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\begin{document}

\title{Light Chain Amyloidosis due to Waldenstr\selectlanguage{ngerman}öm's Macroglobulinemia Showing
Papular/Nodular Lesions\selectlanguage{english}}



\author[1]{Yumeno  Toma}%
\author[2]{Yoshimasa Nobeyama}%
\author[1]{Hiroyuki Matsuzaki}%
\author[1]{Ken-ichi  Yasuda}%
\author[1]{Akihiko  Asahina}%
\affil[1]{Jikei University School of Medicine}%
\affil[2]{The Jikei University School of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
A 67-year-old Japanese man was referred to us with numerous papules and
nodules. Examination revealed i) IgM-monoclonal proteinemia, ii) amyloid
protein deposition around vessels in the dermis and subcutis, and iii)
lymphoplasma cells into bone marrow. This report shows that
Waldenstr\selectlanguage{ngerman}öm's macroglobulinemia causes papules/nodules through the
development of amyloidosis.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\selectlanguage{ngerman}\textbf{Light Chain Amyloidosis due to Waldenström's Macroglobulinemia
Showing Papular/Nodular Lesions}

\textbf{Short title: Amyloidosis in WM}

Yumeno Toma, MD\textsuperscript{1}, Yoshimasa Nobeyama,
MD\textsuperscript{1}, Hiroyuki Matsuzaki, MD\textsuperscript{1},
Ken-ichi Yasuda, MD\textsuperscript{1}, and Akihiko Asahina,
MD\textsuperscript{1}

Department of Dermatology, The Jikei University School of Medicine,
Tokyo, Japan

Correspondence: Yoshimasa Nobeyama

Department of Dermatology, The Jikei University School of Medicine

25-8 Nishi-Shimbashi 3-chome, Minato-ku, Tokyo 105-8461, Japan

Tel.: +81-3-3433-1111 ext. 3341; Fax: +81-3-5401-0125

E-mail: nobederm@jikei.ac.jp

The authors received no financial support for this study.

The authors have no conflicts of interest to declare.

530 words, 1 figure

Key words: amyloidosis, Waldenström's macroglobulinemia, cutaneous
manifestation, lymphoplasma cell, non-Hodgkin lymphoma.

\textbf{Key Clinical Message}

Waldenström's macroglobulinemia may cause cutaneous manifestations
represented as papules/nodules through the development of light chain
amyloidosis. This report potentially provides novel findings in
Waldenström's macroglobulinemia.

\textbf{Introduction}

Light chain (AL) amyloidosis is a disease characterized by the
deposition of AL amyloid protein in each tissue/organ, typically
followed by lymphoproliferative disorder accompanied with globulinemia.
Although monoclonal gammopathy of undetermined significance and multiple
myeloma are well-known causes of AL amyloidosis, AL amyloidosis due to
Waldenström's macroglobulinemia (WM) has rarely been reported. Here, we
report a case of AL amyloidosis developing during the course of WM.

\textbf{Case Reports}

A 67-year-old Japanese man was referred to our department with numerous
papules and nodules on the trunk and extremities, without any subjective
symptoms (\textbf{Fig. 1a} ). The patient did not experience fever,
hepatosplenomegaly, or systemic lymphadenopathy. The complete blood cell
count indicated mild anemia and no atypical lymphocyte in the peripheral
blood. A biochemical blood test revealed a high \selectlanguage{greek}β\selectlanguage{english}2-microglobulin level
of 4.2 mg/L (normal range: 0.8 to 1.8) and high immunoglobulin M level
of 2,928 mg/dL (33 to 190), represented as a monoclonal peak by
electrophoresis. The examination also disclosed mild abnormalities of
the coagulation/fibrinolysis system including factor X, 40\% (70 to
130); fibrin/fibrinogen degradation products, 9 \selectlanguage{greek}μ\selectlanguage{english}g/mL (0 to 5); and
plasmin-\selectlanguage{greek}α\selectlanguage{english}2 plasmin inhibitor complex, 2.8 \selectlanguage{greek}μ\selectlanguage{english}g/mL (0 to 0.8). Flow
cytometric analysis of bone marrow showed T-cell dominants.
Histopathological examination of the skin revealed an amorphous
substance around vessels in the dermis and subcutis (\textbf{Fig. 1b and
1c} ), which was highlighted in an orange color (\textbf{Fig. 1d} ) and
apple-green-birefringence (\textbf{Fig. 1e} ) by direct fast scarlet
staining and polarization, respectively. Histopathological examination
of the bone marrow revealed mild proliferation of lymphocytes,
plasmacytes, and lymphoplasma cells with Dutcher's bodies without atypia
(\textbf{Fig. 1f and 1g} ), and the presence of CD20-positive cells
(\textbf{Fig. 1h} ). A diagnosis of AL amyloidosis due to WM was made.

\textbf{Discussion}

WM is a non-Hodgkin lymphoma characterized by the invasion of
lymphoplasma cells into bone marrow and IgM-monoclonal proteinemia. The
incidence rate of WM is 3--4 cases per million persons per year,
accounting for only 1\% of lymphomas\textsuperscript{1}. WM causes AL
amyloidosis in only 3\% of WM cases\textsuperscript{2}. Information
about cutaneous manifestations of WM-related AL amyloidosis is limited.

AL amyloidosis affects various organs/tissues including the kidneys,
heart, nerves, and skin\textsuperscript{3}. Cutaneous manifestations are
dependent on the histological area where amyloid protein deposits;
previous literature reported that protein deposition in vessel walls,
folliculosebaceous units, and the epidermis/dermis causes purpura,
alopecia, and papules/nodules, respectively\textsuperscript{4}. Purpura
is reportedly caused by vessel fragility due to the deposition and
abnormality of the coagulation/fibrinolysis system\textsuperscript{5}.
Our case, however, presented with papules/nodules and not purpura. The
cutaneous manifestation was considered to have developed by the
following mechanisms: i) abnormalities of factors controlling
coagulation and fibrinolysis were not severe enough to cause the
collapse of the coagulation/fibrinolysis system; ii) the vascular
endothelial cells were not destroyed by the deposition, compatible with
the histopathological findings that vascular endothelial cells were not
affected by the deposition; and iii) marked deposition around vessels in
the dermis and subcutis caused papules/nodules.

This case report provides evidence that WM may cause cutaneous
manifestations represented as papules/nodules through the development of
AL amyloidosis.

\textbf{Acknowledgement:} None

\textbf{Statement of Ethics:} This study protocol was approved by The
Ethics Committee of The Jikei University School of Medicine and the
patient provided written informed consent.

\textbf{Author Contributions}

Yumeno Toma: The author contributed to data curation and resources.

Yoshimasa Nobeyama: The author contributed to conceptualization and
project administration.

Hiroyuki Matsuzaki: The author contributed to resources and supervision.

Ken-ichi Yasuda: The author contributed to resources and supervision.

Akihiko Asahina: The author contributed to review and supervision.

\textbf{References}

1 Wang W, Lin P. Lymphoplasmacytic lymphoma and Waldenstrom
macroglobulinaemia: clinicopathological features and differential
diagnosis. \emph{Pathology} 2020. \textbf{52} : 6-14.

2 Dispenzieri A, Katzmann JA, Kyle RA \emph{et al.} Prevalence and risk
of progression of light-chain monoclonal gammopathy of undetermined
significance: a retrospective population-based cohort
study.\emph{Lancet} 2010. \textbf{375} : 1721-1728.

3 Bustamante JG, Zaidi SRH. Amyloidosis. In: \emph{StatPearls} .
Treasure Island (FL). 2020.

4 Saoji V, Chaudhari S, Gohokar D. Primary systemic amyloidosis: three
different presentations. \emph{Indian J Dermatol Venereol Leprol}
2009.\textbf{75} : 394-397.

5 Colucci G, Alberio L, Demarmels Biasiutti F, Lammle B. Bilateral
periorbital ecchymoses. An often missed sign of amyloid
purpura.\emph{Hamostaseologie} 2014. \textbf{34} : 249-252.

\textbf{Figure Legends}

\textbf{Fig. 1}

\textbf{a)} Clinical findings. Numerous papules and nodules on the trunk
and extremities are evident. \textbf{b)} Histopathological findings of
the skin (hematoxylin-eosin stain, \selectlanguage{ngerman}× 20). Amorphous eosinophilic nodular
lesions can be noted in the dermis and subcutis. \textbf{c} )
Histopathological findings of the skin (hematoxylin-eosin stain, ×100).
Amorphous eosinophilic nodular lesions are present around
vessels.\textbf{d} ) Histopathological findings of the skin (direct fast
scarlet stain, ×100). An amorphous substance around vessels is stained
with orange dye. \textbf{e} ) Histopathological findings of the skin
(×100). Apple-green-birefringence with polarization is evident in the
amorphous substance around vessels. \textbf{f)} Histopathological
examination of the bone marrow (hematoxylin-eosin stain, ×400).
Proliferation of lymphocytes and plasmacytes without atypia is evident.
\textbf{g)}Histopathological examination of the bone marrow
(hematoxylin-eosin stain, ×1000). Lymphoplasma cells with Dutcher's
bodies without atypia are evident. Dutcher's bodies are indicated by
arrowheads. \textbf{h} ) Histopathological examination of the bone
marrow (×400). Some lymphocytes react with anti-CD20 antibody (Nichirei
Biosciences, Tokyo, Japan).\selectlanguage{english}
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