A case of renal primary neuroendocrine tumor (G3) in which 177Lu-PRRT was effective for disease control

Abstract

Primary renal neuroendocrine tumor (NET) is extremely rare, with no established treatment for advanced cases. We report high-grade (G3) renal NET effectively treated with peptide receptor radionuclide therapy (PRRT). A 30-year-old man was diagnosed with primary renal NET G3 with liver metastases. After everolimus failure, he received 177Lu-DOTATATE (Lutathera®). Although the tumor continued growing after the first cycle, disease stabilized from the second cycle onwards. Stable disease was maintained for 12 months without severe adverse events, preserving quality of life. 177Lu-PRRT is a promising therapeutic option for high-grade, somatostatin receptor-positive renal NET when other treatments fail.

1. Introduction

Neuroendocrine tumors (NETs) are a relatively rare group of tumors arising from neuroendocrine cells throughout the body.^1,2 Primary renal NETs are exceptionally rare, with only about 200 cases reported worldwide since 1966, making evidence for their diagnosis and treatment scarce 3, 4, 5, 6. Primary renal NETs often present with non-specific symptoms such as hematuria, flank pain, and abdominal mass, making preoperative differentiation from other renal cell carcinomas challenging.^5,7 A definitive diagnosis requires histological evaluation of the tumor and immunohistochemical staining for neuroendocrine markers such as synaptophysin and chromogranin A.⁸ According to the World Health Organization (WHO) classification, NETs are graded into G1, G2, and G3 based on mitotic count and Ki-67 labeling index.⁹ In particular, NET G3, although distinct from the poorly differentiated neuroendocrine carcinoma (NEC), has high proliferative potential and often follows an aggressive clinical course.¹⁰

Surgical resection, such as radical nephrectomy, is the primary treatment for localized primary renal NETs. However, no standard treatment has been established for advanced cases with metastasis at diagnosis or postoperative recurrence. Cytotoxic chemotherapy and the molecular targeted agent everolimus are used empirically, but their efficacy is limited.¹¹ Recently, peptide receptor radionuclide therapy (PRRT) has emerged as a new treatment option for somatostatin receptor (SSTR)-positive NETs. Specifically, 177Lu-DOTATATE (Lutathera®) was shown to significantly prolong progression-free survival in the Phase III NETTER-1 trial for advanced midgut NETs.¹² However, reports on the efficacy of PRRT for primary renal NETs, especially high-grade G3 cases, are extremely limited.¹³

Here, we report a rare case of a young patient diagnosed with progressive, metastatic primary renal NET G3 who was resistant to standard therapy but achieved favorable disease control and quality of life for approximately 12 months with the introduction of 177Lu-PRRT. We report this case with a review of the literature.

2. Case presentation

A 30-year-old man with no significant past medical or family history presented to a local clinic with left flank pain. An abdominal CT scan suggested perirenal hematoma due to spontaneous rupture of a left renal mass, and he was referred to our department for further evaluation and treatment.

On admission, physical examination revealed no remarkable findings. Blood tests showed an inflammatory response with a white blood cell count of 11,500/μL and C-reactive protein of 129 mg/L, but no other significant abnormalities. A contrast-enhanced abdominal CT scan on admission revealed an extensive hematoma around the left kidney and a poorly enhanced mass in the upper pole (Fig. 1A and B). Abdominal MRI showed the mass to be of low intensity on T2-weighted images (Fig. 1C) with mild diffusion restriction (Fig. 1D).

Fig. 1.

Pre-operative imaging findings.

The CT scan showed a hematoma around the left kidney, with a poorly enhanced mass-like area in the upper pole (A: arterial phase, B: parenchymal phase). On MRI, the mass showed low signal intensity on T2-weighted imaging (C), mild diffusion restriction on Diffusion-weighted imaging (D).

Initially, a hemorrhagic renal cyst or a ruptured renal cell carcinoma was suspected, and a CT-guided percutaneous renal biopsy was performed 3 days after the initial presentation. However, the obtained specimen consisted mostly of necrotic tissue with only some epithelial components, and a definitive diagnosis of malignancy could not be made. Subsequently, the hematoma showed a tendency to shrink spontaneously, but the tumor size remained unchanged. A follow-up CT scan performed three months after the initial presentation revealed multiple liver metastases that were not present initially, strongly suggesting a malignant tumor, and surgery was planned.

A left radical nephrectomy and renal hilar lymph node dissection were performed. The resected kidney showed an ill-defined, brownish tumor approximately 5 cm in size (Fig. 2A). Histopathological examination revealed that the tumor was composed of a mixture of extensive necrotic tissue and tumor components. The tumor cells were arranged in well-differentiated ribbon-like and trabecular patterns (Fig. 2B) as well as solid sheets (Fig. 2C). The Ki-67 labeling index in the solid areas was high at 40–50 % (Fig. 2D). Immunohistochemical staining showed that the tumor cells were diffusely positive for synaptophysin (Fig. 2E), chromogranin A (Fig. 2F). Based on these findings, a final diagnosis of primary renal neuroendocrine tumor (NET), Grade 3, was made. Following this definitive diagnosis, the initial CT-guided biopsy specimen was re-evaluated. Additional immunohistochemical staining of a small cluster of cells found in a limited portion of the specimen (Fig. 3A) showed that these cells were positive for synaptophysin (Fig. 3B), chromogranin A (Fig. 3C), consistent with the findings of NET.

Fig. 2.

Pathological and immunohistochemical findings of the resected specimen.

The resected specimen (A) showed a mixture of necrotic tissue and tumor. The tumor consisted of well-differentiated ribbon-like structures (B) and solid sheets (C). The Ki-67 index in the solid part was high at 40–50 % (D), and the tumor cells were positive for neuroendocrine markers synaptophysin (E), chromogranin (F).

Fig. 3.

Re-evaluation of the initial CT-guided biopsy specimen.

Re-evaluation of the initial biopsy specimen revealed a small cluster of small cells (A) that stained positive for synaptophysin (B), chromogranin (C).

Postoperative endoscopy and PET-CT found no other primary lesion, confirming the diagnosis of primary renal NET. A SSTR scintigraphy (OctreoScan) showed abnormal uptake in the left para-aortic lymph nodes and multiple liver metastases (Fig. 4A). Additional immunohistochemical staining for SSTR2 on the surgical specimen demonstrated strong and diffuse positive staining (Fig. 4B), confirming SSTR positivity.

Fig. 4.

SSTR expression evaluation

(A) SSTR scintigraphy (OctreoScan) showing abnormal uptake in the left para-aortic lymph nodes and multiple liver metastases, confirming functional SSTR expression. (B) Immunohistochemical staining for SSTR2 ( × 400) on the renal tumor specimen demonstrating strong and diffuse cytoplasmic positive staining throughout the tumor cells, providing histological confirmation of SSTR expression.

The clinical timeline from diagnosis to outcome is shown in Fig. 5. As postoperative drug therapy, the mTOR inhibitor everolimus (10 mg/day) was started, following the treatment for pancreatic NET G3. However, the liver metastases continued to grow after administration. Therefore, the treatment effect was judged as progressive disease (PD). As the next treatment, 177Lu-PRRT was introduced 4 months after surgery due to SSTR positivity. At the evaluation after the first cycle (5 months postoperatively), the liver metastases were still growing, but treatment was continued because the patient's condition was stable. As a result, from the second to the fourth cycle, the size of the liver metastases stabilized, and a state of stable disease (SD) was achieved. For approximately 12 months from the introduction of 177Lu-PRRT, the patient had no new subjective symptoms or serious adverse events, and a good general condition (ECOG Performance Status 0–1) and quality of life were maintained. 177Lu-PRRT was completed after a total of 4 cycles.

Fig. 5.

Clinical timeline

The timeline shows the clinical course from diagnosis, through radical nephrectomy, everolimus treatment, and four cycles of 177Lu-PRRT, indicating the period of stable disease.

In preparation for disease progression after the end of treatment, a cancer genome profiling test was performed, which identified gene mutations in MTAP, CDK4, CDKN2A, and MDM2, and several candidate drugs for clinical trials were suggested. However, approximately 4 months after the completion of 177Lu-PRRT, local recurrence and enlargement of liver metastases became prominent, and the patient's general condition deteriorated rapidly due to intra-abdominal bleeding from the metastatic lesions. Therefore, participation in a clinical trial was deemed difficult, and the patient was transitioned to palliative care and passed away.

3. Discussion

This is a case of an extremely rare primary renal NET G3 that occurred in a 30-year-old man. It is characterized by a very high Ki-67 index of 40–50 % and an extremely aggressive clinical course, with the development of multiple liver metastases early after diagnosis. Although reports of primary renal NETs are sporadic 5, 6, 7, reports of cases like this one, occurring in a young patient and being of high grade (G3), are even rarer.

The difficulty in diagnosis is also an instructive point of this case. The initial CT-guided biopsy did not lead to a definitive diagnosis due to extensive necrosis within the tumor. It is known that NETs, especially high-grade ones, are prone to internal necrosis, suggesting the need to consider surgical biopsy or resection, which can provide a larger tissue sample, when a needle biopsy is inconclusive.

The treatment strategy for advanced/metastatic NET G3 remains a major challenge. NET G3 is a heterogeneous group that includes tumors with a high Ki-67 index (>20 %) but retaining the characteristics of a well-differentiated NET, and tumors with properties closer to poorly differentiated neuroendocrine carcinoma (NEC) with a poor prognosis.¹⁰ In general, platinum-based chemotherapy is the first-line treatment for NEC, but the optimal treatment for well-differentiated NET G3 has not been established.¹¹ In this case, everolimus, one of the standard treatments for pancreatic and gastrointestinal NETs, was administered first but was not effective. This suggests that the proliferative capacity of this tumor may have surpassed the inhibitory effect of the mTOR inhibitor.

Therefore, we confirmed SSTR positivity with both OctreoScan and SSTR2 immunohistochemistry and introduced 177Lu-PRRT. It is noteworthy that although the disease was judged as PD after the first cycle, continuing the treatment led to the achievement of SD from the second cycle onwards, and ultimately, disease control was maintained for a long period of approximately 12 months. During this time, the patient was able to maintain a good quality of life without serious side effects. Considering the extremely rapid progression of this case, this is of great clinical significance.

The therapeutic effect is likely due to the tumor's dual nature: a high Ki-67 index (40–50 %) and abundant SSTR expression, confirmed by OctreoScan and SSTR2 immunohistochemistry. PRRT is a treatment method that selectively delivers radionuclides to SSTR-expressing cells and damages tumor cells by internal irradiation with β-rays.¹² Tumors with high proliferative capacity are generally considered to be highly radiosensitive, and in this case, it is possible that 177Lu, which accumulated in the tumor due to high SSTR expression, effectively suppressed cell proliferation by taking advantage of its high proliferative capacity. Unlike drugs such as everolimus that inhibit a part of the cell proliferation signal, PRRT has a more direct cytotoxic effect, which may have been effective even against an aggressive tumor like this one.

Reports showing the effectiveness of PRRT for primary renal NETs are limited to a few cases, such as a report on a case with bone metastases.¹³ The effectiveness of PRRT for high-grade NET G3 of gastrointestinal origin has been increasingly debated in recent years. A review by Sorbye et al. reported that the response rate of PRRT in NET G3 is around 20–30 %, and the disease control rate is around 60–80 %, which is comparable to chemotherapy.¹⁴ The result of approximately 12 months of SD obtained in this case is consistent with these reports and strongly suggests that PRRT may be an important treatment option for patients with standard treatment-resistant NET G3, even in the rare primary site of the kidney.

On the other hand, the effect of PRRT was not permanent in this case, and the disease progressed again after the completion of 4 cycles of treatment. This shows the limitation of PRRT, and the establishment of a post-PRRT treatment strategy is a future task. In recent years, it has been suggested that neoadjuvant chemotherapy may improve the prognosis for NEC of the urinary tract.¹⁵ In high-grade NET G3 like this case, a multidisciplinary treatment approach combining PRRT with chemotherapy or other molecular targeted drugs may lead to a longer-term improvement in prognosis. Additionally, cancer genome profiling identified several targetable mutations, highlighting the potential of personalized medicine for this intractable tumor.

Finally, a limitation of this report is that it is a single case report. Therefore, generalization of the results obtained in this case should be done with caution. However, in such a rare and rapidly progressive disease, each case report provides valuable knowledge for the development of future treatment methods.

4. Conclusion

We experienced a rare case of a 30-year-old man with metastatic primary renal neuroendocrine tumor (NET G3) who achieved approximately 12 months of stable disease and good quality of life with 177Lu-PRRT. This case strongly suggests that 177Lu-PRRT can be an effective treatment option for high-grade NETs characterized by high proliferative capacity and abundant SSTR expression. In order to establish an optimal treatment method for this rare disease, further accumulation of cases and multicenter clinical studies are essential.

CRediT authorship contribution statement

Saki Inaba: Conceptualization, Writing – original draft. Toshiki Kijima: Conceptualization, Writing – original draft, Writing – review & editing. Mina Takaoka: Data curation. Toshitaka Uematsu: Data curation. Kohei Takei: Data curation. Masahiro Yashi: Supervision. Kazuyuki Ishida: Data curation, Supervision. Taku Aoki: Conceptualization, Supervision, Writing – review & editing. Takao Kamai: Conceptualization, Supervision, Writing – review & editing.