Cytoreductive Nephrectomy Following Immunotherapy for Metastatic Renal Cell Carcinoma and IVC Tumor Thrombus Arising from a Horseshoe Kidney

Abstract

INTRODUCTION:

Performing surgery for renal cell carcinoma (RCC) in patients with horseshoe kidneys presents unique anatomic challenges. The complexities of clinical decision-making and technical challenges are further compounded by the presence of both IVC tumor thrombus extension and metastatic disease.

CASE PRESENTATION:

We encountered the unique case of a 66-year-old woman with a horseshoe kidney who presented with a 14cm mass in her right kidney with level II tumor thrombus extension into the IVC, retroperitoneal lymphadenopathy, and pulmonary nodules that were biopsy-proven to be consistent with metastatic clear cell RCC (cT3aN1M1). She was treated with combination immune checkpoint inhibition (ICI) and targeted therapy upfront. Given her durable response to systemic therapy, we elected to perform a consolidative cytoreductive nephrectomy for residual ypT3aN0 disease, and she has since remained disease-free radiographically. Using step-by-step illustrative photographs obtained intraoperatively, we detail our surgical approach and highlight technical pearls to manage similar cases of advanced RCC arising from horseshoe kidneys.

CONCLUSION:

We present a complex case of metastatic RCC with IVC tumor thrombus arising from a horseshoe kidney. We share our clinical and technical approach to overcoming the medical and surgical challenges inherent to her case. The optimal role and timing of cytoreductive nephrectomy relative to ICI administration continue to evolve based on both tumor- and patient-related factors. Indeed, we favor a multidisciplinary approach to optimize patient outcomes.

INTRODUCTION

As the incidence of renal cell carcinoma increases over time, there has been an increased interest in identifying preoperative biomarkers that could be used for diagnosis and prognosis.^1,2 However, despite ongoing research, no liquid biomarkers in urine or serum have been identified that are both of prognostic value and are readily available for use in the clinic.²

Horseshoe kidney is the most common fusion anomaly in the genitourinary tract, caused by aberrant ascent and rotation of the developing kidneys during early gestation.¹ The fused isthmus connecting the left and right renal moieties typically causes incomplete ascent by anchoring the horseshoe kidney at the level of the inferior mesenteric artery (IMA) divergence from the abdominal aorta.² Several anatomic variations exist with respect to features such as renal vasculature, isthmus density, and collecting system duplication. Surgical management of renal cell carcinoma (RCC) in patients with horseshoe kidneys provides unique challenges and considerations with respect to this anatomic variability. These challenges include controlling accessory hilar vessels, adapting dissection for a malrotated and aberrantly located kidney, and sparing the contralateral renal moiety’s blood supply and collecting system during isthmus division in the case of a radical nephrectomy.^3–5 Further complexity is added in the setting of tumor thrombus vascular extension, which can be observed in 10–15% of RCC cases.⁶ A tumor thrombus can propagate into the inferior vena cava (IVC) and extend as far superiorly as the right atrium,⁷ necessitating coordination across different surgical disciplines for vascular reconstruction and even cardiopulmonary bypass in the most severe cases.

Management of metastatic RCC also requires a multidisciplinary team to ensure appropriate risk stratification, selection among an increasing number of systemic therapy options, surgical candidacy, and timing for cytoreductive nephrectomy.⁸ The advent of immune checkpoint inhibitors (ICI) has allowed for improved response rates for metastatic RCC and can yield durable responses when combined with cytoreductive nephrectomy.^9–13 However, the sequencing of cytoreduction and systemic therapy administration can vary based on factors such as metastatic burden, severity of symptoms, and overall disease risk as measured by validated models such as the International Metastatic RCC Database Consortium (IMDC) risk criteria.^14–16

We performed a deferred cytoreductive nephrectomy following receipt of systemic ICI in a patient with metastatic RCC and a level II IVC tumor thrombus arising from a horseshoe kidney. Herein we detail our surgical approach and highlight technical pearls to manage similar cases of advanced RCC arising from horseshoe kidneys. We also discuss the evolving role and feasibility of performing cytoreductive nephrectomy following systemic ICI for metastatic RCC.

Case Presentation

A 64-year-old woman with no remarkable medical history presented with one month of right flank pain, fatigue and hematuria. A CT abdomen/pelvis with IV contrast revealed a 14 cm heterogeneously enhancing right renal mass emanating incidentally from a horseshoe kidney with a tumor thrombus extending into the infrahepatic IVC (level II). She was also noted to have mild interaortocaval lymphadenopathy measuring just over 1 cm, and multiple pulmonary nodules measuring up to 1.5 cm (Figure. 1A, B). Her labs were notable for anemia (Hgb 8.8 g/dL). Her platelet count (358 K/μL), neutrophil count (6.3 K/μL), calcium (9.6 mg/dL) and renal function were all within normal range. Biopsy of one of the lung nodules revealed a poorly differentiated malignant neoplasm consistent with metastatic clear cell RCC. A brain MRI was negative for intracranial pathology.

Figure 1.

CT abdomen/pelvis with intravenous contrast imaging demonstrating a large renal mass in the right moiety of a horseshoe kidney measuring 11.2 × 10.3 × 13.7cm with tumor thrombus extension into the infrahepatic IVC. Images shown in axial and coronal views from initial presentation (A, B) and following immunotherapy just prior to surgery (C, D). Key structures identified by white asterisk (primary tumor), yellow arrow (isthmus), and blue arrow (IVC thrombus)

Following a multidisciplinary discussion, the patient was initiated on pembrolizumab and axitinib for intermediate-risk metastatic RCC per IMDC criteria. She was unable to tolerate this regimen due to mucositis and acute kidney injury and was transitioned to ipilumimab/nivolumab, completing four cycles. Following this course, interval imaging showed a decrease in the size of her renal mass from 14cm to 10cm as well as thrombus regression into the renal vein (Figure 1C, D). Her pulmonary nodules decreased in size (all <5 mm), and retroperitoneal lymphadenopathy remained stable. Given her favorable response, she was continued on maintenance nivolumab for 18 months amidst an ongoing multidisciplinary discussion regarding her candidacy for cytoreductive nephrectomy.

Given the resolution of her pulmonary metastases, shrinkage of the primary renal mass, and stability of her retroperitoneal lymphadenopathy while on maintenance nivolumab, we elected to offer her a cytoreductive nephrectomy, tumor thrombectomy, and lymphadenectomy.

1. Renal access and mobilization of the horseshoe kidney: Given the anticipated complexities in her case, we elected to perform her case in an open manner. As her horseshoe kidney was in a relatively inferomedial location, we gained access to her abdomen via a midline laparotomy incision from the xiphoid to just inferior to the umbilicus. We exposed the right kidney by medializing the right colon and sharply kocherizing her duodenum. We encountered and prospectively controlled numerous parasitic vessels around her right kidney, which were likely due to a combination of tumor angiogenesis and collateral drainage from her occluded IVC. The IVC was quite firm and diminutive, with evidence of complete thrombosis below the level of the renal vessels. There was also considerable edema surrounding the kidney, likely due to treatment effect from her ICI. We mobilized her horseshoe kidney, revealing a bulky isthmus connecting the lower poles of her kidneys at the midline just caudal to the IMA (Figure 2A). The anteriorly coursing right ureter was divided to optimize mobility of her kidney. We recommend fully mobilizing and clearing off the isthmus, including the lower pole of the contralateral kidney, to optimize exposure of the isthmus prior to division. We prefer using a Penrose drain to encircle the isthmus. We also recommend exposing the aorta as an important landmark, as ascent of horseshoe kidneys is classically halted by the IMA. In her case, we performed a concomitant regional retroperitoneal lymphadenectomy in the para-aortic, inter-aortocaval, and para-caval regions given her enlarged retroperitoneal lymph nodes.

2. Hilar control: Next, we individually isolated and ligated the main renal artery and accessory arteries (two in her case) with the assistance of vessel loops. We also encircled the main renal vein with a vessel loop. In the absence of thrombus, we typically recommend dividing the vein before the isthmusectomy to minimize back-bleeding and maximize renal mobility during division of the isthmus. In our patient’s case, the regressed and now fibrotic thrombus caused complete occlusion of her renal vein and IVC, so we elected to perform the isthmusectomy before managing the renal vein and IVC.

3. Division of the isthmus: Prior to dividing the isthmus, we recommend first identifying the extent of the contralateral collecting system using intra-operative ultrasound guidance to ensure that it is not violated during the isthmusectomy and to confirm the absence of tumor at the planned area of division. We also assess the thickness and vascularity of the isthmus to determine the optimal method of division. In cases in which the isthmus is diminutive, use of cautery, a vessel sealing device, or a vascular stapler may suffice. However, for bulkier or more vascular isthmuses we prefer to divide the isthmus in a controlled manner followed by oversewing the stump. Specifically, we use a Cosgrove flex clamp with Fogarty jaw inserts to clamp across the isthmus, erring towards the side of the contralateral kidney. We then divide the isthmus either sharply or with energy and oversew the residual isthmus stump with running suture, akin to a renorrhaphy performed during partial nephrectomy, prior to removing the clamp (in this case, we used 3–0 barbed suture; Figure 2B, 2C). As the blood supply to the right kidney was already ligated and the renal vein thrombosed, we did not encounter much bleeding from the right-sided isthmus stump.

4. Managing the regressed tumor thrombus: Together with our vascular surgery colleagues we assessed the right renal vein and suprarenal IVC, which appeared firm yet fibrotic and completely occluded. On incision of the renal vein ostium, there was no bleeding encountered from the IVC, and she had already developed extensive collateral venous flow, with alternative anatomic routes of venous drainage from her left kidney as well (gonadal vein, adrenal vein, lumbar vein). Thus, we divided and ligated her thrombosed IVC, with no residual viable tumor seen intravascularly. We submitted a frozen section from the IVC margin for pathologic assessment, which returned negative for malignancy. If viable IVC tumor thrombus is suspected, then at this point it would safe to proceed with the tumor thrombectomy in a manner similar to that performed in patients without horseshoe kidney. Once we ligated the IVC, we removed the entire specimen (right kidney with mass, adrenal gland, retroperitoneal lymph nodes, right renal vessels and thrombosed IVC) en bloc (Figure 2D) and completed the case in standard fashion.

Figure 2.

Intra-operative photo demonstrating (A) Penrose drain around U-shaped isthmus (yellow arrow), with right kidney exposed (white asterisk) [note: representative photo acquired from a separate case] (B) Isthmus just after division, anterior to the abdominal aorta (green arrow). Cosgrove clamp is on the left sided isthmus stump (black asterisk), now separated from the right kidney (white asterisk). (C) Divided isthmus anterior to aorta (green arrow) with exposed right kidney (white asterisk) and oversewn isthmus stump (yellow arrow) (D) Resected right kidney with stitch marking the IVC margin.

The final pathology revealed residual clear cell renal cell carcinoma (11cm in largest dimension), WHO/ISUP Grade 3, with extension into the renal sinus fat and into the renal vein (Figure 3). Resection margins, retroperitoneal lymph nodes, and the adrenal gland were all negative for carcinoma (ypT3aN0). The IVC lumen was obliterated by fibrosis without evidence of viable carcinoma. At six months post-operatively, she has continued to do well and remains disease-free radiographically.

Figure 3.

(A) Gross pathology photo demonstrating a well-circumscribed, tan-white, and nodular renal mass within the right kidney with gross obliteration of the renal sinus (arrow) and extensive areas of gross necrosis (asterisk). (B), Histopathologic images of the resected right renal moiety demonstrating a clear cell renal cell carcinoma with sheets and nests of cells with optically clear cytoplasm, distinct cell membranes, and an arborizing network of thin-walled vessels (H&E, 20x magnification). (C) Additional areas of necrosis seen in the tumor (H&E, 4x magnification). (D) Fibrous obliteration of the IVC in the regressed thrombus specimen seen histopathologically, with associated calcifications, acellular debris, and hemosiderin laden macrophages (H&E, 2x magnification).

DISCUSSION

Although horseshoe kidney is not inherently associated with an increased risk of RCC, surgical management of RCC arising from this renal fusion anomaly entails increased technical complexity. The emerging paradigm of systemic treatments with novel combinations of ICI and tyrosine kinase inhibitors (TKIs) has shown promise in improving patient selection for cytoreductive nephrectomy. In our patient’s case, given the favorable response of her metastatic disease to systemic treatment, cytoreductive nephrectomy is expected to provide a durable long-term response.

Performing a cytoreductive nephrectomy in a horseshoe kidney necessitates a thorough understanding of the vascular anatomy, which is facilitated by pre-operative multiphase cross-sectional imaging that includes intravenous contrast. Identification and separation of the isthmus, which can vary in location and thickness, is a crucial step of the operation. For a bulky parenchymal isthmus, intra-operative ultrasound can be especially helpful in confirming the absence of calyceal involvement at the planned division point. Regarding surgical approach, an open midline incision may best facilitate cytoreductive nephrectomy in the presence of a midline U-shaped isthmus and possible IVC involvement. However, minimally invasive robotic approaches have been described for localized renal masses in horseshoe kidneys.¹⁷ It has been demonstrated that minimally invasive approaches are safe and feasible for select cases involving horseshoe kidneys, including for partial and radical nephrectomy.^4,18 Benefits of these approaches include enhanced visibility and possibly decreased blood loss; however, adequate exposure of large tumors and aberrant vasculature may be more optimal with the open approach.¹⁹ Perhaps most important in complex cases of metastatic RCC in horseshoe kidneys is close collaboration among a multidisciplinary team of surgeons, medical oncologists, radiologists and pathologists.²⁰

The benefit of pre-operative systemic immunotherapy in this case was demonstrated by primary tumor shrinkage as well as significant response in her metastatic disease burden. In addition to facilitating surgical resection, the durable response to systemic therapy allowed for more appropriate patient selection for cytoreductive surgery. While it is reasonable to suspect that pre-operative ICI exposure allows for improved optimization of surgical resection for patients with adequate response to systemic therapy, the optimal sequencing of systemic immunotherapy and cytoreductive nephrectomy remains under investigation. Some have hypothesized the potential for increased efficacy of ICI while the primary tumor is in situ due to a higher number of neoantigens and increased tumor mutational burden, which has been associated with stronger responses to ICI.^21,22 Administering upfront ICI for those with higher-risk disease also has the advantage of expediting systemic exposure to therapy while assessing disease response to inform eligibility for deferred cytoreduction. Institutional series have demonstrated safety, feasibility, and generally favorable pathologic responses with performing cytoreductive nephrectomy following ICI.^12,23,24 Surgeons must, however, be mindful of the possibility of increased desmoplastic reaction and edematous tissue planes following longer durations of ICI, as seen in our patient’s case.²⁵ Reassuringly, ICI-induced treatment effect on surgical dissection planes generally does not increase the risk of major intraoperative complications outcomes or adverse oncologic outcomes.²³ Ultimately, patient selection remains paramount when optimizing individualized approaches to multimodal treatment in metastatic RCC.^14,26

Our patient’s regression of her tumor thrombus and subsequent thrombosis of her IVC is a notable hallmark of this case. Complete tumor thrombus regression in response to pre-operative ICI for metastatic RCC has been demonstrated in a prior report.²⁷ As shown in our case, ICI may provoke differential responses in the primary kidney tumor and the IVC thrombus. This may be explained by differences in the molecular landscape between primary tumors and tumor thrombi.²⁸ However, not all tumor thrombi are expected to respond to systemic therapy, and surgery remains the mainstay approach to treating non-metastatic RCC with IVC tumor thrombus extension. Surgical management of these cases must include preparation for extensive collateral venous flow when IVC thrombosis is suspected on pre-operative imaging. Consultation with vascular surgery colleagues can be helpful to determine appropriateness for IVC ligation versus reconstruction. Indeed, a multidisciplinary surgical approach can be helpful to optimize outcomes for complex nephrectomies.

CONCLUSION

Our unique case of successful cytoreductive nephrectomy with tumor thrombus management following systemic ICI in a patient with metastatic RCC arising from a horseshoe kidney highlights the importance of patient selection and multidisciplinary care teams, both for clinical decision-making and intra-operatively. We describe our preferred surgical approach that allows adequate exposure and control of the horseshoe kidney, hilar vasculature, and isthmus. The combination of ICI and targeted therapy will likely continue to play an important role in facilitating durable responses for patients with metastatic RCC, and deferred cytoreductive surgery remains a safe and feasible option even in patients with complex renal masses arising from horseshoe kidneys.