Curative‐Intent Pancreatectomy for Pancreatic Metastasis From Renal Cell Carcinoma 30 Years After Nephrectomy Following Lenvatinib Plus Pembrolizumab Therapy: A Case Report

ABSTRACT

Introduction

Renal cell carcinoma (RCC) is the most common primary site of pancreatic metastases, and complete resection confers a favorable prognosis. Lenvatinib plus pembrolizumab (LEN + PEM) is standard first‐line therapy for advanced RCC; however, induction therapy before resection of pancreatic metastasis has not been reported.

Case Presentation

A 77‐year‐old man presented with weight loss, anemia, and elevated inflammatory markers 30 years after radical nephrectomy for RCC. Contrast‐enhanced computed tomography revealed a 42‐mm pancreatic head mass compressing the inferior vena cava, considered resectable, but high risk. Endoscopic ultrasound‐guided fine‐needle aspiration confirmed metastatic clear cell RCC. After LEN + PEM induction, the tumor decreased to 29 mm, vena cava compression resolved, and subtotal stomach‐preserving pancreaticoduodenectomy achieved R0 resection. The patient remained recurrence‐free at 5 months.

Conclusion

LEN + PEM induction enabled R0 resection of pancreatic RCC metastasis, a site for which this strategy has not previously been reported.

Keynote Message

Lenvatinib plus pembrolizumab induction therapy may sufficiently reduce tumor size to enable R0 pancreaticoduodenectomy for pancreatic metastasis from renal cell carcinoma, supporting the consideration of curative‐intent surgery even for metastases arising decades after nephrectomy.

Abbreviations

CT

computed tomography

ICI

immune checkpoint inhibitor

LEN + PEM

lenvatinib plus pembrolizumab

OS

overall survival

RCC

renal cell carcinoma

TKI

tyrosine kinase inhibitor

1. Introduction

Renal cell carcinoma (RCC) is the most common primary site of pancreatic metastases, accounting for 56.4%–62.6% of resected cases [1, 2]. The disease‐free interval is characteristically long; in a pooled analysis of 436 patients, the median interval was 108 months [3]. When technically feasible, complete resection confers a comparatively favorable prognosis, with reported 5‐year overall survival (OS) > 70% [4].

Combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are the standard first‐line treatment for advanced RCC, and lenvatinib plus pembrolizumab (LEN + PEM) was superior to sunitinib in the Phase III CLEAR trial [5]. ICI‐based combinations have also been used as induction therapy before resection of recurrent or metastatic disease after nephrectomy; however, to the best of our knowledge, no such report has involved pancreatic metastasis.

We describe a patient who developed pancreatic metastasis 30 years after radical nephrectomy for clear cell RCC and underwent pancreatectomy after LEN + PEM induction therapy.

2. Case Presentation

A 77‐year‐old man presented with weight loss, anemia, and elevated inflammatory markers. He had undergone right radical nephrectomy for RCC at another institution 30 years earlier; however, these records were unavailable, and the original histopathology could not be retrieved. The patient had been followed up for approximately 5 years with no symptoms or radiological recurrence and underwent no surveillance thereafter. Contrast‐enhanced computed tomography (CT) revealed a 42‐mm mass in the pancreatic head without other metastases (Figure 1). The tumor abutted the portal vein over < 180° of its circumference without superior mesenteric artery involvement, which would not meet the anatomical criteria for borderline resectable disease [6, 7]. It compressed the inferior vena cava, however, and abutted the gastrocolic trunk and proximal dorsal jejunal vein. Endoscopic ultrasound‐guided fine‐needle aspiration confirmed metastasis from clear cell RCC, and immunohistochemistry was positive for PAX8, carbonic anhydrase IX, CD10, and cytokeratin AE1/AE3 and negative for cytokeratin 7 and c‐kit, excluding a primary pancreatic ductal or neuroendocrine neoplasm. The patient was at intermediate risk according to the International Metastatic RCC Database Consortium criteria, with anemia (hemoglobin, 10.7 g/dL) as the qualifying factor.

FIGURE 1.

Contrast‐enhanced computed tomography before lenvatinib plus pembrolizumab induction therapy, showing a 42 mm metastatic tumor in the pancreatic head (yellow arrow). Scale bar, 5 cm.

As the lesion was an isolated metastasis, upfront resection was considered. However, the venous relationships were judged to pose a substantial risk of hemorrhage and unplanned venous resection, and the established criteria apply to pancreatic ductal adenocarcinoma rather than metastases. Accordingly, the multidisciplinary conference deemed the lesion resectable but high risk, and preoperative systemic therapy was selected. LEN (14 mg/day) plus PEM (200 mg every 3 weeks) was administered for approximately 4 months (6 cycles). Although the patient developed Grade 2 hypertension, treatment was not interrupted.

CT revealed a reduction in tumor size from 42 to 29 mm (Figure 2), consistent with a partial response according to the Response Evaluation Criteria in Solid Tumors, and loss of demonstrable contact with the inferior vena cava. The planned procedure—subtotal stomach‐preserving pancreaticoduodenectomy without vascular resection—remained unchanged; what improved was the anticipated operative risk. Adhesions from the previous nephrectomy were encountered around the ascending colon and hepatic flexure, but no severe adhesion or fibrosis was observed around the pancreatic head or surrounding vasculature. The postoperative course was uneventful, and the patient was discharged on Day 15. Histopathology confirmed metastatic clear cell RCC with no lymphatic invasion (Ly0), minimal venous invasion (V1a), and no nodal metastasis (ypN0). All margins (ypPCM0, ypBCM0, ypDPM0) were negative, indicating R0 resection. No adjuvant therapy was administered and the patient has remained recurrence‐free for 5 months.

FIGURE 2.

Contrast‐enhanced computed tomography obtained at the same slice level, window setting, and contrast phase as Figure 1, after lenvatinib plus pembrolizumab induction therapy, showing reduction of the pancreatic‐head metastasis to 29 mm (yellow arrow) and resolution of inferior vena cava compression (blue arrow). Scale bar, 5 cm.

3. Discussion

Metastatic tumors account for only 2%–5% of pancreatic neoplasms, among which RCC is consistently the most frequent primary site [1, 2]. Late presentation is characteristic; in a pooled analysis of 436 patients, the median disease‐free interval was 108 months, with 44.4% of patients developing late recurrence more than 10 years after nephrectomy [3]. The 30‐year interval in the present patient approaches the upper extreme of the reported range.

The prognosis is comparatively favorable when complete resection is achieved. A systematic review of 311 surgically treated patients reported a 5‐year OS of 72.6% after pancreatectomy versus 14% without resection [4], and a pooled analysis reported a median OS of 116 months [3]. A longer disease‐free interval [8], asymptomatic presentation, and R0 resection [9] have also been identified as favorable factors, supporting an aggressive surgical approach when technically feasible.

The Phase III CLEAR trial established LEN + PEM as a first‐line standard treatment, with benefits maintained on extended follow‐up, irrespective of the metastatic site or burden [5, 10, 11, 12]. Accordingly, LEN + PEM is the preferred first‐line regimen in the European Association of Urology and American Society of Clinical Oncology guidelines. Cytoreductive nephrectomy combined with immunotherapy improved OS compared with systemic therapy alone in a systematic review of 2397 patients (hazard ratio, 0.53) [13], and prospective trials are ongoing [14]. ICI‐TKI combinations achieve greater tumor reduction and higher rates of histopathological downstaging than dual ICI regimens [15], making them well suited to settings requiring substantial downsizing before curative‐intent resection.

Beyond cytoreductive nephrectomy, post‐nephrectomy recurrence or metastasis rendered resectable by ICI‐based combination therapy has been reported at several sites (Table 1) [16, 17, 18], and the strategy itself is not novel. Table 1 lists the sites and regimens documented to date, and the heterogeneity in sites, regimens, and intervals reflects the small number of cases available. However, its application in pancreatic metastasis, in which resection requires pancreaticoduodenectomy, a procedure with substantial morbidity, has not been described. In the present case, induction therapy did not alter the planned procedure, but resolution of the inferior vena cava compression reduced the anticipated risk of hemorrhage and unplanned venous resection; this, rather than the 31% reduction in diameter alone, constituted the surgical benefit. This report is limited by a postoperative follow‐up of only 5 months, which permits no inference regarding long‐term oncological outcomes.

TABLE 1.

Reported cases of post‐nephrectomy local recurrence or distant metastasis from renal cell carcinoma rendered surgically resectable after immune checkpoint inhibitor–based combination therapy, with the present case shown for comparison.

References	Regimen	Recurrence/metastatic site	Interval from nephrectomy	Treatment course	Surgical and pathological outcome
Ell et al. [16]	LEN + PEM	Retroperitoneal local recurrence; dedifferentiated sarcomatoid RCC; 10 cm	≈14 months	5 cycles of pembrolizumab with 3 months of lenvatinib (induction)	En bloc resection; ypT0 (pathological complete response)
Sejima et al. [17]	NIVO + IPI	Local recurrence and liver metastasis; sarcomatoid‐component RCC	Not reported	4 cycles of NIVO+IPI followed by 30 cycles of NIVO maintenance	Partial hepatectomy; no viable tumor cells; disease‐free at 1 year
Hartl et al. [18]	NIVO + CABO	Locally invasive thyroid metastasis (prevertebral fascia involvement)	13 years	Neoadjuvant systemic therapy (duration not reported)	Total thyroidectomy with internal jugular vein resection; laryngeal function preserved
Present case	LEN + PEM	Pancreatic head metastasis; clear‐cell RCC; 42 mm	30 years	6 cycles of pembrolizumab with lenvatinib over approximately 4 months (induction)	Subtotal stomach‐preserving pancreaticoduodenectomy; R0 resection with viable tumor

Abbreviations: CABO, cabozantinib; IPI, ipilimumab; LEN, lenvatinib; NIVO, nivolumab; PEM, pembrolizumab; RCC, renal cell carcinoma.

4. Conclusion

We describe the R0 resection of a pancreatic metastasis from RCC after LEN + PEM induction therapy, a site for which this approach has not previously been reported. LEN + PEM may represent a feasible induction option before curative‐intent resection in this setting, although further studies are required to determine the optimal treatment sequence and appropriate patient selection.

Ethics Statement

The study was approved by the Ethics Committee of National Hospital Organization Tokyo Medical Center (Approval No. R24‐078).

Consent

Informed consent was obtained from the patient for the publication of this case report and accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.