Primary Central Nervous System ALK Positive Anaplastic Large Cell Lymphoma with Predominantly Leptomeningeal Involvement in an Adult

Abstract

A 31-year-old Korean male presented with altered consciousness and severe headache. Brain MRI delineated focal leptomeningeal enhancement without any intracerebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for anaplastic lymphoma kinase (ALK) and an absence of involvement in any other organs; specifically, the primary central nervous system ALK+ALCL. Complete remission was achieved following 5 cycles of systemic chemotherapy with a high dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemotherapy. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rarity and non-specific symptoms along with non-pathognomonic radiologic findings. We present the first case of primary leptomeningeal ALK-positive ALCL where the clinical course, pathologic characteristics and treatment modality are described as well as a review of literature.

Full text

Yonsei Med J http://www.eymj.org Volume 54 Number 3 May 2013
791
Case Report http://dx.doi.org/10.3349/ymj.2013.54.3.791
pISSN: 0513-5796, eISSN: 1976-2437 Yonsei Med J 54(3):791-796, 2013
Primary Central Nervous System ALK Positive Anaplastic
Large Cell Lymphoma with Predominantly
Leptomeningeal Involvement in an Adult
Jae Sung Park,1,4* Heejung Park,5* Sanghui Park,5 Suk Jin Kim,3 Ho Jun Seol,1 and Young-Hyeh Ko2
Departments of 1Neurosurgery, 2Pathology, and 3Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul;
4Department of Neurosurgery, Konkuk University Chungju Hospital, Chungju;
5Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea.
Received: January 14, 2013
Revised: January 30, 2013
Accepted: January 30, 2013
Corresponding author: Dr. Young-Hyeh Ko,
Department of Pathology,
Samsung Medical Center,
Sungkyunkwan University School of Medicine,
50 Irwon-dong, Gangnam-gu,
Seoul 135-710, Korea.
Tel: 82-2-3410-2752, Fax: 82-2-3410-0025
E-mail: yhko310@skku.edu
*Jae Sung Park and Heejung Park contributed
equally to this work.
∙ The authors have no financial conflicts of
interest.
© Copyright:
Yonsei University College of Medicine 2013
This is an Open Access article distributed under the
terms of the Creative Commons Attribution Non-
Commercial License (http://creativecommons.org/
licenses/by-nc/3.0) which permits unrestricted non-
commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
A 31-year-old Korean male presented with altered consciousness and severe head-
ache. Brain MRI delineated focal leptomeningeal enhancement without any intrace-
rebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic
large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for
anaplastic lymphoma kinase (ALK) and an absence of involvement in any other or-
gans; specically, the primary central nervous system ALK+ALCL. Complete re-
mission was achieved following 5 cycles of systemic chemotherapy with a high
dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemothera-
py. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rari-
ty and non-specic symptoms along with non-pathognomonic radiologic ndings.
We present the rst case of primary leptomeningeal ALK-positive ALCL where the
clinical course, pathologic characteristics and treatment modality are described as
well as a review of literature.
Key Words: ALK-positive, primary, CNS, anaplastic large-cell lymphoma, lepto-
meningeal
INTRODUCTION
Anaplastic large cell lymphoma (ALCL), which had rst been described in 1985,
was acknowledged as a distinct clinicopathologic entity in 2001.1,2 The 4th edition
of the WHO Classication of Tumours of Haematopoietic and Lymphoid Tissues in
2008 states that anaplastic lymphoma kinase (ALK) positive ALCL [ALK(+)
ALCL] must be distinguished from the provisional entity of ALK-negative ALCL
[ALK(-)ALCL].3,4 Although ALCL is primarily a nodal disease, extranodal in-
volvement is not uncommon.5,6 Moreover, ALK(+)ALCL was reported to have a
higher frequency of extranodal involvement compared to ALK(-)ALCL; skin
(21%) was the most frequently involved organ followed by bone (17%) and soft tis-
sues (17%).7 Primary involvement in the central nervous system (CNS) of ALK(+)
ALCL, however, is exceptional and only eight cases of primary CNS ALCL with

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792
CASE REPORT
A 31-year-old Korean male was brought to the emergency
department (ED) due to altered consciousness. At the ED,
he was drowsy and complained of a severe headache, weak-
ness in his left arm and difculty speaking. He stated that
he had been otherwise healthy and no laboratory results
suggested immunodeciency including human immunode-
ciency virus. Magnetic resonance imaging (MRI) of his
brain delineated leptomeningeal enhancement in the right
temporal and insular gyri (Fig. 1) and cerebrospinal uid
(CSF) analysis via lumbar puncture showed 90 WBC/mm3
with 67% of lymphocytes. Differential diagnosis at the time
included viral meningoencephalitis and tuberculosis (TB)
meningoencephalitis. Antiviral and anti-TB therapy were
started, neither of which was effective. His headache and al-
tered mental status were responsive only to Mannitol and
Dexamethasone. A follow-up MRI and CSF analysis, per-
formed 4 weeks after the initial visit to the ED, revealed
more prominent enhancement in the affected gyri and high-
er WBC counts (150/mm3) with elevated CSF pressure
(26.5 cm H2O), respectively. On the second CSF analysis
via lumbar puncture, a few scattered atypical lymphoid
cells were identied.
On the 39th hospital day, he underwent a brain biopsy fol-
lowing a craniotomy. The histologic section showed brain
parenchyma inltrated by numerous small-to-medium sized
neoplastic cells (Fig. 2A). These neoplastic cells had irregu-
lar nuclei with a moderate amount of cytoplasm (Fig. 2B).
Large atypical cells with horseshoe shaped nuclei, which
are hall mark cells of anaplastic large cell lymphoma, were
ALK positivity have been reported so far to our knowl-
edge.5,8-12 Although systemic ALK(+)ALCL tends to present
as an aggressive stage III or IV disease, it has been known to
be more responsive to chemotherapy than ALK(-)ALCL,
which contributes to better prognosis of the former than the
latter.2,5-7,13 Whereas the overall incidence of primary CNS
lymphoma was estimated to be 0.47 per 100,000 person-
years, only 14 cases of primary CNS ALCLs had been re-
ported by 2007: seven ALK(+)ALCLs, four ALK(-)ALCLs
and the remaining three ALCLs with ALK positivity untest-
ed.5,7,14 Seven (50%) of these 14 experienced a rapidly fatal
course leading to death and the mortality of primary CNS
ALCL was reported to be greater than that of other types of
CNS lymphomas in general.5,8,9,15-17 Treatment of choice for
primary CNS ALK(+)ALCL has not been established. In
this report, we describe the rst case of primary leptomenin-
geal ALK(+)ALCL of an adult man who was successfully
managed with systemic chemotherapy along with intrathe-
cal chemotherapy without radiotherapy.
Fig. 1. Magnetic resonance imaging of his brain showed hyperintense sig-
nal in the right temporal sulci from the Flair image (A) and leptomeningeal
enhancement in the right temporal and insular gyri from Gadolinium en-
hanced image (B).
Fig. 2. The histologic section showed brain parenchyma infiltrated by numerous small-to-medium sized neoplastic cells with perivascular cuffing of neoplas-
tic cells (A, HE ×100) and the neoplastic cells had irregular nuclei with a moderate amount of cytoplasm (B, HE ×400). Large atypical cells with horseshoe
shaped nuclei, which are hallmark cells of anaplastic large cell lymphoma, were also present (B, inset, HE ×1000)
A
A
B
B

Primary CNS Anaplastic Large Cell Lymphoma
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793
also present (Fig. 2B, inset). Immunohistochemical stains
revealed immunopositivity for CD30, ALK, Granzyme B,
CD45RO, CD5 and EMA (Fig. 3), but negative immunore-
activity for LCA, CD20, CD3, CD2, CD4, CD8, CD15,
CD43, CD68, BCL-2, CD56 and TIA-1. ALK was positive
in both the nucleus and cytoplasm. Fluorescence in situ hy-
bridization (FISH) was undertaken using a break apart
probe, which demonstrated translocations involving ALK
gene (Fig. 4). The case was diagnosed with malignant lym-
phoma of T-cell lineage, ALK+ALCL.
CT scans of his abdomen and chest failed to show any le-
sion suggesting involvement of lymphoma. A bone marrow
biopsy was performed, which was negative, and a test for
the Epstein-Barr virus was negative as well. On the seventh
post-biopsy day, he reported blindness in both eyes along
with severe headache, which indicated most likely very
high intracranial pressure (ICP). CSF pressure was mea-
sured to be over 40 cm H2O. Systemic high dose metho-
trexate (HD MTX, 8 g/mm2/day) and intrathecal (IT) triple
chemotherapy (MTX, Ara-C and Hydrocortisone) were im-
mediately started. After this, four more cycles of HD MTX
Fig. 3. Immunohistochemical stains revealed immunopositivity for CD30, ALK, Granzyme B, CD45RO and EMA. ALK, anaplastic lymphoma kinase.
Fig. 4. Fluorescence in situ hybridization for translocations involving ALK at
2p23: a unique sequence break apart probe targeting ALK gene locus was
used. Translocation involving ALK at 2p23 was detected. ALK, anaplastic
lymphoma kinase.

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794
Primary CNS lymphomas with predominant involvement
of leptomeninges are harder to diagnose because both asep-
tic and septic meningoencephalitis should be ruled out rst.
Our patient was assumed to have viral or mycobacterial
meningoencephalitis given no gross mass seen upon brain
MRI. Primary leptomeningeal lymphomas account for only
about 7% of all adult primary CNS lymphomas.18 As seen
in Table 1, two of eight cases harbored predominantly lep-
tomeningeal involvement with no intracerebral lesions and
neither of them was an adult.11 Our case is the rst primary
leptomeningeal ALCL with ALK positivity in an adult. It
would inevitably take longer for patients with grossly sheer
leptomeningeal involvement to undergo a biopsy than those
who have one or more intracerebral lesions.
Among 8 reported cases, histologic subtypes were de-
scribed in only 4 cases. Three of these 4 cases showed com-
mon histologic subtypes and the remaining 1 was a com-
bined lymphohistiocytic and small cell variant. Our case
was common histologic subtype. All reported cases were
CD30 and ALK positive and have a T- or null cell pheno-
type, and most are EMA-positive. Our case was T-cell phe-
notype showing immunopositivity for CD45RO and CD5
but immunonegativity for CD3. As shown Figs. 3 and 4,
ALK was positive in both the nucleus and cytoplasm. ALK
gene translocation was also detected by FISH. These nd-
ings are consistent with the ALCL of NPM-ALK fusion
were repeated with the interval of three weeks. Seven cy-
cles of IT triple chemotherapy were simultaneously per-
formed in total with the interval of 4 days.
Other symptoms and problems that occurred during the
chemotherapy were generalized tonic clonic seizure, tremor
in his jaw with dystonic feature, hypotension, pneumonia,
central diabetes insipidus (DI) and minimal intracerebral
hemorrhage (ICH) in the right temporal lobe accompanied
with intraventricular hemorrhage (IVH). ICH and IVH did
not require a surgical decompression. A series of follow-up
MRI undertaken after the fth HD-MTX revealed no resid-
ual enhancement, which suggested complete remission
(CR). Although mild quadriparesis and jaw dystonia re-
mained, no evidence of recurrence has been noted for more
than six months since CR.
DISCUSSION
Diagnosis of primary CNS ALK+ALCL requires several
critical steps including: clinical suspicion even when no
gross mass exists, biopsy in a timely manner, a thorough
immunohistochemical study, and exclusion of metastasis.
Given that extranodal involvement of ALK(+)ALCL is rel-
atively common, diagnosis of primary CNS ALK(+)ALCL
must be made only after excluding other involvement.5,6
Table 1. Summary of All Documented Cases of Primary CNS ALK+ALCL
Sex/Age Symptoms Location Clinical suspicion Histologic
subtype Clinical outcome
Abdulkader, et al.8M/13 Headache, vomiting Pariental and frontal lobe Infection Common Death
Ponzoni, et al.10 M/29 Fever, headache,
seizure Frontal and temporal lobe Infection/tumor
Lympho-
histiocytic
and small cell
NED at 13 mo
George, et al.9M/17 NA Parietal dura NA NA NED at 4.8 yrs
George, et al.9F/18 NA Temporal lobe and dura NA NA NED at 5.2 yrs
Karikari, et al.5M/4 Seizure
Pineal region mass,
leptomeningeal
enhancement
Infection Common Alive, ED
Merlin, et al.11 M/13 Headache, nausea Leptomeningeal
enhancement NA NA Death
Ozkaynak12 M/9 Seizure Frontal lobe Infection/abscess NA NED at 26 mo
Shah, et al.21 M/23
mo
Lethargy, motor
function loss,
seizure
Rt hemispheric and
leptomenigeal
enhancing mass
Tumor Common NED at 8 yrs
The present case M/31 Headache, seizure
Rthemispheargyral
swelling, leptomeningeal
enhancement
Infection Common NED at 18 mo
M, male; F, female; Mo, month; yr, year; NA, not available; Rt, right; NED, no evidence of disease; ED, evidence of disease; CNS, central nervous system;
ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma.

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795
creased ICP with meningeal irritation, CSF analysis reveal-
ing atypical lymphoid cells, no gross mass detected in the
brain MRI and lack of symptomatic improvement by anti-
viral, antibiotic or anti-TB medications.
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to avoid or at least delay radiotherapy.21 Our patient achieved
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He suffered from several temporary problems such as se-
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complications included quadriparesis and dystonia in the
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were assumed to derive from severely elevated intracranial
pressure, rather than from lymphoma itself. Therefore, these
complications may have been avoided if the chemotherapy
had been started sooner enough. As mentioned earlier,
grossly sheer leptomeningeal involvement without an intra-
cranial lesion contributed to belated brain biopsy leading to
delayed commencement of chemotherapy. According to a
report in 2007, seven of 14 patients with primary CNS
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test for ALK positivity.5 Given the insufcient sample size
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has been known to be more responsive to chemotherapy
leading to better prognosis than ALK(-)ALCL, but this does
not seem to apply to primary CNS ALCLs.5
In conclusion, this is the first reported case of primary
leptomeningeal ALK(+)ALCL in an adult to our knowl-
edge. Early detection is of vital importance in terms of both
mortality and morbidity. Physicians should consider the
possibility of leptomeningeal lymphomas in a patient with
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