CD23, and cyclin D1 was negative (( figure 2 ) C, D, E).
VJ PCR analysis for rearrangement of the immunoglobulin heavy-chain
showed a monoclonal population. Routine detection of t(11;14) and
t(14;18) was negative. These characteristics were consistent with
the diagnosis of marginal lymphoma of MALT type. The examination of
the cerebrospinal fluid showed normal protein content but the
presence of atypical lymphoid cells.
Staging work-up was normal, including bone marrow aspiration and
biopsy, CT of the chest and abdomen. The ophthalmological
examination did not show any involvement by the lymphoma. Using the
Ann-Arbor staging system, the above-mentioned features suggested a
stage IE primary marginal zone B-cell lymphoma of the dura
according to the WHO classification.
Because of the presence of atypical lymphoid cells in the
cerebral fluid, the patient was treated with one cycle of systemic
high-dose methotrexate (3 g/m2) followed by five
intrathecal injections combining methotrexate, cytarabine, and
hydrocortisone. External radiation therapy of 30.6 Gy was
subsequently delivered on the primary site with a security margin,
without whole-brain irradiation. Treatment was well tolerated, and
neurological symptoms resolved quickly. The MRI performed
6 months after the end of radiotherapy showed a significant
regression of the subdural lesion, without any change 6 months
later (one year after treatment) (( figure 1 )B). The
cerebrospinal fluid was further controlled and showed rare lymphoid
cells, without evidence of monoclonality by PCR analysis. Three
years after treatment, the patient remains well and free of
symptoms besides discrete memory loss.
Discussion
Leptomeningeal infiltration by NHL is most often a secondary
complication of systemic aggressive lymphomas presenting with a
high IPI (International Prognostic Index) or predominant extranodal
involvement [13, 14], or it may be found also in PCNSL. Conversely,
isolated lymphomatous meningeal infiltration is a rare entity,
which is mainly reported in the literature as case reports. We
report here a rare case of indolent dural lymphoma presenting as a
huge bilateral frontal mass in a 75-year-old woman, and being
consistent with a marginal zone lymphoma (MZL) of MALT type.
In the early nineties, leptomeningeal infiltration of
lymphomatous origin without evidence of parenchymal central nervous
system involvement or systemic tumor was recognized as a distinct
entity by Lachance, and was called "primary leptomeningeal
lymphoma" (PLML) [2]. In his report as well as in the series
reported later on by Miranda [3], the majority of PLML were of
intermediate or high-grade type according to the International
Working Formulation’s (IWF) classification and presented an
aggressive course with a dismal prognosis, similar to the
PCNSL.
Only few cases in that series were described as indolent
lymphomas, and showed a more benign course. Other than our patient,
we collected in the literature 23 cases of indolent PLML
(table 1( Table 1 )). Surprisingly,
while the first low grade PLML was described as small lymphocytic
lymphoma according to the IWF classification, most of them were
described since 1997 with histological features and clinical
behavior compatible with a MZL of MALT type [7, 15-18, 20-24].
This, actually, reflects the recognition of new lymphoma entities
by the REAL and the WHO classifications, based not only on
morphological, but mainly on immunological, molecular, and
cytogenetic criteria. These ancillary studies may help to
distinguish between a diffuse small lymphocytic lymphoma (SLL) of
chronic lymphocytic lymphoma (CLL) type, and a MZL of MALT type.
Both of them express the B-cell panel (CD20, CD19, CD79a), but
CLL/SLL are almost invariably positive for CD23 and CD5, whereas
MZL usually lack the CD5 positivity, with a CD23 antigen scarcely
expressed as in our case. Trisomy 3 or t(11;18) have been
reported in some cases of extranodal MZL. Indeed, recognized in
1994 by the REAL classification, the MALT lymphoma is in fact a
relatively new entity. We believe that some of PLML cases reported
before 1997 and diagnosed as SLL may belong to the extranodal MZL
subtype. It is also interesting to note that since 1997 no case in
the literature has been reported as SLL intra-cranial PLML
(table 1). Finally, 20 out of the 24 patients of our review
are women, which is consistent with the female predominance
observed in MZL.
The pre-biopsy diagnosis of PLML is difficult. Most of the
indolent intracranial PLML reported in the literature present with
clinical symptoms and radiological findings that are similar to
those met in meningiomas or in subdural effusions, even though the
routine use of MRI allows us now in some cases to have a
preoperative differential diagnosis between a carcinomatous and a
granulomatous process. Occasionally, a positive cytology of the
cerebrospinal fluid (CSF) is found [2, 3], but an isolated
lymphomatous meningitis without any radiological solid lesion is
rarely described [2]. In our patient, the radiological features of
the meningeal mass implied the differential diagnosis of meningeal
lymphoma, meningeal metastases, meningeal primary tumor such as
hemangiopericitoma or granulomatous inflammatory meningeal lesion
such as sarcoidosis. Clinically, the neurological abnormalities may
be scarce, and depend on the localization and on the extension of
the tumor. Symptoms may include focal deficit, psychological
disturbance, signs of intracranial hypertension, or epilepsy. The
interval between the onset of the symptoms and the diagnosis is
typically prolonged, and may be as long as several years [16, 18,
24], reflecting the slow proliferation rate of the tumor. Our
patient presented a 2-year history of neurological symptoms, though
the physical exam was normal.
As reported in the literature, most of the indolent PLML have a
favorable clinical course following a local therapy consisting in
surgery, radiotherapy, or both (table 1). Out of the 24
patients of the present review, only 3 had unfavorable clinical
course [2, 16]. They presented a form of PLML with predominant
lymphomatous meningitis and hydrocephalus combined in one of them
with multiple intradural cervical nodules. Two were treated with
craniospinal irradiation, and the third one received chemotherapy,
but they did not respond neither to first line nor to salvage
treatment and all died 3, 13, and 26 months after diagnosis. In
contrast, all other patients presenting essentially with a
localized mass had a favorable outcome following local treatment,
comprising radiotherapy in most cases. It is worth noting that
several of them were reported to be in remission several years
after the treatment. More than 3 years following the diagnosis, our
patient remains well without clinical or radiological signs of
progression. This reflects the importance of local treatment and
probably the key role of radiotherapy, knowing that radical
excision is rarely possible in this disease. However, one should
note that 4 patients in our review did not receive radiotherapy and
that 2 of them were alive 2 and 4 years after diagnosis [7, 15],
suggesting that irradiation might not be strictly required for the
control of this indolent disease, if adequate surgery is
feasible.
While radiotherapy appears to be the cornerstone of the
treatment, the role of intrathecal and systemic chemotherapy in the
management of indolent PLML is less clear. The cytology of CSF is
not reported in the majority of publications. Several patients
received intrathecal chemotherapy but only 2 of them were described
to have a CSF contamination. Those patients showed no evidence of
disease after combined treatment with radiotherapy, intrathecal
chemotherapy, and intravenous methotrexate or aracytine. It is,
therefore, difficult to draw any guidelines or recommendations
regarding the need of systemic treatment in indolent PLML.
Intrathecal chemotherapy seems reasonable in case of positive
cytology of the CSF, whereas intravenous treatment probably does
not play a major role in the management of this disease.
Table 1 Primary indolent intracranial leptomeningeal
lymphoma: review of the literature
|
Authors, year [reference]
|
N° of cases
|
Age/sex
|
Radiological findings
|
Pathologic findings
|
Therapy/outcome
|
|
Jazy et al., 1980 [4]
|
1
|
59/M
|
R temporal mass
|
Diffuse lymphocytic lymphoma*
|
- SX + RXT (40+14 Gy)
- + 25 Gy (spinal axis)
- NED at 16 mo
|
|
Nguyen et al., 1989 [5]
|
2
|
74/M
|
L frontal mass
|
Small lymphocytic lymphomaa
|
|
|
Lachance et al., 1990 [2]
|
3
|
35/F
|
Hydrocephalus
|
Small lymphocytic lymphomaa (CSF cytology)
|
- MTX i.t.
- RXT (30 Gy) + 25 Gy (spinal axis) at PD
- Dead of disease 27 mo after the onset of symptoms
|
|
4
|
58/F
|
- Hydrocephalus
- Multiple dural nodules
|
Small lymphocytic lymphomaa
|
- RXT (35,5 Gy) + 20,5 Gy (spinal axis)
- Dead of disease 13 mo after the onset of symptoms
|
|
Miranda et al., 1996 [3]
|
5
|
51/F
|
R frontal mass
|
Small lymphocytic lymphomaa
|
- SX + RXT (44 Gy)
- NED at 14 mo
|
|
Narberhaus et al., 1996 [6]
|
6
|
48/F
|
Right temporo-parietal mass
|
Small lymphocytic lymphomaa
|
- SX + RXT (42+6 Gy)
- + 32 Gy (spinal axis)
- NED at 36 mo
|
|
Kumar et al., 1997 [7]
|
7
|
40/F
|
Right cavernous sinus mass
|
MALT type lymphomab
|
|
|
8
|
62/F
|
Biparietal thickening
|
MALT type lymphomab
|
- SX a + i.v. fludarabine
- NED at 22 mo
|
|
9
|
52/F
|
Left frontal mass
|
MALT type lymphomab
|
- SX a + RXT
- i.v. AraC/MTX, i.t. MTX
- NED at 7 mo
|
|
10
|
43/F
|
Left tentorial mass
|
MALT type lymphomab
|
|
|
11
|
57/F
|
Left anterior falx cerebri mass
|
MALT type lymphomab
|
|
|
Kambham et al., 1998 [15]
|
12
|
39/F
|
Left cerebellar pontine angle
|
MALT type lymphomab
|
|
|
13
|
62/F
|
Left parieto-occipital mass
|
MALT type lymphomab
|
|
|
King et al., 1998 [16]
|
14
|
60/F
|
- Meningeal calcification
- Hydrocephalus
|
MALT type lymphomab
|
- Chemotherapy
- Dead of disease at 3 mo
|
|
Altundag et al., 2000 [17]
|
15
|
66/F
|
R parietal mass
|
MALT type lymphomab
|
- SX + RXT (30+20 Gy)
- A at 12 mo
|
|
Lehman et al., 2002 [18]
|
16
|
63/F
|
Extensive dural plaque-like mass
|
MALT type lymphomab with massive amyloid deposition
|
- SX + RXT (36+14,4 Gy)
- A at 8 mo
|
|
Pernot et al., 2002 [19]
|
17
|
40/M
|
Frontoparietal mass
|
Diffuse B-cell lymphoma with small cleaved cells ±
|
|
|
Goetz et al., 2002 [20]
|
18
|
64/F
|
Frontoparietal mass
|
MALT type lymphomab
|
|
|
Vazquez et al., 2002 [21]
|
19
|
44/M
|
R hemispheric mass
|
MALT type lymphomab
|
SX
|
|
Benouaich et al., 2003 [22]
|
20
|
38/F
|
L frontoparietal mass
|
MALT type lymphomab
|
- SX a + RXT
- i.v. + i.t. chemotherapy
- NED at 20 mo
|
|
21
|
45/F
|
R temporo-parieto-occipital mass
|
MALT type lymphomab
|
- i.v. chemotherapy + RXT
- NED at 12 mo
|
|
Bodi et al., 2003 [23]
|
22
|
56/F
|
Large frontal mass
|
MALT type lymphomab
|
|
|
Lima et al., 2003 [24]
|
23
|
36/F
|
Bilateral parietal mass + falx cerebri
|
MALT type lymphomab
|
i.v. MTX + RXT
|
|
Current case
|
24
|
75/F
|
Bilateral frontal mass
|
MALT type lymphomab
|
- SX biopsy, i.t. MTX/AraC,
- i.v. MTX, RXT (30.6 Gy)
- NED at 36 mo
|
aInternational Working Formulation (IWF) classification.
bREAL or WHO classification.
cIn the Kumar’s paper, the 5 patients were reported
to have surgical biopsy or resection, without further
precisions.
Conclusion
This review highlights the importance of recognizing indolent PLML
as a distinct clinicopathological entity. This latter frequently
corresponds to lymphomas of MALT subtype, and is characterized by a
relatively good prognosis following local therapy.
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