Discussion:
Since its discovery in 1964, Epstein-Barr virus (EBV) has been causally
linked to a variety of B-cell lymphoproliferative disorders (EBV-LPD).
EBV-LPD range from indolent and/or self-limited inflammatory disorders
to aggressive lymphomas. These include infectious mononucleosis, Burkitt
lymphoma, Hodgkin lymphoma, post-transplant- and other iatrogenic
immunodeficiency associated- lymphoproliferative disorders (PTLD and
Oii-LPD), EBV positive diffuse large B-cell lymphoma
(not-otherwise-specified and chronic inflammation associated), primary
CNS lymphoma, lymphomatoid granulomatosis (LYG), EBV positive
mucocutaneous ulcer, germinotropic B-LPD, primary effusion and
plasmablastic lymphomas.
First described in 1972 by Liebow et al. , lymphomatoid
granulomatosis (LYG) is a rare form of EBV-LPD. LYG is characterized by
an angiocentric and angiodestructive, polymorphous infiltrate of
numerous small T-lymphocytes, histiocytes, and variable numbers of
large, atypical EBV (+) B-cells. Despite its name, granuloma formation
is rarely observed.
LYG is a complex, extra-nodal EBV-LPD which usually affects middle-aged
adults in the fourth to sixth decades of life with a 2:1 male
predominance. LYG is most commonly encountered in pulmonary tissue but
can rarely show primary central nervous system (CNS)
involvement.2-5 Vascular damage and tissue necrosis in
LYG is postulated to be cytokine-mediated by CXCL9 and CXCL10. The
cellular infiltrate is predominantly composed of CD3(+)/CD4(+) helper
T-cells and variable amounts of histiocytes. EBV (+) B-cells range from
rare, scattered cells to numerous clusters of
cells.3,5,6
LYG is histologically divided into low-grade (Grade I/II) and high-grade
(Grade III) disease. Grade I lesions contain rare large atypical B-cells
and minimal necrosis whereas Grade II and III lesions contain greater
number of large atypical B-cells and extensive necrosis. There is a
paucity of EBER+ B-cells (<5/high power field [hpf]) in
Grade I lesions, but higher numbers are observed in Grade II (5-50/hpf)
and Grade III (>50-100/hpf) lesions. Lesions with higher
numbers of EBV (+) large B-cells behave aggressively, usually
necessitating chemotherapy. Low-grade lesions, in contrast, are often
treated aiming to improve immune surveillance of
EBV.3,5
The lung is the most common site of involvement in LYG, followed by the
CNS (40%), skin (34%), kidney (19%), and liver (17%). Lymph node and
bone marrow involvement are rare. Immunologic studies have shown a
decrease in CD3+ T cells, specifically CD8+ cells in
LYG.5 Though initial reports had noted LYG in setting
of immunodeficiency states like Wiskott-Aldrich syndrome and HIV, no
underlying immunodeficiency state has been demonstrated in most
patients.3,5,7
CNS involvement in LYG is seen in approximately one-third of patients
and clinical presentation may include variable neurologic symptoms such
as hearing loss, diplopia, dysarthria, hemiparesis, ataxia, peripheral
neuropathy and atonic bladder. In a series of LYG from the National
Cancer Institute (NCI), CNS involvement was reported in 28 (40%)
patients.5 Isolated CNS involvement (primary CNS-LYG)
was reported in 19 patients in another series.8
As in our case, MRI commonly reveals focal intraparenchymal brain
lesions with multiple foci of increased signal intensity on fluid
attenuation inversion recovery (FLAIR) and T2-weighted imaging. Lesions
may evolve over time into ring-enhancing lesions with a non-enhancing
core. Similar rates of CNS involvement by low- and high-grade LYG have
been reported.5,8-10
There are no established consensus treatments for LYG due to its rarity.
Treatment modalities that have been employed include observation,
surgical resection, radiation therapy, corticosteroids, interferon
(IFN), intravenous immunoglobulin (IVIG), chemotherapy and rituximab,
with more intense strategies used for high-grade
disease.2,3,5,6
Historically, 14-27% of patients, achieved durable remissions without
therapy. However, early series showed overall mortality of over 60%,
with most deaths from progressive lung damage and infections. A
prospective treatment strategy was formulated at the NCI in 1994 with
low-grade LYG managed with dose-escalated IFN-alfa2b, while high-grade
disease was treated with chemo-immunotherapy with dose-adjusted R-EPOCH
(rituximab, etoposide, prednisone, vincristine, cyclophosphamide and
doxorubicin). Crossover therapy was allowed if alternate grade disease
developed after initial therapy. With this approach, in their cohort of
70 patients, after 13 years of median follow-up, more than half of
treated patients are alive for at least 10 years.5
Published experience with isolated CNS-LYG has been limited. The
anti-CD20 monoclonal antibody, rituximab as a single agent has shown
efficacy in treating CNS-LPD. We used the combination strategy of
rituximab and ULD-RT (2 Gy x 2). ULD-RT has shown immune modulating
effects and long-lasting remissions in treating indolent lymphomas.
Though the mechanism of action of ULD-RT is not entirely clear,
induction of the pro-apoptotic pathways including p53, and immunogenic
tumor cell death is postulated for its beneficial
effects.11 Rituximab may also enhance the
radio-sensitivity of lymphoma cells, providing a synergistic rationale
for this radioimmunotherapy combination.12 In the
prospective MIR trial, the combination of involved field RT and
rituximab was shown to be successful with preventing out-of-field
relapses in early-stage follicular lymphoma and a 2-year PFS of
85%.13 In our experience with ULD-RT in indolent
lymphomas, the progression-free and overall survival at 1-year was 58%
and 82%, respectively. In the seven patients who received combined
ULD-RT and single-agent rituximab, the response rate was 100% (7/7), of
which 5 had complete response at the time of latest
follow-up.14 ULD-RT is being explored in combination
with various immunotherapies in clinical trials for lymphomas.
Our case is unique due to the co-existence of a low-grade B-cell
lymphoma in the bone marrow along with CNS-LYG, which has not yet been
described before. While the clonal relatedness of these two processes is
unknown, the low-grade B-cell lymphoma was likely responsible for ITP in
our patient and both disorders responded well to rituximab therapy. The
underlying immunodeficiency state with LYG combined with steroid use led
to disseminated zoster. Acute illness and ITP likely resulted in
hypercoagulability and pulmonary embolism.
Treatment of relapsed/refractory LYG remains a clinical challenge.
Autologous and allogeneic stem cell transplantation has been utilized in
this setting with some success. Novel therapies being evaluated for LYG
include immunotherapies like anti-PD1 (programmed death-1) agents,
anti-CD30 monoclonal antibodies like brentuximab vedotin, targeted
agents like histone deacetylase inhibitors (HDACis) in combination with
anti-viral agents and cellular therapies like EBV-specific cytotoxic
T-lymphocytes and chimeric antigen receptor T-cell (CAR T-cell)
therapies.5,15
In summary, we present a unique and challenging case of CNS-LYG,
presenting as a large ring-enhancing mass, mimicking glioblastoma, but
with clinicopathologic features of low-grade LYG. The disease occurred
concurrently with chronic immune thrombocytopenia (ITP), disseminated
zoster, sub-massive pulmonary embolism, and bone marrow involvement by
low-grade B-cell lymphoma. Despite the complexity of the presentation,
our patient was successfully managed with a combination of immunotherapy
with rituximab and ultra-low-dose radiation therapy (ULD-RT). This
approach has shown promise in low-grade B-cell lymphomas but requires
further study and more comprehensive investigation. This highlights the
complex spectrum of EBV-LPD and supports the need for increased
awareness and further study of this unique form of disease.