\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Crystal Storing Histiocytosis and Bing-Neel-like syndrome revealing a
marginal zone lymphoma with plasmacytic differentiation.}



\author[1]{Hippolyte Lequain}%
\author[1]{Mathieu Gerfaud-Valentin}%
\author[1]{Juliette Fontaine}%
\author[2]{Emmanuelle FERRANT}%
\author[1]{Pierre GRUMET}%
\author[1]{Yvan Jamilloux}%
\author[1]{Alexandra Traverse-glehen}%
\author[1]{Pascal Seve}%
\affil[1]{Hospices Civils de Lyon}%
\affil[2]{Centre Hospitalier Lyon-Sud}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Crystal Storing Histiocytosis and Bing Neel Syndrome are two diseases
induced by paraprotein. Herein, we report a rare case of Crystal Storing
Histiocytosis associated with Bing-Neel-like neurological manifestations
in the context of marginal zone lymphoma with plasmacytic
differentiation.%
\end{abstract}%



\sloppy


\textbf{Crystal Storing Histiocytosis and Bing-Neel-like syndrome
revealing a marginal zone lymphoma with plasmacytic differentiation.}

\selectlanguage{ngerman}\textbf{Hippolyte Lequain MD\textsuperscript{1}; Mathieu
Gerfaud-Valentin MD\textsuperscript{1}; Juliette Fontaine
MD\textsuperscript{2~}; Emmanuelle FERRANT, MD~; Pierre GRUMET
MD\textsuperscript{1},MD ; Yvan Jamilloux MD, PhD\textsuperscript{1};
Alexandra Traverse-Glehen MD\textsuperscript{2}, PhD~; Pascal Sève MD,
PhD\textsuperscript{1, 3}}

\textsuperscript{1} Department of Internal Medicine, Hôpital de la
Croix-Rousse, Hospices Civils de Lyon,

Université Claude Bernard-Lyon1, Lyon, France

\textsuperscript{2} Department of Pathology, Centre Hospitalier Lyon
Sud, Hospices Civils de Lyon, Lyon, France

\textsuperscript{3} Pôle IMER, Lyon, France ; HESPER EA 7425, Lyon,
France

\textbf{Corresponding author:} Prof. Pascal Sève, Department of Internal
Medicine, Hôpital de la Croix-Rousse, 103 grande rue de la Croix-Rousse,
F-69004, Lyon, France

\emph{Abstract:}

Crystal Storing Histiocytosis and Bing Neel Syndrome are two diseases
induced by paraprotein. Herein, we report a rare case of Crystal Storing
Histiocytosis associated with Bing-Neel-like neurological manifestations
in the context of marginal zone lymphoma with plasmacytic
differentiation.

\emph{Keywords:} \textbf{Crystal Storing Histiocytosis, Marginal zone
lymphoma, Bing Neel syndrome.}

\emph{Key message:}

This case shows the need to search for a B lymphoproliferative disorder
after a Crystal Storing Histiocytosis diagnosis and to hypothesize that
a B-lymphoproliferative disorder other than Waldenström
Macroglobulinemia can induce Bing-Neel Syndrome

\emph{Introduction:}

Crystal storing histiocytosis (CSH) is a rare entity characterized by
the intra-lysosomal accumulation of crystals composed of immunoglobulin
light and/or heavy chain fragments enriched in Ig variable regions
within histiocytes {[}1{]}. In 90\% of CSH, an underlying B
lymphoproliferative or plasma cell disorder is present {[}2{]}. The
pathophysiology of CSH seemed to be associated with the type of light
chain rather than the heavy chain {[}3{]}. Some mutations in variable
sequences may induce crystallization of immunoglobulins and resistance
from lysosome clearance leading to the formation of crystal storing
inclusions and secondary granulomatous lesions. Bing-Neel syndrome is a
rare and probably underdiagnosed neurologic complication of Waldenström
macroglobulinemia (WM) with infiltration of central nervous system (CNS)
by malignant lymphoplasmacytic cells {[}4-5-6{]}.

Herein, we report the case of a 69-year-old Caucasian male presenting
atypical manifestations of a marginal zone lymphoma with plasmacytic
differentiation and IgM paraprotein complicated by CSH and neurological
impairment similar to BNS which is known as a complication of Waldenstöm
macroglobulinemia.

\emph{Case report:}

A 69-year-old Caucasian male presented with an impaired general
condition with abdominal pain. He gradually exhibited a degradation of
his neurological state with confusion, headache, hearing loss, and
aphasia. His physical examination showed a static cerebellar syndrome
associated with major ataxia and pyramidal syndrome.

An abdominal-chest computed tomography revealed enlarged spleen and
liver, and an upper and under diaphragmatic polyadenopathy. Laboratory
findings were the following: haemoglobin 10g/dL, a monoclonal gammopathy
(IgM lambda 8g/L) with cryoglobulinemia type I activity and a serum free
light chain ratio kappa/lambda at 0.08. The urine test found a Bence
Jones proteinuria at 4.5 g/24h composed of 78\% light chain lambda.

The cerebral MRI found hypersignal FLAIR in the supra-tentorial white
matter with hypersignal on diffusion sequence without restriction in ADC
induced by vasogenic edema. Moreover, there was a leptomeningeal
contrast enhancement in Gadolinium sequences (Figure 1).

The lumbar puncture found a mild hyperproteinorachia (0.53 g/L; norm
\textless{} 0,4 g/L) and 4 cells/mm\textsuperscript{3} composed of
lymphocytes and plasma cells, with a pathological elevation of IgM at 14
mg/L and an IgM index at 0,42. Flow cytometry analysis failed to detect
a monotypic B cell population in the cerebro-spinal fluid, but
cellularity was very low.

Several histological specimens were studied:

1/ A colonoscopy was performed because of abdominal pain and showed a
mild colitis with multiple small whitish lesions. The colonic biopsies
showed submucosal clusters of histiocytes with abundant crystalline
eosinophilic cytoplasm inclusions (Figure 2).

2/ The bone marrow biopsy was hypercellular, with a normal
representation of the three hematopoietic lineages. There was a discrete
lymphoid infiltrate, made of small B and T lymphocytes. The plasma cells
represented 5 to 10\% of the bone marrow cellularity and showed an
inversion of their kappa/lambda ratio (Figure 3). A monoclonal B-cell
population was found by polymerase chain reaction (PCR). Any mutation
was detected by Next Generation Sequencing (NGS), in particular no MYD88
L265P mutation. Some clusters of histiocytes with abundant crystalline
eosinophilic cytoplasmic inclusions were also identified.

3/ A cervical lymph node biopsy showed a massive infiltration by the
same histiocytes as observed in colon biopsy and bone marrow (Figure 4).
It was associated with small lymphoid B-cell nodules, lacking a specific
phenotype by immunohistochemistry, and numerous monotypic lambda plasma
cells. The PCR identified the same monoclonal B-cell population than in
the bone marrow. No mutation was found by NGS, in particular no MYD88
L265P mutation. Cytogenetic analyses of the lymph node showed a complex
caryotype with 2q, 3p, 10q, 17p deletions and 9p addition, any of these
anomalies being specific of a B lymphoproliferative syndrome.

Finally, these clinical, biological, histological and imaging
presentation were consistent with the diagnosis of a CNS involvement
similar to BNS which usually occurs in the setting of WM, associated
with CSH. However, in our case, underlying lymphoma was more accurately
diagnosed as a marginal zone lymphoma (MZL) with plasmacytic
differentiation.

The patient was first treated as a BNS by 3 cures of
Rituximab-Bendamustine and intrathecal Methotrexate --
Methylprednisolone - Aracytine. This treatment allowed an improvement of
his clinical and cognitive state, with disappearance of cerebellar
ataxia and pyramidal signs. An MRI realized after treatment find a
stabilization of white matter lesions and a disappearance of the
leptomeningeal contrast enhancement (Figure 1).

\emph{Discussion:}

To the best of our knowledge, this is the first reported case of a CNS
involvement similar to BNS associated with a generalized CSH in the
setting of a MZL.

Here we present a generalized form of CSH which represents 42\% of
clinical presentation of this disease, whereas the localized pattern is
more frequent and often localized in the head and neck region {[}2{]}.
CSH do not usually impair CNS: Dogan S. et al. report only 3\% of dura
and pia mater involvement in patients with generalized CSH, and Flanagan
ME et al. report one case of CSH involving cerebellum and caudal brain
stem {[}2, 7{]}.

In our case, neurological manifestations and MRI findings were highly
suggestive of BNS with signs of parenchymal and leptomeningeal
involvement. The lumbar puncture cellularity was consistent with a type
B BNS according to the Fintelmann's proposed classification {[}8{]}.
Type B BNS represents 25\% of total BNS and is defined by a very low
cells rate (\textless{}5 cells/mm\textsuperscript{3}) in the
cerebrospinal fluid. This suggested neurological manifestations being
associated with IgM deposition with an intrathecal secretion, as the
pathological CSF IgM index indicates, rather than lymphoplasmacytic
infiltration {[}8{]}.

There is no clear causal link between CSH and BNS. We consider that they
are just two manifestations of an abnormal circulation of
immunoglobulins in quantity and quality.

In our case, definitive classification of the underlying small B-cell
lymphoma, which shows a striking plasmacytic differentiation, remains
difficult. Lymphoplasmacytic lymphoma (LPL) usually involves bone marrow
and sometimes lymph nodes and spleen. WM is defined as a LPL with bone
marrow involvement and an IgM monoclonal gammopathy. MYD88 L265P
mutation has been described in almost all, if not all (this is a point
of debate) LPL/WM, associated with a CXCR4 mutation in approximately
30\% of cases. Conversely, this MYD88 L265P mutation is rarely
(\textasciitilde{}5\% of cases) present in MZL. So, in our case,
polyadenopathy with minimal bone marrow involvement and absence of MYD88
L265P mutation would favor MZL with plasmacytic differentiation rather
than LPL/WM. However, because this neurological presentation similar to
BNS, which is, to our knowledge, exclusively described as a complication
of WM in literature, our patient was considered as having WM complicated
by a BNS for therapeutic decision. Nevertheless, one can legitimately
wonder why BNS could not also complicate a MZL with plasmacytic
differentiation and IgM paraprotein, knowing that neurological
manifestations in BNS type B are probably related to IgM rather than to
lymphoma cells infiltration.

The patient was treated as a BNS with R-Bendamustine associated and
intrathecal treatment allowing a clinical and radiological improvement.
Ibrutinib appears to be a good alternative as an oral treatment for this
disease {[}9{]}. CSH treatment depends of the causal pathology. There is
little information concerning specific response of CSH after
chimiotherapy but the histologic lesions persist in available
observations {[}10{]}.

\emph{Conclusion:}

This unique case associate two complications of a marginal zone lymphoma
with plasmacytic differentiation and IgM paraprotein. This observation
underlines the need to search for a B lymphoproliferative disorder after
an histological CSH diagnosis and to hypothesize that a
B-lymphoproliferative disorder with plasmacytic differentiation and
paraprotein secretion other than WM can induce neurological
presentations similar to BNS.

\textbf{Fig1} Cerebral MRI. Leptomeningeal contrast enhancement in T1
Gadolinium sequence before treatment (arrow) (1A). Disappearance of the
leptomeningeal contrast enhancement in T1 Gadolinium sequence after
treatment (1B). Hypersignal lesions in the supra-tentorial white matter
in T2 FLAIR sequence before treatment (arrow) (1C). Stabilization of
hypersignal lesions in the supra-tentorial white matter in T2 FLAIR
sequence after treatment (arrow) (1D).

\textbf{Fig2} Colon biopsy. Submucosal clusters of histiocytes with
crystalline eosinophilic cytoplasm inclusions (2A: HPS x 2.5, 2B: HPS x
40)

\textbf{Fig3} Bone marrow biopsy. Hypercellular bone marrow with a
discret lymphoid infiltrat (arrow) (3A: HPS x 2.5). Histiocytes with
abundant crystalline eosinophilic cytoplasmic inclusions were
identified, scattered or in clusters (3B: HPS x 40). The lymphoid
infiltrate is made of a mixture of a B and T lymphocytes (3C: CD20 x 5,
3D: CD3 x 5). The plasma cells represented 5 to 10\% of the bone marrow
cellularity (3E: CD138 x 5).

\textbf{Fig4} Lymph node biopsy. Massive infiltration by the same
crystalline histiocytes as observed in colon biopsy and bone marrow,
associated with small lymphoid nodules at the periphery of the lymph
node (4A: HPS x 2.5). The crystalline histiocytes are admixed with
numerous plasma cells (4B: HPS x 40).

\textbf{Conflict of Interest:}

The authors declare that they have no conflict of interest.

\textbf{Author contributions:}

HL, PS, MGV, PG and EF: Clinical diagnosis, treatment of the patient and
described clinical part of the manuscript.

JF and ATG: Anatomopathological diagnosis and described
anatomopathological part of the manuscript.

YJ: Revised the manuscript.

\textbf{References:}

1. Kanagal-Shamanna R, Xu-Monette ZY, Miranda RN, Dogan A, Zou D, Luthra
R, et al. Crystal-storing histiocytosis: a clinicopathological study of
13 case. Histopathology. 2016 Mar;68(4):482-91

2. Dogan S, Barnes L, Cruz-Vetrano WP. Crystal-storing histiocytosis:
report of a case, review of the literature (80 cases) and a proposed
classification. Head Neck Pathol. 2012 Mar;6(1):111-20.

3. Lebeau A, Zeindl-Eberhart E, Muller EC, et al. Generalized
crystal-storing histiocytosis associated with monoclonal gammopathy:
molecular analysis of a disorder with rapid clinical course and review
of the literature. Blood 2002; 100:1817--1827

4. Minnema MC, Kimby E, D'Sa S, Fornecker LM, Poulain S, Snijders TJ, et
al. Guideline for the diagnosis, treatment and response criteria for
Bing-Neel syndrome. Haematologica. 2017 Jan;102(1):43-51

5. Simon L, Fitsiori A, Lemal R, Dupuis J, Carpentier B, Boudin L et al.
Bing-Neel syndrome, a rare complication of Waldenström
macroglobulinemia: analysis of 44 cases and review of the literature. A
study on behalf of the French Innovative Leukemia Organization (FILO).
Haematologica. 2015 Dec;100(12):1587-94.

6. Fitsiori A, Fornecker LM, Simon L, Karentzos A, Galanaud D, Outteryck
O, and al. Imaging spectrum of Bing-Neel syndrome: how can a radiologist
recognise this rare neurological complication of Waldenström's
macroglobulinemia? Eur Radiol. 2019 Jan;29(1):102-114

7. Flanagan ME, Keene CD, Louis DN, Juric-Sekhar G.
Localized~crystal-storing~histiocytosis~of the~posterior~fossa.
Neuropathology. 2018 Oct;38(5):529-534.

8. Fintelmann~F, Forghani R, Schaefer PW, Hochberg EP, Hochberg FH.
Bing-Neel Syndrome revisited. Clin Lymphoma Myeloma. 2009
Mar;9(1):104-6.

9. Castillo JJ, Itchaki G, Paludo J, Varettoni M, Buske C, Eyre TA et
al. Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter
study. Blood. 2019 Jan 24;133(4):299-305.

10. Jones D, Bhatia VK, Krausz T, Pinkus GS. Crystal-storing
histiocytosis : a disorder occurring in plasmacytic tumors expressing
immunoglobulin kappa light chain. Hum Pathol. 1999;30:1441--8.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-MRI/Figure-1-MRI}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-(Bone-Marrow)/Figure-3-(Bone-Marrow)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-(Cervical-node)/Figure-4-(Cervical-node)}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

