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\begin{document}

\title{Juxtaglomerular cell tumor with pulmonary metastases: A case report and
review of the literature}



\author[1]{Hideki Sakiyama}%
\author[1]{Satoru Hamada}%
\author[1]{Tokiko Oshiro}%
\author[1]{Nobuyuki Hyakuna}%
\author[2]{Masaaki Kuda}%
\author[3]{Tomoro Hishiki}%
\author[4]{hajime Aoyama}%
\author[5]{N Kuroda}%
\author[6]{Kenji Yorita}%
\author[2]{Naoki Wada}%
\author[7]{Takako Yoshioka}%
\author[8]{Yuhki  Koga}%
\author[1]{Koichi Nakanishi}%
\affil[1]{Ryukyu Daigaku Igakubu Fuzoku Byoin}%
\affil[2]{Ryukyu Daigaku Igakubu Daigakuin Igaku Kenkyuka}%
\affil[3]{Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu}%
\affil[4]{Heart Life Byoin}%
\affil[5]{Department of Internal Medicine Kinro Hospital Kochi Japan}%
\affil[6]{Kochi Sekijuji Byoin}%
\affil[7]{Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo}%
\affil[8]{Kyushu Daigaku Igakubu Daigakuin Igakukei Gakufu Daigakuin Igaku Kenkyuin}%


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  \date{May 24, 2024}


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Juxtaglomerular cell tumor with pulmonary metastases: A case report and
review of the literature

Hideki Sakiyama\textsuperscript{1}, Satoru Hamada\textsuperscript{1,2},
Tokiko Oshiro\textsuperscript{1,2}, Nobuyuki
Hyakuna\textsuperscript{1,2} Masaaki Kuda\textsuperscript{3}, Tomoro
Hishiki\textsuperscript{4}, Hajime Aoyama\textsuperscript{5}, Naoto
Kuroda\textsuperscript{6}, Kenji Yorita\textsuperscript{7}, Naoki
Wada\textsuperscript{8}, Takako Yoshioka\textsuperscript{9}, Yuhki
Koga\textsuperscript{10}, Koichi Nakanishi\textsuperscript{1,2}

1) Department of Pediatrics, University of the Ryukyus Hospital, Uehara,
Nishihara, Okinawa, Japan

2) Department of Child Health and Welfare, Graduate School of Medicine,
University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan

3) Department of Digestive and General Surgery Graduate School of
Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan

4) Department of Pediatric Surgery, Chiba University Graduate School of
Medicine, Chiba, Japan

5) Department of Pathology, Heartlife Hospital, Okinawa, Japan

6) Department of Internal Medicine, Kinro Hospital, Kochi, Japan

7) Department of Diagnostic Pathology, Japanese Red Cross Kochi
Hospital, Kochi, Japan

8) Department of Pathology and Oncology, Graduate School of Medicine,
University of Ryukyus, Uehara, Nishihara, Okinawa, Japan

9) Department of Pathology, National Center for Child Health and
Development, Tokyo, Japan

10) Department of Pediatrics, Graduate School of Medical Science, Kyusyu
University, Fukuoka, Japan

Correspondence: Satoru Hamada,

Department of Pediatrics, Faculty of Medicine, University of Ryukyus,
207 Uehara, Nishihara-cho, Okinawa 903-0125, Japan

\emph{shamada@med.u-ryukyu.ac.jp}

To the Editor: Juxtaglomerular cell tumor (JGT) is a relatively rare,
benign renin-producing tumor that causes hypertension,
hyperaldosteronism, and hypokalemia due to excessive renin secretion.
Here, we report a case of malignant JGT with pulmonary metastases. A
7-year-old male patient was referred to the hospital for proteinuria
found during a school medical checkup. An ultrasound examination
revealed a tumor on the right kidney. His blood pressure was 170/120
mmHg, and plasma renin activity was high at 30 ng/mL/hr. Computed
tomography (CT) revealed a mass of 3.4 cm diameter on the right kidney
with multiple pulmonary metastases, which was suggestive of
nephroblastoma. He underwent right nephrectomy, resulting in a return of
blood pressure and plasma renin activity to normal levels (reference
range, 0.2--2.3 ng/mL/hr). Gross examination of the tumor revealed a 3.2
\selectlanguage{ngerman}× 3.2 × 10-cm yellowish-white mass with necrosis in the mid pole of the
kidney. Most of the tumor was covered with a fibrous membrane that
partially extended into the normal tissue. Histology revealed a
mesenchymal neoplasm with a blastemal component that was suggestive of
nephroblastoma. No vascular invasion was observed within the analyzed
area (Supplemental Figures S1, S2). Subsequently, he received
chemotherapy according to the DD-4A regimen of the National Wilms Tumor
Study Group. The immunophenotype demonstrated renin and CD34 positivity
(Supplemental Figures S3, S4). This led to a definitive diagnosis of
JGT, which was consistent with the clinical feature of hypertension.
Chemotherapy was stopped at week 6, at which point CT revealed unchanged
metastatic lung lesions. He then underwent a two-stage surgical
resection for bilateral lung metastases, and total resection was
achieved. Pathologically, the metastatic lung lesions were consistent
with the resected renal tumor. Because no reports of effective
chemotherapy for malignant JGT were found, we followed-up this patient
without administering adjuvant chemotherapy. He showed no evidence of
disease after a 2-year follow-up. Targeted DNA sequencing using
FoundationOne\textsuperscript{®} CDx detected six genetic
mutations:\emph{NOTCH3} T272M, \emph{BRAF} D22N, \emph{MAP3K1} L78P,
\emph{CDKN2B}A56D, \emph{DAXX} E451del, and \emph{ERBB4} P3L in the
primary tumor.

JGT is a rare benign tumor that is more common in relatively young
adults. JGT causes various clinical symptoms, such as headache, nausea,
dizziness, weakness, hypertension, and
proteinuria.\textsuperscript{1,2}JGT is generally curable by surgical
resection, and tumor removal results in the improvement of
hyperreninemia and clinical symptoms.\textsuperscript{1}
Immunohistochemically, the diagnosis is confirmed by renin positivity in
the cytoplasm. In addition, CD34, CD117, vimentin, and ACTA2 are often
positive.\textsuperscript{2,3}Although JGT is generally considered
benign, eight malignant or pathologically atypical cases have been
reported in the literature (Table).\textsuperscript{3--10} Six were
adult cases, and one was a pediatric case. In all cases, the tumor
diameter was relatively large (\textgreater{}5 cm). Pathologically,
seven of eight showed either vascular invasion or mitotic figures, and
among these cases, four had distant metastasis: case 1 demonstrated
bilateral lung metastases 6 years after nephrectomy,\textsuperscript{4}
case 4 demonstrated bilateral lung metastases at initial
diagnosis,\textsuperscript{9} case 6 demonstrated multicentric
synchronous disease in the liver and spleen,\textsuperscript{7} case 8
succumbed to hepatic and bone metastases 10 months after
nephrectomy.\textsuperscript{3} In our case, complete metastasectomy of
the bilateral pulmonary nodules was achieved after nephrectomy. Thus, he
was in remission at 2 years without adjuvant chemotherapy.

Ours is the first reported case of pediatric malignant JGT with multiple
pulmonary metastases. Although most patients with malignant JGT present
with a large tumor that is pathologically characterized by vascular
invasion, our case had a relatively small-sized tumor with no vascular
invasion or nuclear atypia. Few reports have described genetic
abnormalities in JGT. Targeted DNA sequences in our case revealed six
gene mutations although the significance of these mutations in the
pathogenesis of malignant JGT is unclear. A previous study reported that
the \emph{NOTCH3} receptor is highly expressed in reninoma in
mice.\textsuperscript{11} Dysregulation of \emph{NOTCH3} signaling plays
a role in soft tissue tumor pathogenesis.\textsuperscript{12} Therefore,
the \emph{NOTCH3} mutation in our case might have been involved in this
malignant transformation. In addition, \emph{NOTCH3} signaling has shown
to contributed to chemoresistance to doxorubicin\textsuperscript{13},
which was consistence with the clinical feature of an ineffective for
metastatic lung lesions after chemotherapy including doxorubicin. JGT is
generally considered to be a benign tumor, but malignant cases have
recently been reported. Our patient was successfully treated with
complete pulmonary metastasectomy after primary tumor resection without
adjuvant chemotherapy. Pulmonary metastasectomy represents an effective
approach in the treatment of JGT-related lung metastases alone. However,
no established reports on the prognosis and treatment of malignant JGT
exist; thus, additional case reports are needed.

Conflict of Interest Statement

The authors declare that there is no conflict of interest.

1. McVicar M, Carman C, Chandra M, Abbi RJ, Teichberg S, Kahn E.
Hypertension secondary to renin-secreting juxtaglomerular cell tumor:
case report and review of 38 cases. Pediatr Nephrol 1993;7:404-412.

2. Kuroda N, Gotoda H, Ohe C, et al. Review of juxtaglomerular cell
tumor with focus on pathobiological aspect. Diagn Pathol 2011;6:80.

3. Zhou J, Zheng S, Zhang Y, et al. Juxtaglomerular cell tumor:
clinicopathologic evaluation in a large series emphasizing its broad
histologic spectrum. Pathol Int 2020;70:844-856.

4. Duan X, Bruneval P, Hammadeh R, et al. Metastatic juxtaglomerular
cell tumor in a 52-year-old man. Am J Surg Pathol 2004;28:1098-1102.

5. Beaudoin J, Périgny M, Têtu B, Lebel M. A patient with a
juxtaglomerular cell tumor with histological vascular invasion. Nat Clin
Pract Nephrol 2008;4:458-462.

6. Shera AH, Baba AA, Bakshi IH, Lone IA. Recurrent malignant
juxtaglomerular cell tumor: a rare cause of malignant hypertension in a
child. J Indian Assoc Pediatr Surg 2011;16:152-154.

7. Cucchiari D, Bertuzzi A, Colombo P, et al. Juxtaglomerular cell
tumor: multicentric synchronous disease associated with paraneoplastic
syndrome. J Clin Oncol 2013;31:e240-e242.

8. Munakata S, Tomiyama E, Takayama H. Case report of atypical
juxtaglomerular cell tumor. Case Rep Pathol 2018;2018:6407360.

9. Huang PW, Lin YC, Wu KF, Sheng TW, Su PJ. Juxtaglomerular cell tumor
with lung metastases in a young male patient. \emph{J Cancer Surviv} .
2019;6(3):128.

10. Hagiya A, Zhou M, Hung A, Aron M. Juxtaglomerular cell tumor with
atypical pathological features: report of a case and review of
literature. Int J Surg Pathol 2020;28:87-91.

11. Martini AG, Xa LK, Lacombe M-J, et al. Transcriptome analysis of
human reninomas as an approach to understanding juxtaglomerular cell
biology. Hypertension 2017;69:1145-1155.

12. Raimondi L, Ciarapica R, De Salvo M. Inhibition of Notch3 signalling
induces rhabdomyosarcoma cell differentiation promoting p38
phosphorylation and p21(Cip1) expression and hampers tumour cell growth
in vitro and in vivo. Cell Death Differ 2012;19:871-881.

13. Xiu M, Wang Y, Li B, et al. The Role of Notch3 Signaling in Cancer
Stemness and Chemoresistance: Molecular Mechanisms and Targeting
Strategies. Front Mol Biosci. 2021;14:694141.

Figure legends

Figure S1. Neoplastic cells with an ovoid shape proliferate in a solid
sheet growth pattern, 40×.

Figure S2. Neoplastic cells display rare mitotic activity and mild
nuclear atypia, 200×.

Figure S3. Neoplastic cells show CD34 labeling, 200×.

Figure S4. Renin is diffusely distributed in the tumor cytoplasm, 200×.

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