Immunotherapy and Tyrosine Kinase Inhibitor as a Bridge to Surgery for Clear Cell Renal Cell Carcinoma Metastases to the Thyroid: A Case Report and Literature Review

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of kidney cancer in adults, representing a significant clinical challenge due to its resistance to traditional chemo- and radiotherapy. Standard treatments for ccRCC have primarily revolved around surgical interventions, including nephrectomy, which remains the cornerstone for localized disease management. However, postoperative follow-up and management strategies are crucial for detecting recurrences and managing disease progression [1].

The metastatic potential of ccRCC is well-documented, with the disease often spreading to the lungs, bones, and brain, complicating treatment and influencing prognosis. The past decade has witnessed transformative changes in the management of metastatic ccRCC. Developments in our understanding of the molecular and genetic underpinnings of ccRCC have paved the way for targeted therapies that have substantially altered the therapeutic landscape. Among these, immunotherapy agents, particularly immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have emerged as up-front treatments that offer hope for improved survival rates [2‒4].

Recent trials and studies have highlighted the efficacy of combining ICI with TKI, showing significantly improved outcomes compared to traditional approaches [5, 6]. These advancements underscore a pivotal shift toward precision medicine in ccRCC treatment, emphasizing the need to adapt clinical practices to integrate new scientific insights and therapeutic options [6].

This paper presents a case of oligometastatic high-grade ccRCC, wherein a combination of ICI and TKI was employed as a bridging strategy to transform non-resectable thyroid metastases into resectable ones. Additionally, it illuminates a significant milestone in treatment development and current therapeutic considerations that are shaping the management of ccRCC [5, 7, 8].

The patient is a previously essentially healthy man. At the time of diagnosis, he was approximately 50 years old, with no prior medical history of any abdominal surgery or chronic disease medication. Figure 1 summarizes the key events of the patient’s medical history, marked by numbers as follows: In 2016, he was investigated for abdominal pain and blood in the urine, where the clinical workup revealed a right-sided renal tumor with a solid radiological suspicion of kidney cancer. Additional examination with fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT showed no evident metastases, and bladder wash fluid strongly suggested the diagnosis of ccRCC (Fig. 1, event 1). The patient underwent a right-sided nephrectomy, including local lymph node dissection (Fig. 1, event 2). The postoperative course was without complications, and the patient could return home after just 5 days in the hospital. Pathology reported a 90-mm ccRCC, Fuhrman grade 4, with invasion of the renal vein. Tumor cells were immunoreactive to CD10 and PAX8. Surgical margins were negative. At the time of surgery, no adjuvant treatment was approved for ccRCC; hence, the patient was offered active surveillance following a multidisciplinary conference, in accordance with national healthcare guidelines. The patient was followed with CT scans at 6-month intervals. After about 3 years, metastases in the liver and pancreas were discovered. Further investigation with FDG-PET/CT showed no additional metastases apart from those described in the CT examination. The patient was again discussed at a multidisciplinary conference where pancreas resection and focal liver segmental resection were recommended due to limited metastases (Fig. 1, event 3). Afterward, the patient was seemingly tumor-free, and no adjuvant treatment was administered. Approximately 2 years later, a new single metastasis in the liver was detected, and the patient underwent repeated liver resection (Fig. 1, event 4). At the first postoperative checkup after the liver resection, enlargement of the thyroid was detected, and further cytology confirmed the diagnosis of metastatic ccRCC, with cells immunoreactive to PAX8 but not TTF1. CT examination showed a bilaterally enlarged thyroid (Fig. 2a). No additional metastases were detected, and the patient was once again evaluated at a multidisciplinary conference with participation from dedicated oncologists, surgeons, pathologists, and radiologists. The conference recommended targeted surgery, leading to the decision to proceed with a total thyroidectomy. Although the preoperative CT scan did not reveal any obvious overgrowth, intraoperative findings revealed an extensive tumor burden in close proximity to the bilateral common carotid arteries, esophagus, and trachea. As a result, the operation was aborted, deemed unresectable (Fig. 1, event 5).

The patient still had metastases in the thyroid, and treatment with pembrolizumab and lenvatinib was initiated (Fig. 1, event 6). Pembrolizumab was given in cycles of 3 weeks, while lenvatinib was given continuously. The patient tolerated the treatment well without notable side effects and was able to follow the initially planned course without any adverse events. The patient’s ECOG performance status remained at 0 or 1 throughout the treatment. After 3 cycles, a clinical effect was noted with a reduced thyroid size and renewed radiological evaluation after 8 months of treatment (Fig. 2b) showed significant, though not complete, remission. Radiologically, no additional metastases were seen. At discussion in the multidisciplinary conference, it was decided to recommend the patient for another attempt at thyroid resection (Fig. 1, event 7). The patient underwent a thyroidectomy, during which significant scarring from previous surgery in the area was noted. This time, the thyroid and metastases were successfully removed, preserving the parathyroid glands and maintaining adequate postoperative PTH levels. Similarly, both recurrent laryngeal nerves were preserved, maintaining their function. Both thyroid surgeries (Fig. 1, events 5 and 7) were performed by the same two highly experienced endocrine surgeons. Pathology reported extensive tumoral engagement of both thyroid lobes, with extensive growth of a viable malignant tumor with predominantly solid patterns (Fig. 3a). The tumor cells exhibited large pleomorphic nuclei with vesicular chromatin and macronuclei (Fig. 3b). Multinucleated and bizarre cells were noted focally, but no rhabdoid or sarcomatous components were present. The tumor extended into the accompanying ventral strap muscle and invaded the inked resection margins multifocally. Tumor cells were immunoreactive to PAX8 and CAIX while negative for TTF1 (Fig. 3c, d). A diagnosis of metastatic ccRCC was favored. PD-L1 immunohistochemistry showed membranous expression in 10% of tumor cells and up to 30% of tumor-infiltrating lymphocytes (Fig. 3e). In Figure 3f, a previous biopsy from a liver metastasis taken prior to liver resection 2022 is presented for comparison. Postoperative CT showed no evidence of residual macroscopic tumor tissue.

This case study presents several intriguing aspects of advanced renal cell carcinoma management. While we and others have presented long-term overall survival data following surgical metastasectomy (or stereotactic radiotherapy) of oligometastatic ccRCC, patient selection remains crucial and challenging [4, 9, 10]. The patient described herein, originally in good health, developed a localized high-grade ccRCC several years ago. His initial treatment involved a nephrectomy. Over the years, metastases sporadically emerged in multiple organ systems, beginning with the liver and pancreas and later involving the thyroid. The metastatic spread of renal cancer to the thyroid, while well-documented in medical literature, remains a rare and complex challenge. Several case reports and studies highlight similar instances, consistently advocating for surgical intervention when feasible [11].

An important aspect of metastatic RCC is the varying clinical significance of different metastatic sites. The prognosis and therapeutic approach can be heavily influenced by the location of the metastases. For instance, metastases to organs such as the liver and pancreas are typically associated with a poorer prognosis due to the aggressive nature and critical functions of these organs. Conversely, metastasis to the thyroid, while rare, may offer a different therapeutic window. The thyroid gland, being a relatively isolated organ, often allows for more targeted surgical intervention, as demonstrated in this case. The distinct biological behavior and accessibility of different metastatic sites highlight the need for a tailored approach in managing metastatic RCC, taking into account the specific challenges and opportunities presented by each site.

In this particular case, efforts to resect the metastases were initially undertaken by two very experienced endocrine surgeons. However, the complexity of the tumor burden and its advanced stage unexpectedly necessitated the termination of the surgical attempt. This underscores the unpredictable nature of metastatic renal cancer and the need for adaptable treatment strategies. Following the unsuccessful surgery, the patient was administered an innovative treatment regimen combining immunotherapy and a TKI. Specifically, pembrolizumab was given in 3-week cycles, and lenvatinib was administered continuously as an oral medication, in accordance with the pivotal phase 3 CLEAR trial [6]. The therapeutic impact was pronounced, demonstrating a significant reduction in tumor size, as it illustrated in Figure 2. This figure contrasts the state of the metastases before the commencement of the treatment (a) and after approximately 8 months (b).

Encouraged by the significant tumor mass reduction, a second surgical attempt was undertaken. This time, thyroidectomy was successfully performed. The postoperative period was notably uneventful, and the patient currently remains tumor-free. This outcome highlights the efficacy of combining pembrolizumab and lenvatinib as a treatment strategy [6, 12] and marks a significant milestone in the management of metastatic renal cell carcinoma.

This case underscores the pivotal shift in treatment strategy that ultimately led to a successful outcome. Initially, conventional surgical interventions were prioritized, which, despite being guided by experienced surgeons, proved insufficient due to the complexity and advanced nature of the metastatic burden. This contrasts sharply with the subsequent therapeutic approach, where the integration of immunotherapy (pembrolizumab) and a TKI (lenvatinib) provided a more effective, non-surgical method of reducing tumor mass. The significant tumor reduction achieved with this combination therapy not only facilitated a successful second surgical attempt but also highlights the superior efficacy of this modern treatment strategy over traditional approaches, particularly in managing complex, metastatic ccRCC cases.

To our knowledge, this is the inaugural instance where ICI combined with TKI served as an effective bridge therapy for ccRCC, metastatic to the thyroid. This approach allowed an initially non-resectable tumor to be managed to a point where surgical resection became a viable option. This case may pave the way for future protocols in treating similarly complex cases, potentially shifting paradigms in how certain oligometastatic cancers are approached and managed [3, 6, 8].

Ethical approval is not required for this study in accordance with national guidelines. The case report has been prepared in accordance with good clinical practice, and written informed consent was obtained from the patient for publication of this case report and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000541329).

The authors declare no conflicts of interest.

This project was funded by grants provided by the Swedish Cancer Society, Karolinska Institutet and the Stockholm County Council.

R.B., J.Z., and I.S. have contributed to the idea and conceptual design of the study. R.B. and C.C.J. have made the figures, and R.B., J.Z., I.S., M.L., and C.C.J. have contributed to the writing of the manuscript. All authors have approved the conclusions, figures, and the final version of the manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author (R.B.).