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

Hideki Sakiyama¹, Satoru Hamada^1,2, Tokiko Oshiro^1,2, Nobuyuki Hyakuna^1,2 Masaaki Kuda³, Tomoro Hishiki⁴, Hajime Aoyama⁵, Naoto Kuroda⁶, Kenji Yorita⁷, Naoki Wada⁸, Takako Yoshioka⁹, Yuhki Koga¹⁰, Koichi Nakanishi^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

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 × 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^® CDx detected six genetic mutations:NOTCH3 T272M, BRAF D22N, MAP3K1 L78P, CDKN2BA56D, DAXX E451del, and 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.^1,2JGT is generally curable by surgical resection, and tumor removal results in the improvement of hyperreninemia and clinical symptoms.¹ Immunohistochemically, the diagnosis is confirmed by renin positivity in the cytoplasm. In addition, CD34, CD117, vimentin, and ACTA2 are often positive.^2,3Although JGT is generally considered benign, eight malignant or pathologically atypical cases have been reported in the literature (Table).^3–10 Six were adult cases, and one was a pediatric case. In all cases, the tumor diameter was relatively large (>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,⁴ case 4 demonstrated bilateral lung metastases at initial diagnosis,⁹ case 6 demonstrated multicentric synchronous disease in the liver and spleen,⁷ case 8 succumbed to hepatic and bone metastases 10 months after nephrectomy.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 NOTCH3 receptor is highly expressed in reninoma in mice.¹¹ Dysregulation of NOTCH3 signaling plays a role in soft tissue tumor pathogenesis.¹² Therefore, the NOTCH3 mutation in our case might have been involved in this malignant transformation. In addition, NOTCH3 signaling has shown to contributed to chemoresistance to doxorubicin¹³, 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.

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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×.