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\begin{document}

\title{A unique case of laparoscopically resected gastric adenocarcinoma
concurrent with lanthanum deposition}



\author[1]{Kosuke Hirose}%
\author[2]{Shunichi Saito}%
\author[3]{Yumi Oshiro}%
\author[3]{Kazuhito Minami}%
\author[3]{Koji Ikegami}%
\author[3]{Koichi Kurahara}%
\author[1]{Takuya Honbo}%
\author[1]{Noriaki Sadanaga}%
\author[1]{Hiroshi Matsuura}%
\affil[1]{Saiseikai Fukuoka General Hospital}%
\affil[2]{Kyushu University}%
\affil[3]{Matsuyama Red Cross Hospital}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
We present a unique case of laparoscopically resected gastric
adenocarcinoma with concurrent lanthanum deposition. Lanthanum
depositions occasionally appear similar to carcinomas on endoscopy. and
surgical resection should be considered for such concurrent carcinoma.
Furthermore, more research is needed to clarify the relationship between
carcinogenesis and lanthanum deposition.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Lanthanum carbonate is one of the widely used phosphate binders, which
are orally taken to reduce serum phosphate levels in dialysis patients
with chronic kidney disease.\textsuperscript{1}Lanthanum carbonate binds
to dietary phosphate and forms insoluble complexes and is excreted in
feces, but recently lanthanum carbonate deposition in the gastric and
duodenal mucosa has been reported in patients taking
them.\textsuperscript{2-8}\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}In previous studies, the findings of
lanthanum deposition with endoscopy in gastric mucosa, white lesions,
elevations, erosions, and ulcerations have been usually described in the
gastric mucosa. Pathologically, lanthanum depositions usually appear as
subepithelial collections of histocytes or small foreign body
granulomas, accompanied by intestinal metaplasia, regenerative changes,
and foveolar hyperplasia.\textsuperscript{1,9-11}Although some studies
have reported that lanthanum deposition and subsequent mucosal changes
potentially induce neoplastic lesions, the relationship between
lanthanum deposition and carcinogenesis is
unknown.\textsuperscript{11,12}

There are few reports of gastric cancer concurrent with lanthanum
deposition\textsuperscript{2,12-14} and surgical resection of gastric
cancer concurrent with lanthanum
deposition.\textsuperscript{2,12}Furthermore, unlike past resected
cases, in this case, it was difficult to clearly distinguish gastric
adenocarcinoma from mucosal changes because of its confusing appearance
following lanthanum deposition.

\textbf{Case presentation}

A 73-years-old man had been on peritoneal dialysis for 9 years for
chronic renal failure due to immunoglobulin A nephropathy and had
switched to hemodialysis 3 years before the operations.

He had been taking lanthanum carbonate for seven years. Several months
after lanthanum carbonate initiation, regular endoscopy revealed white
granular lesions on the gastric mucosa at the gastric body and fundus
(Fig.1-A). A biopsy of these lesions revealed chronic active
inflammation with regenerative epithelium, intestinal metaplasia, and
lanthanum deposition. Regular annual endoscopy revealed that these
lesions had grown, changed morphologically, and spread gradually
(Fig.1-B), but they showed no malignancy. Two months before the
operation, regular endoscopy revealed a gradually growing, reddish, and
elevated mucosa surrounded by white granular mucosa in the gastric
antrum (Fig.2-A). Narrow band imaging (NBI) showed no signs of
malignancy, such as an irregular microvascular pattern (Fig.2-B), but
histological examination revealed well-differentiated adenocarcinoma.
The clinical stage was T1bN0M0 stage I based on the TNM classification
specified by the International Union Against Cancer (UICC). The boundary
between the adenocarcinoma and mucosal changes with lanthanum deposition
was unclear by endoscopy with NBI, and neoplastic lesions seemed to be
spread around the gastric body. Therefore, we planned to perform a
surgical operation to achieve curative resection and laparoscopic distal
gastrectomy with lymph node dissection. Histopathological examination
revealed a well-differentiated tubular adenocarcinoma, which was limited
to the antrum surrounded by lanthanum nodules (Fig.3-A). The tumor was
limited to the mucosa at the gastric antrum, and the pathological stage
was T1aN0M0 stage I. Lanthanum deposition was observed in the lamina
propria of the carcinoma and gastric mucosa (Fig.3-B). Histological
alterations, such as glandular atrophy and hyperplasia, were also
observed. The resected lymph nodes also included lanthanum deposits
eaten by macrophages (Fig.3-C). In the interstitium of cancerous and
non-cancerous lesions, lanthanum was mostly eaten by macrophages that
expressed CD68 (Fig.4-A, B).

\textbf{Discussion}

We report a rare case of laparoscopically resected gastric
adenocarcinoma with concurrent lanthanum deposition. In this case, we
chose surgical resection because of the ambiguous boundary between
malignant tissue and mucosal changes with lanthanum deposition.

There are a few reports of surgically resected gastric cancer with
lanthanum deposition, as summarized in Table
1.\textsuperscript{2,12}Yabuki et al. reported a summary of three
patients with gastric cancer accompanied by lanthanum deposition who
underwent surgical resection.\textsuperscript{11} They reported that the
duration of lanthanum administration ranged from 3 to 36 months, and the
depth of cancer was the entire submucosa (range: 1.5--5 mm). Lanthanum
deposition was identified in the regional lymph nodes to some degree in
all three cases. These findings support the hypothesis that lanthanum
malabsorption in the gastric mucosa leads to other lymph nodes via
lymphatic flow. Tonooka et al. reported a case of multiple but early
gastric cancers in a patient with lanthanum deposition who underwent
subtotal gastrectomy after 7 months of drug use.\textsuperscript{12} In
this case, many macrophages with lanthanum deposits accumulated in the
lamina propria of the gastric wall and tumors, which was confirmed by
scanning electron microscopy-energy-dispersive X-ray spectroscopy
(SEM-ESD). They also showed intestinal metaplasia associated with
lanthanum deposition and considered that altered tight junction proteins
may lead to its permeability, possibly resulting in lanthanum
deposition. Our case showed mucosal atrophy and metaplasia, including a
cancerous lesion at the gastric antrum, with CD68-positive macrophages
containing lanthanum deposits, which were also identified in regional
lymph nodes.

In gastric adenocarcinoma concurrent with lanthanum deposition, the
findings of lanthanum deposition by endoscopy are occasionally similar
to carcinoma, and it can be difficult to mark the boundary of the
neoplasm and lesions. The findings of lanthanum deposition have been
usually described as shiny, bright white, and of varied sizes and
shapes, from small and flat to elevated
plaques.\textsuperscript{9}Gastric carcinoma is also known to show
various findings with endoscopy. In previous reports, early gastric
cancer with lanthanum deposition was observed as a depressed area
surrounded by annular whitish lanthanum-deposited
mucosa\textsuperscript{8,13} and resected by endoscopy. Yabuki et al.
summarized the cases of three patients with concurrent gastric cancer
who received laparoscopic distal gastrectomy, but the endoscopic
findings showed a clear boundary between malignant tissue and the
surrounding mucosa with lanthanum deposition.\textsuperscript{11}
Tonooka et al. also reported concurrent gastric cancer with lanthanum
deposition in patients receiving subtotal gastrectomy, but they did not
refer to the endoscopic findings.\textsuperscript{12} The usefulness of
magnified imaging using NBI was recently reported, and it shows
irregular vascular and pit structures of malignant
tissues.\textsuperscript{13} However, in this case, the carcinoma was
detected within multiple reddish granular areas with lanthanum
deposition without any specific malignant findings with NBI, and it was
difficult to find the boundary between the neoplasm and lanthanum
deposition. Therefore, we considered the possibility of non-curative
resection with endoscopy and other lurking regions, and the carcinoma
was surgically resected. Furthermore, using laparoscopy made it possible
to observe the whole serous membrane of the stomach, nearby lymph nodes,
and other organs in detail.

The relationship between malignancy and lanthanum deposition in gastric
cancer concurrent with lanthanum deposition is unknown. Yabuki et al.
examined the effect of oral administration of lanthanum carbonate on
gastric mucosa in a rat model.\textsuperscript{11} They showed that it
caused various histologic alterations such as glandular atrophy, the
proliferation of mucous neck cells, and intestinal metaplasia, and
concluded that these mucosal injuries, named lanthanum gastropathy,
could potentially induce abnormal cell proliferation or neoplastic
lesions. In sequential changes of the gastric epithelium due to
lanthanum gastropathy, it becomes difficult to identify the boundary
between the neoplasm and mucosal changes without malignancy, and
surgical resection is recommended in such cases.

We present a rare case of gastric adenocarcinoma concurrent with
lanthanum deposition in a patient who underwent laparoscopic distal
gastrectomy due to ambiguous borders. In our case, it is difficult to
mark the border between the neoplasm and lesions due to lanthanum
deposition, and we performed surgical resection to secure a curative
margin. The clinical significance and relationship between neoplasm and
lanthanum deposition have been suggested, but enough evidence has not
been reported. Our results add to this growing body of data and will aid
in clarifying this relationship.

Table.1\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}Summary of surgically resected gastric cancer with lanthanum
deposition, including this case\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
case\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
age/sex\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
location\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
histology\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
differentiation\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
pT\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
pN\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
dose of LC (mg/day)\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
duration of LC administration (months)\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
H.pylori infection\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
PPI\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
Laparoscopic surgery\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
reseced range\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
prognosis\strut
\end{minipage} & \begin{minipage}[b]{0.04\columnwidth}\raggedright\strut
author\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
81/F\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
multiple\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Adeno.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
well\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
T1a\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
750\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
subtotal\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
3y alive no reccurence\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Tonooka et al\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
77/F\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
antrum\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Adeno.\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
well\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
T1b\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
1500\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
negative\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
use\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
yes\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
distal\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
unknown\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Yabuki et al\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
68/F\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
body\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Adeno.\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
por/sig\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
T1b\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
750\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
use\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
yes\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
distal\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
unknown\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Yabuki et al\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
77/M\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
antrum\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Adeno.\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
well\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
T1b\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
750\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
not use\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
yes\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
distal\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
unknown\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Yabuki et al\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
73/M\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
antrum\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Adeno.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
well\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
T1a\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
750\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
84\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
negative\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
use\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
yes\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
distal\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
8m alive no reccurence\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
our case\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

LC, lanthanum carbonate; PPI, proton pump inhibitor; Adeno,
adenocarcinoma; NA, not available



\textbf{Authors' contributions}

KH operated on and followed the patients, selected the associated data
and edited the manuscript accordingly. SS also operated on and took care
of the patients. YO analyzed the specimens and supervised the pathology.
KM performed the surgery on the patient as a superviser. KI and KK
participated in the treatment of the patient as gastroenterologists. TH,
NS, TN and HM supervised and revised the article. All the authors have
read and approved the final manuscript.

\textbf{Acknowledgments}

We would like to thank Editage (https://www.editage.jp/) for the English
language editing of this manuscript.



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\textbf{Figure legends}

\textbf{Figure 1.}

(A) The endoscopic image of lanthanum deposition on stomach few months
after drug initiation.

(B) Follow-up endoscopic image of lanthanum deposition at the same
lesions

\textbf{Figure 2.}

(A) The endoscopic images of grown lanthanum deposition and gastric
cancer at antrum (arrowhead).

(B) Narrow band imaging of cancer showing no irregular microvascular
pattern.

\textbf{Figure 3.}

(A) Resected specimen and mapping of the malignant region (yellow line)

(B) Histological image of gastric adenocarcinoma with hematoxylin and
eosin staining. Arrowheads indicate lanthanum carbonate eaten by
histiocytes.

(C) Histological image of a resected lymph node. It also includes
histiocytes eating lanthanum carbonate (arrowhead).

\textbf{Figure 4.}

The histological images indicate the distribution of CD68-positive
macrophages eating lanthanum carbonate with hematoxylin and eosin
staining (A). Immunohistochemical staining with CD68 monoclonal antibody
at almost the same specimen (B)

\textbf{Hosted file}

\verb`figure_0517.pptx`  available at \url{https://authorea.com/users/484335/articles/570193-a-unique-case-of-laparoscopically-resected-gastric-adenocarcinoma-concurrent-with-lanthanum-deposition}

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