Discussion
Waldenstrom macroglobulinemia (WM) is defined by the World Health
Organization (WHO) as an indolent lymphoplasmacytic lymphoma (LPL)
belonging to the category of non-Hodgkin B-cell lymphomas (NHL) [4].
Although there remains a lack of specific chromosomal or oncogene
abnormalities in LPL, 90% of cases share MYD88 L265P mutations
that are most commonly associated with IgM monoclonal gammopathies such
as WM [4]. While WM remains incurable, median survival rates have
increased from 5 to 8 years due to increased awareness of the disease
and advancements in therapy over the last decade [2]. Essential
aspects of the initial evaluation for WM include a detailed history and
physical examination prior to pursuing diagnostic workup. Although
constitutional symptoms of this disease are shared amongst various other
lymphoid malignancies, thorough history taking may reveal clinical
manifestations specific to hyperviscosity syndrome such as spontaneous
epistaxis, recurrent headaches, visual changes, and blurred vision
[1,2]. Peripherally circulating antibodies not only cause
detrimental effects through changes in blood viscosity, but also by
their deposition in end-organs and through immune system autoreactivity
[5]. However, the multiple complications associated with WM are not
simply related to the effects of a monoclonal gammopathy. For example,
peripheral neuropathy which is observed in approximately 20% of
patients who suffer from this disease process may be a result of direct
lymphoplasmacytic infiltration or IgM deposition of nerve fibers,
amyloidosis from excess light chain production, or development of
autoimmunity [1,2].
In approximately 1% of WM cases, patients develop Bing-Neel syndrome
(BNS) in which there is infiltration of the CNS by lymphoplasmacytic
cells. The absolute incidence of BNS is unknown, but in a retrospective
cohort study of 1,523 WM patients, only 13 patients (0.8%) were
diagnosed with BNS, suggesting a very low prevalence [3,6]. A review
of published literature shows primarily case reports and few small
retrospective surveys, demonstrating the rarity of this disease
manifestation. Retrospective analysis has demonstrated a significantly
lower median survival time (4 months) between symptom onset and
diagnosis of BNS as compared to WM [3]. To further complicate
matters, BNS can present at any time during the active treatment course
for WM, even when the patient is in apparent remission from disease
[1-3]. Rarely, BNS precedes the diagnosis of WM and appears as a
primary CNS LPL, having only been described in twenty-four cases
[7]. Prognosis appears to be better in these cases as compared to
those with a prior history of WM whose disease progresses to BNS
[3].
The evaluation for BNS begins with diagnostic testing including
gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and
whole spine as well as cerebrospinal fluid (CSF) sampling for cytology,
flow cytometry, and mutational analyses [1-3]. Findings on MRI
include contrast-enhanced infiltrations with or without thickening of
the meningeal sheaths depending on leptomeningeal involvement, in
addition to accentuated diffusion weight imaging (DWI) with elevated or
normal apparent diffusion coefficient (ADC) values suggestive of
vasogenic edema due to perivascular space invasion by malignant cells
[9]. Of note, there are two categories of BNS that can be
distinguished on MRI: a diffuse form, in which there is leptomeningeal
and perivascular infiltration versus a tumoral form which is unifocal or
multifocal and usually involves the deep subcortical hemispheric regions
[3, 9]. Infrequently, infraorbital or periorbital involvement can
also be seen [20]. In regards to our patient, she presented as the
tumoral form of BNS with evidence of multiple enhancing lesions within
the subcortical white matter. Although these different forms of BNS from
MRI findings are described extensively in literature, actual invasion of
malignant lymphoplasmacytic cells may be more extensive than what is
evident on imaging. Autopsy reports are scarce given the rarity of this
disease, but there appears to be prominent perivascular infiltration by
malignant cells without deposition of IgM in BNS that is not readily
apparent on MRI imaging [10].
Despite these sensitive imaging techniques, MRI cannot distinguish
between other forms of CNS lymphoma thus necessitating further testing
with both CSF analysis and tissue biopsy. CSF should be collected and
sent for cytology, flow cytometry, in addition to electrophoresis and
immunofixation in order to determine whether M-protein and specific
immunoglobulin elevations are present within the CNS [1-3]. Yet,
results from immunofixation may be skewed by other form of
lymphoplasmacytic lymphomas. Thus, mutational analysis of CSF plays a
prominent role in the workup of BNS. As is seen in approximately 90-97%
of WM cases, MYD88 L265P gene mutation identified by either next
generation sequencing (NGS) or real-time quantitative PCR (qPCR) aids in
diagnosis of BNS and the absence of such may be associated with poorer
prognosis [3,8,11,12]. As demonstrated by Hiemcke-Jiwa et al, when
clinical suspicion remains high for BNS and there is concern for low
tumor DNA concentration within the CSF, highly sensitive double droplet
PCR (ddPCR) techniques may be used as an alternative for identifying
MYD88 L265P mutations [11]. In addition, testing for immunoglobulin
gene rearrangements can help establish whether or not there are
monoclonal heavy and light chain gene rearrangements in
lymphoplasmacytic cells identified from the CSF, further augmenting the
diagnostic workup of BNS [3]. Of note, the presence of these genetic
mutations in either biopsy or CSF analysis is not necessarily specific
for BNS as it can be found in other forms of primary CNS lymphoma
[3,8,11]. Regardless of CSF results, biopsy of cerebral or meningeal
lesions remains the gold stand for diagnosis of BNS with pathological
evidence of lymphoplasmacytic lymphoma and immunochemical demonstration
of monotypic B cells expressing antigens such as CD19, CD20, CD79a, and
CD79b [3].
Given the paucity of BNS cases, there remains a lack of universal
guidelines pertaining to the management of this disease process.
Although there is no standardized approach for treatment, therapy should
begin with identifying individuals who are symptomatic from their
disease and requires antineoplastic agents that have the ability to
penetrate the blood-brain barrier or agents available for intrathecal
administration [3,13,21]. Treating those who are asymptomatic is
felt to be contraindicated since the aim of treatment is not curative
and tailored more towards reversing symptoms and inducing long term
progression free survival [3,13]. Previously, systemic chemotherapy
with purine nucleoside analogs such as cytarabine, fludarabine, and
bendamustine, known to be effective at treating other
lymphoproliferative disorders such as WM, showed promise as therapy for
the treatment of BNS [14-16]. High-dose methotrexate and rituximab
have been effective for the treatment of BNS as well, but only in
combination with one another, as monotherapy with either of these agents
has proven to be ineffective [13,14]. Rituximab itself is believed
to have poor penetrance of the blood-brain barrier, thus contributing to
its modest effect. In recent years, the oral Bruton tyrosine kinase
(BTK) inhibitor ibrutinib has demonstrated promising results for the
treatment of BNS, with it already having proven to be effective as
therapy for WM [17-19]. The CNS penetrance of ibrutinib has been
well-established in mouse models in addition to individual cases
assessing the concentrations of active metabolite, PCI-45227, between
synchronous measurements of plasma and CSF [18]. In a multicenter
study conducted by Castillo et al. involving 28 patients with BNS
treated with ibrutinib, it was found that 86% of patients had
improvement of their associated symptoms with 83% of cases
demonstrating tumor response on brain MRI [17].
Additional potentially targetable mutations have been identified
throughout the past decade and thus offer further therapeutic
alternatives for the treatment of WM and BNS. WHIM (warts,
hypogammaglobulinemia, infections, and myelokathexis) syndrome caused by
heterozygous mutations within the CXCR4 gene is observed in the
pediatric population and characterized by chronic noncyclic neutropenia
[24]. Although MYD88 L265P mutation is the most common somatic
mutation in WM, this is followed closely by CXCR4 WHIM-like frameshift
and nonsense mutations [22,23]. Plerixafor is an FDA-approved CXCR4
partial agonist and allosteric antagonist of CXCR7 which has been
studied for clinical efficacy and safety in treatment of WHIM syndrome
[26,27]. In vitro studies have demonstrated that ibrutinib
resistance can be potentially reversed by CXCR4 inhibition, yet MYD88
inhibition superseded the survival benefits provided by CXCR4 frameshift
mutations [25]. Therefore, it is theorized that plerixafor may have
potential use in reversing ibrutinib failure in patients with WM and its
efficacy is currently being evaluated within clinical trials. CXCL12 is
another molecule that has been identified as an activator of AKT 1 and
MPK1 pathways which helps confer the ability of malignant WM cells to
resist ibrutinib-triggered apoptosis through mechanisms that increase
frameshift and nonsense mutations [27]. Through continued research
of molecular alterations leading to the development of WM and BNS, as
well as genetic pathways contributing to resistance of targeted therapy,
we can expect to see further improvement in both progression free and
overall survival in this patient population.
As illustrated in our patient’s case, switching from ibrutinib to
rituximab had short-lived efficacy and soon led to worsening serum
viscosity and IgM gammopathy. It is possible that she had already
developed BNS at the time of disease progression which resulted in an
inadequate response to rituximab monotherapy because of its poor
blood-brain barrier permeability. Resuming therapy with ibrutinib
resulted in significant improvements of her lab values and symptoms.
However, despite continued treatment and relatively stable disease the
patient developed BNS, raising concern given ibrutinib’s proven efficacy
for the treatment of BNS. Once systemic therapy was combined with WBRT
there was noted improvement in both the patient’s neurological symptoms
as well as extent of disease evident on repeat imaging. Our case
illustrates the importance of recognizing the early signs and symptoms
of BNS within those who have a history of WM, regardless of their
current and past treatment regimens. Diagnostic evaluation should be
thorough and include biopsy of intracranial lesions when the suspicion
remains high for BNS, as this remains the gold standard of practice.
Early recognition of BNS can ultimately lead to more prompt treatment
and rapid improvement of symptom burden, extended progression free
survival, and overall improved quality of life in this scarce patient
population.