Metastasis‐Directed Surgery for Solitary Pulmonary Metastasis After Pembrolizumab in Urothelial Carcinoma: A Case Report

ABSTRACT

Introduction

The role of metastasis‐directed therapy in urothelial carcinoma remains uncertain, particularly in the immune checkpoint inhibitor era. We report a case of solitary pulmonary metastasis that developed after a favorable response to pembrolizumab and was managed with metastasectomy.

Case Presentation

A 65‐year‐old man with ureteral carcinoma underwent radical nephroureterectomy followed by adjuvant gemcitabine plus carboplatin. Three months later, a solitary pulmonary metastasis was detected and pembrolizumab was initiated. After initial enlargement, the lesion regressed and achieved a partial response after 13 cycles, followed by slight regrowth after 18 cycles, consistent with oligoprogression. Video‐assisted thoracoscopic metastasectomy was performed 14 months after pembrolizumab initiation. Pembrolizumab was continued for 1 year postoperatively, with no recurrence observed 17 months after surgery.

Conclusion

This case suggests that metastasis‐directed therapy may be a reasonable option for carefully selected patients with oligoprogressive urothelial carcinoma during immune checkpoint inhibitor therapy.

Keynote Message

This case demonstrates that metastasis‐directed surgery can be a viable option for solitary pulmonary oligoprogression in urothelial carcinoma following pembrolizumab therapy. Careful patient selection and integration of metastasis‐directed surgery may contribute to durable disease control in selected cases.

Abbreviations

CPS

combined positive score

CT

computed tomography

CTCAE

Common Terminology Criteria for Adverse Events

EAU

European Association of Urology

ESMO

European Society for Medical Oncology

ESTRO

European Society for Radiotherapy and Oncology

EV

enfortumab vedotin

ICI

immune checkpoint inhibitor

Mb

megabase

MDT

metastasis‐directed therapy

OMBC

oligometastatic bladder cancer

PD‐L1

programmed death ligand 1

RECIST

Response Evaluation Criteria in Solid Tumors

SBRT

stereotactic body radiotherapy

UC

urothelial carcinoma

UICC

Union for International Cancer Control

VATS

video‐assisted thoracoscopic surgery

1. Introduction

The role of metastasis‐directed local treatment for metastatic urothelial carcinoma (UC) remains controversial and far from standardized. Although retrospective series suggest that selected patients with limited metastatic burden may achieve prolonged survival following metastasectomy, the overall level of evidence remains low and is derived from small, biased cohorts [1, 2, 3]. Pulmonary metastasectomy for UC has been reported to result in favorable outcomes, especially when the metastasis is solitary and the primary tumor is controlled. Several studies have demonstrated 5‐year overall survival rates of approximately 40%–60% after lung metastasectomy [4, 5, 6].

The therapeutic landscape of UC has shifted markedly with the introduction of immune checkpoint inhibitors (ICIs). Pembrolizumab is now established as a standard systemic option in metastatic UC. With the increasing use of ICIs, a new clinical phenomenon—oligoprogression, in which a limited number of metastatic sites acquire resistance while the remaining disease continues to respond—has gained clinical relevance. In such situations, metastasis‐directed therapy (MDT), including surgical metastasectomy or stereotactic body radiotherapy (SBRT), may provide sustained disease control and allow continuation of effective systemic immunotherapy. Recent single‐center experiences and systematic reviews have suggested that MDT in the ICI era can be feasible and may contribute to prolonged survival in patients with oligometastatic or oligoprogressive UC [7, 8].

However, evidence specifically addressing metastasectomy following a favorable response to pembrolizumab remains scarce. To date, only a limited number of reports have described surgical resection for isolated metastatic lesions after or during ICI therapy in UC. Clarifying the clinical course of such cases may help improve patient selection and define the role of MDT.

Here, we report a case of metastatic UC in which a solitary pulmonary metastasis developed after disease control with pembrolizumab and was subsequently managed with curative‐intent pulmonary metastasectomy. This case contributes to the emerging literature on MDT in the context of ICI‐treated UC and highlights the potential value of surgical intervention for carefully selected patients.

2. Case Presentation

A 65‐year‐old man with a history of chronic kidney disease under medical follow‐up presented with right flank pain. Computed tomography (CT) revealed a right ureteral tumor associated with hydronephrosis, without evidence of nodal or distant metastasis. He was diagnosed with ureter carcinoma, cT2N0M0 (UICC 8th). The patient subsequently underwent right nephroureterectomy. Pathological examination revealed high‐grade urothelial carcinoma, pT3, pNx, INFα, ly0, and v1 (Figures 1 and 2a,b). Three months after surgery, he received 4 cycles of adjuvant gemcitabine plus carboplatin chemotherapy. Follow‐up CT performed after completion of adjuvant therapy revealed a solitary pulmonary nodule in the right middle lobe, clinically consistent with metastatic recurrence (Figure 3a). Given the early recurrence occurring only 3 months after completion of adjuvant chemotherapy, the lesion was considered more likely to represent systemic disease rather than isolated metastasis. Therefore, systemic therapy was prioritized over upfront surgical resection.

FIGURE 1.

Gross examination of the radical nephrectomy specimen demonstrated a firm, white, well‐demarcated solid nodule within the distal ureter.

FIGURE 2.

(a, b) Microscopically, tumor cells with distinct nucleoli proliferated in a nested pattern. The tumor invaded the periureteral fat. Mitotic figures (5 per high‐power field) and apoptotic bodies were observed.

FIGURE 3.

(a–d) Serial chest computed tomography (CT) images demonstrating the clinical course of the solitary pulmonary metastasis during pembrolizumab treatment. (a) CT at the time of diagnosis revealed a solitary pulmonary nodule in the right lung, clinically consistent with metastatic urothelial carcinoma (arrow). (b) After 4 cycles of pembrolizumab, the pulmonary lesion showed a transient increase in size (arrow), which was subsequently interpreted as possible pseudoprogression. (c) After 13 cycles of pembrolizumab, the lesion markedly decreased in size, achieving a partial response (arrow). (d) After 18 cycles of pembrolizumab, follow‐up CT demonstrated mild re‐enlargement of the lesion (arrow), consistent with oligoprogression, while no additional metastatic lesions were detected.

Pembrolizumab therapy, 200 mg/body every 3 weeks, was initiated for recurrent urothelial carcinoma. After 4 cycles, the pulmonary lesion showed slight enlargement (Figure 3b); however, continued treatment led to gradual tumor reduction, and a partial response according to RECIST version 1.1 [9] was achieved after 13 cycles (Figure 3c). After 18 cycles, CT demonstrated mild re‐enlargement of the known pulmonary lesion (Figure 3d). No additional metastatic sites appeared, and the disease remained confined to the solitary lung lesion. MDT was therefore considered appropriate. Fourteen months after initiation of pembrolizumab, the patient underwent video‐assisted thoracoscopic surgery (VATS) with combined partial resection of the right middle and upper lobes. Histopathological findings were consistent with metastatic urothelial carcinoma (Figure 4a–d). Postoperatively, he remained free of radiological evidence of disease. Pembrolizumab was continued for one additional year after metastasectomy, without recurrence on serial CT imaging. A total of 38 cycles of pembrolizumab were administered (including 20 cycles post‐metastasectomy). He has remained recurrence‐free for 17 months following pulmonary resection and is currently under surveillance without systemic therapy.

FIGURE 4.

(a, b) Histopathologic examination of the resected lung lesion revealed metastatic nests of carcinoma with variable architectural complexity and focal marked nuclear pleomorphism. Immunohistochemically, the tumor cells showed diffuse nuclear positivity for GATA3 (c) and focal membranous positivity for Uroplakin II (d).

Comprehensive genomic profiling of the primary tumor using FoundationOne CDx revealed microsatellite stability and a tumor mutational burden of 4.8 mutations/Mb. Immunohistochemical evaluation revealed a PD‐L1 combined positive score (CPS) of 1% in the primary tumor and 5% in the metastatic lung lesion. Pembrolizumab‐related adverse events were limited to grade 1 rash and grade 1 hypothyroidism, as defined by CTCAE version 5.0, and no clinically significant immune‐related toxicities were observed.

3. Discussion

The optimal management of metastatic UC remains challenging, and systemic therapy has traditionally been the cornerstone of treatment. Although metastasectomy is not standard, retrospective series suggest that carefully selected patients with limited metastatic burden may benefit from MDT. Studies focusing on pulmonary metastasectomy have shown favorable outcomes for solitary or oligometastatic lesions when complete resection is feasible [4, 5, 6].

With broader use of ICIs, clinical patterns such as oligorecurrence and oligoprogression have become increasingly relevant. Pembrolizumab has demonstrated durable activity in metastatic UC, and MDT has been considered when limited sites progress during otherwise effective immunotherapy. Several reports indicate that MDT may prolong disease control in ICI‐treated UC, particularly in solitary pulmonary oligometastasis or oligoprogression [7, 8]. An international Delphi consensus supported by the EAU, ESTRO, and ESMO proposed a multidisciplinary definition and diagnostic framework for oligometastatic bladder cancer (OMBC). OMBC is defined as three or fewer metastatic lesions amenable to complete local therapy, including synchronous oligometastasis, metachronous oligorecurrence, and metachronous oligoprogression. According to this consensus, favorable candidates for metastasis‐directed therapy are typically characterized by a limited number of metastatic lesions, controlled primary tumors, and the feasibility of complete local treatment of all lesions. In addition, pulmonary metastases are generally considered suitable for metastasis‐directed therapy [10]. In the present case, the absence of new metastatic lesions during pembrolizumab treatment suggested effective systemic disease control. In this case, disease status was evaluated using computed tomography, while the role of other imaging modalities remains to be established.

EV plus pembrolizumab has improved clinical outcomes in metastatic urothelial carcinoma [11]; however, data on metastasectomy in this setting remain limited. Our case illustrates that metastasectomy following pembrolizumab‐based therapy may contribute to sustained disease control in selected patients.

Our case fits the definition of metachronous oligoprogression. The patient achieved a favorable response to pembrolizumab, followed by isolated progression confined to a single resectable pulmonary lesion. Metastasectomy followed by continuation of pembrolizumab resulted in sustained disease control with no recurrence for more than 1 year after surgery. In the present case, PD‐L1 expression was low in both the primary and metastatic lesions; however, a favorable response to pembrolizumab was observed, suggesting that clinical benefit may occur regardless of PD‐L1 expression levels. The optimal duration of pembrolizumab following metastasectomy remains undefined; however, we administered postoperative pembrolizumab for 1 year, considering prior adjuvant studies and the cumulative treatment duration used in metastatic settings.

This case suggests that metastasectomy may achieve sustained disease control in carefully selected patients during ICI therapy.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report.

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.