American Journal of Hematology 72:216219 (2003)

HIV-Related Hodgkins Disease With Central Nervous

System Involvement and Association With
Epstein-Barr Virus
Suleiman Massarweh,1* Mark M. Udden,1 Imran Shahab,2 Michael Kroll,1 David A. Sears,1
Garrett R. Lynch,1 Bin S. Teh,3 and Hsin H. Lu3
1

Department of Medicine, Division of Oncology-Hematology, Ben Taub General Hospital, Baylor College of Medicine, Houston, Texas
2
Department of Pathology, Baylor College of Medicine, Houston, Texas
3
Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas

Central nervous system (CNS) involvement is a rare occurrence in the course of human
immunodeficiency virus (HIV)-related Hodgkins disease (HD). We report the clinical
course of a patient with HIV infection who developed systemic HD, mixed cellularity
subtype, later complicated by leptomeningeal involvement. The patient died from his
illness, and autopsy was performed. Examining the brain lesion, Epstein-Barr virus (EBV)
presence was demonstrated in Reed-Sternberg cells by immunohistochemistry using an
EBER probe for EBV RNA. This is the second case report in the English literature of HD
involving the CNS in an HIV-positive individual, and the first demonstrating EBV presence. Extranodal presence of Hodgkins disease in patients with HIV infection is probably
related to immunosuppression, and physicians treating this illness should be alert to the
potential of unusual sites of involvement. Am. J. Hematol. 72:216219, 2003.
2003 Wiley-Liss, Inc.

Key words: human Immunodeficiency virus; Hodgkins disease; central nervous system;
Epstein-Barr virus; autopsy

INTRODUCTION

Hodgkins disease is increasing in frequency among

patients infected with human immunodeficiency virus
(HIV) [1,2]. Features of the disease in the HIV setting
include unfavorable histology, advanced stage at presentation, and aggressive clinical behavior [3,4]. Although
extranodal involvement is not common, cases of HD involving unusual sites are reported in the literature [57].
HIV-related HD involving the central nervous system is
an extremely rare occurrence [8]. We describe an HIVinfected patient with Hodgkins disease who developed
intracerebral involvement and demonstrate presence of
Epstein-Barr virus (EBV).
CASE REPORT

A 26-year-old homosexual man with HIV infection

(CD4 count, 140/mm3; viral load of 67,000 copies per
milliliter) was evaluated in July 1998 for increasing right
neck swelling. He had no systemic symptoms and no
previous history of opportunistic infections.
2003 Wiley-Liss, Inc.

Laboratory findings, including a complete blood

count, were within normal limits. Computerized tomography (CT) scan revealed diffuse enlargement of the right
submandibular gland and to a lesser extent the left
submandibular gland, along with extensive cervical adenopathy. Aside from a prominent spleen and increased
axillary lymph node number, there were no other significant CT scan findings. Incisional biopsy of the right submandibular mass revealed the presence of Hodgkins disease, mixed cellularity subtype. A gallium scan showed
marked uptake in the soft tissue of the right side of the
neck, with no other sites of activity. Bone marrow ex-

*Correspondence to: Suleiman Massarweh, M.D., Division of Oncology-Hematology, Smith Tower, Suite 1057, Houston, TX 77030.
E-mail: sam@bcm.tmc.edu
Received for publication 28 June 2002; Accepted 15 November 2002
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.10288

Case Report: HIV-Related CNS Hodgkins Disease

217

Fig. 1. CT scan of the head showing prominent contrast

enhancement in the right sylvian fissure with surrounding
edema.

amination showed no evidence of Hodgkins disease. On

the basis of these clinical findings, his disease was staged
as Ann Arbor stage IIa, and mantle field radiotherapy
was started. He was maintained on antiretroviral therapy
using Lamivudine, Stavudine, and Crixivan. Response to
radiation therapy was good, with nearly complete disappearance of the neck mass.
In January 1999 he presented with abdominal pain and
jaundice. Laboratory work revealed pancytopenia and
abnormal liver function tests. He had hepatosplenomegaly and prominent retroperitoneal adenopathy on CT
scans. Bone marrow biopsy showed replacement of normal marrow by a polymorphic cellular infiltrate of histiocytes, lymphocytes, and Reed-Sternberg cells. ABVD
chemotherapy (Adriamycin, bleomycin, vinblastine, and
DTIC) was given, with the first dose reduced because of
abnormal liver function. He had a good response to chemotherapy with complete disappearance of his symptoms
and normalization of blood counts and liver function
tests.
CNS Involvement

While receiving ABVD he presented in April 1999

with new-onset seizures. Head CT showed marked enhancement in the right insular cortex with surrounding
edema, consistent with a meningoencephalitic picture
(Fig. 1). Brain magnetic resonance imaging (MRI) revealed a large hypointense area within the right insular
cortex with contrast enhancement (Fig. 2A) and intense
flare signal (Fig. 2B). Brain single-photon emission com-

Fig. 2. MRI images showing a large hypointense area

within the right insular cortex with marked enhancement
after contrast administration (A) and on flare images (B).

puted tomography (SPECT) study showed a focal area of

increased thallium uptake corresponding to the CT and
MRI findings, suggestive of neoplasia. Cerebrospinal
fluid examination was normal. He subsequently underwent a stereotactic brain biopsy of the lesion which re-

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Case Report: Massarweh et al.

Fig. 3. Immunohistochemical staining for CD30 showing

the classic binucleated Reed-Sternberg cells (original magnification 1000). [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]

vealed polymorphic cellular infiltrates involving the

meningeal surface composed of large binucleated cells
staining positive for CD30 and negative for T and B
lymphocyte markers. Findings were consistent with
Hodgkins disease. Whole-brain radiation therapy was
administered, and he was continued on systemic chemotherapy. In August 1999 he presented with symptoms of
increased intracranial pressure and obstructive hydrocephalus on imaging studies. He underwent palliative
ventriculostomy placement but died shortly thereafter.
Autopsy Findings

The brain was diffusely edematous with leptomeningeal thickening. Microscopically, there was perivascular
and meningeal infiltration by large binucleated malignant
cells characteristic of the classic Reed-Sternberg cells.
Immunohistochemical staining for CD30 was positive in
these cells (Fig. 3) and other markers including CD3,
CD15, CD20, CD45, as well as ALK (anaplastic lymphoma kinase) were all negative. Bacterial, mycobacterial, and fungal stains were all negative. In situ hybridization for EBV-encoded small ribonucleic acid (EBER)
showed nuclear staining in the large cells (Fig. 4). The
morphologic and immunologic features were consistent
with a diagnosis of Hodgkins disease and did not support a T- or B-cell malignancy. There was no disease
involvement of other organs.
DISCUSSION

Despite the lack of an obvious association between

Hodgkins disease and the acquired immunodeficiency
syndrome epidemic in the early 1980s, subsequent registry-linked data and prospective reports demonstrated a
small but definite increased risk of Hodgkins disease in
HIV-infected patients [912]. Whether Hodgkins dis-

Fig. 4. Binucleated Reed-Sternberg cell with nuclear staining using an in situ probe for EBV-encoded small ribonucleic acid (EBER), performed on paraffin-embedded tissue (original magnification 1000). [Color figure can be
viewed in the online issue, which is available at www.interscience.wiley.com.]

ease will be classified as an AIDS-defining illness or not,

it is clear that the features and natural history of the
disease are altered in the HIV setting. At the time of
diagnosis, 7090% of patients with HIV-related Hodgkins have advanced stage and exhibit a similarly high
frequency of B symptoms (fever, night sweats, and
weight loss). Bone marrow involvement is seen in 40%
of patients, and non-contiguous organ involvement is a
well-described phenomenon [4]. Histologically, HD in
HIV-infected patients is commonly composed of the
mixed cellularity and lymphocyte depletion varieties and
is frequently rich in Reed-Sternberg (RS) cells [13]. In
this setting, RS cells are characterized by a high frequency of EBV infection approaching 100%, suggesting
that EBV has a role in pathogenesis [13,14]. The presence of EBERs, recognized to have oncogenic capacity,
is indicative of latent infection and relates to the immunecompromised state. Interestingly, in the non-HIV setting,
HD shows a strong correlation between histologic subtype and EBV, with the mixed cellularity subtype showing higher rates of EBV infection than the nodular sclerosing variety [1517].
Involvement of the CNS or meninges is a rare but well
recognized complication of HD in the non-HIV setting,
occurring in 0.20.5% of all advanced-stage cases
[18,19] and less commonly as the sole site of involvement [1922]. In the setting of systemic disease, CNS
involvement results from either hematogenous spread or
direct meningeal infiltration from adjacent disease. Typically, patients present with symptoms of increased intracranial pressure, including headache and cranial nerve
palsies.
The English literature has one documented case report
of CNS Hodgkins in the setting of HIV infection, reported by Hair et al. [8] in 1991. The authors described
the case of a 34-year-old HIV-infected intravenous drug
user who presented with advanced mixed-cellularity HD

Case Report: HIV-Related CNS Hodgkins Disease

and later developed intracranial involvement. Our report

describes the second case of HIV-related HD and is the
first to show the EBV association in this setting.
Optimal approach for treatment of HIV-associated HD
is not well defined. Because most patients present with
advanced disease stage, it is generally accepted that systemic combination chemotherapy like ABVD would be
the initial treatment of choice [3]. Compared to HD in
patients without HIV, however, response to treatment is
typically far inferior and relapses are common, reflecting
the natural history of the disease in the presence of immune suppression. Certainly, more work is needed to
clarify the optimum use of chemotherapy in this setting.
It is often stated that CT scans may overstage Hodgkins disease in the setting of HIV infection due to the
possible presence of persistent generalized lymphadenopathy (PGL) [3,4] or lymphadenopathy from a variety
of possible opportunistic infections. We believe that
overstaging the disease is less likely to be clinically relevant, however, since the disease is typically advanced in
the majority of patients at presentation. In fact, there
might be a higher chance for understaging the disease
using current imaging techniques, including gallium
scanning, as exemplified by our case. It is therefore most
appropriate to consider HD in the setting of HIV infection as a disseminated illness unless proven otherwise.
This suggests that systemic chemotherapy should be used
as the initial therapeutic modality, even for apparent localized disease.
In summary, although CNS Hodgkins disease in the
setting of HIV infection is quite unusual, it is a potential
complication of the illness in view of the peculiar behavior and unusual manifestations influenced by AIDSrelated immune suppression. Therefore, the differential
diagnosis of CNS lesions developing in the course of
HIV-associated Hodgkins disease should include intracranial disease extension in addition to the more common
opportunistic infections and other malignant processes
(like primary CNS lymphoma). As part of the diagnostic
evaluation of intracranial or leptomeningeal disease in an
HIV patient with HD, biopsy would be imperative to
establish a diagnosis and make subsequent treatment decisions.
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