Clear cell renal cell carcinoma with stage IV cavoatrial tumour thrombus extension and rapid metastatic reoccurrence postsurgical treatment with review of current treatment strategies
- 1 Internal Medicine, UNC Health Southeastern, Lumberton, North Carolina, USA
- 2 Internal Medicine, Campbell University Jerry M Wallace School of Osteopathic Medicine, Buies Creek, North Carolina, USA
- 3 Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Correspondence to Dr Prathyusha Gudapati; prathyusha.gudapati@hotmail.com
Abstract
Renal cell carcinoma (RCC) is the most aggressive urological malignancy, with a high recurrence rate. Despite the rapid evolution of the treatment of RCC from non-specific cytotoxic therapies to specific novel combination therapies, the general prognosis for advanced RCC remains poor because patients’ responses to these therapies vary. Herein, we present the case of a male in early forties who was diagnosed with a right lower pole renal mass with a level IV tumour thrombus, which was later confirmed as stage IIIc clear cell RCC. About 19 months after radical nephrectomy (curative surgery), the patient was diagnosed with a biopsy-proven metastatic disease, which was not responsive to first-line treatment owing to insufficient data on the best treatment regimen. Herein, we also present a literature review on the pathological impact of genomic alterations in tumour suppressors and highlight emerging paradigm shifts in the treatment of RCC.
Background
Renal cell carcinoma (RCC) is the deadliest of urological malignancies, with one-third of patients developing metastatic disease and about 40% eventually dying from it.1 2 RCC has a unique predisposition for direct vascular invasion, with tumour thrombus frequently extending into the renal vein or inferior vena cava (IVC) in 10%–25% of patients.3 Intraluminal extension of the tumour thrombus into the right cardiac chambers (stage IV tumour thrombus) occurs in 1% of patients.4 Regardless of the histological subtype, radical nephrectomy results in complete remission with a mean overall survival rate of 5 years.4 RCC recurs after surgical treatment of locoregional disease in about 20%–40% of patients.2
Adenocarcinoma of the renal tubules is the classic histology of RCC. The most common histological subtype of RCC is clear cell RCC (ccRCC), which accounts for 75%–80% of RCCs and the majority of cancer-related deaths.5 6 ccRCC occurs sporadically, usually unilaterally, and has been linked to loss of function mutations in the von Hippel–Lindau tumour (VHL) suppressor gene on chromosome 3p.7 The elucidation of the role of the von Hippel–Lindau—hypoxia inducible factor (VHL–HIF) pathway in ccRCC pathogenesis has led to the development of highly specific novel combination therapies for the treatment of advanced ccRCCs. Despite these improvements, the prognosis for advanced ccRCCs remains poor because of a lack of data on the best treatment regimens and durations. Herein, we report a case of ccRCC with stage IV cavoatrial tumour thrombus extension that exhibited metastatic recurrence after curative surgery and was not receptive to highly specific novel combination therapy because of insufficient data on the best treatment regimen for poor-risk metastatic RCC with high tumour burden.
Case presentation
A man in early forties with a 1-week history of right-sided abdominal pain and urgency was presented. The associated symptoms were 25-lbs weight loss and progressive exertional dyspnoea over 4–6 months prior to presentation. He had no significant medical problems, but he had a 16-pack-year smoking history. He also had stable vital signs. After nephrectomy, the patient followed up for 6 months and then was lost to follow-up. About 19 months later, he arrived at the hospital with acute respiratory distress. His vital signs revealed tachycardia of 118, tachypnoea with a respiratory rate of 24, and oxygen saturation in the low 80s.
Investigations
The initial laboratory workup was grossly normal, except for normocytic anaemia with a haemoglobin level of 9.8 g/dL and haematocrit of 32.6%, as well as leucocytosis of 14.5 K/mm3 . Urinalysis revealed microscopic haematuria. The CT angiography (CTA) pulmonary embolism protocol showed no evidence of thromboembolism. However, the CT of the abdomen and pelvis revealed a large infiltrative right kidney mass (12×7 cm) associated with tumour thrombus extension from the right renal vein into the IVC (figure 1). His cancer was staged with a bone scan and MRI of the abdomen. The MRI of the abdomen revealed a level 4 vena cava tumour thrombus poking just into the right atrium. Surgical pathology revealed morphological and immunohistochemical features consistent with stage III ccRCC (pT3c, pN0, cM0). The patient’s germline DNA was tested using the Invitae 83 gene Multi-Cancer Panel. This test was positive for a variant of uncertain significance, c.1292 C>T (p. Pro431Leu), which was identified in telomerase reverse transcriptase (TERT).
Coronal view of contrast enhanced CT scan of the abdomen demonstrating tumour thrombus extension into inferior vena cava and cavoatrial junction (green arrow).
When he was presented 19 months later, his laboratory workup revealed an elevated alkaline phosphatase of 226 IU/L, normocytic anaemia with haemoglobin of 9.7 g/dL and haematocrit of 32.9%, neutrophilia with a neutrophil count of 12.4 K/mm3, leucocytosis with a white blood cell count of 17.1 K/mm3, and thrombocytosis. A CTA pulmonary embolism protocol was performed, and it revealed no evidence of PE but did reveal bilateral pulmonary nodules, which are indicative of metastatic disease (figure 2A,B). A CT scan of the abdomen and pelvis revealed a 5.9 cm hypodense mass within the right lobe of the liver (figure 3). There was no radiographic evidence of metastases to the other organs. The CT-guided liver biopsy was consistent with metastatic ccRCC and immunohistochemistry was negative for programmed death ligand-1 (PDL-1) expression. His cancer was staged as stage IV metastatic RCC with a poor risk because of neutrophilia, anaemia, thrombocytosis and a Karnofsky performance status of 50.
Axial view of contrast enhanced CT scan of the chest (CT angiography (CTA) PE) demonstrating metastatic disease to lungs (green arrows). (A) Lung window and (B) soft-tissue window.
Coronal view of contrast enhanced CT scan of the abdomen demonstrating metastatic disease to liver (green arrow).
Differential diagnosis
The presence of microscopic haematuria and the urgency pointed to a renal source. Based on the CT and MRI findings, the preliminary diagnosis was RCC with stage IV cavoatrial tumour thrombus extension. Other possibilities include adrenal carcinoma, Wilms’ tumour and hepatocellular carcinoma.
Treatment
The patient underwent an open right radical nephrectomy, IVC thrombectomy, interaortocaval and paracaval lymphadenectomy, IVC reconstruction and cardiac tumour resection with debulking after a cardiopulmonary bypass without deep hypothermic circulatory arrest. He was diagnosed with a right pulmonary artery embolism intraoperatively by transoesophageal echocardiography, and he also underwent a right pulmonary embolectomy. The surgical pathology revealed a grade 3 of 4 ccRCC, with extensive venous invasion, including renal vein and renal sinus invasions. At that time, three clinical trials with targeted therapies had been conducted, with two showing no benefit and one showing only a partial benefit. Owing to a lack of evidence for adjuvant immunotherapy at the time, a decision was made to closely monitor the patient with imaging every 3 months.
When the patient was presented 19 months later with poor-risk stage IV metastatic RCC, the decision was made to place him on ipilimumab/nivolumab doublet immunotherapy because it had the longest follow-up data. The following is the typical treatment regimen: day 1: nivolumab 3 mg/kg intravenous over 30 min and ipilimumab 1 mg/kg intravenous over 30 min every 3 weeks for four dosing cycles. Subsequently, day 1: nivolumab 240 mg intravenous over 30 min (repeat cycle every 2 weeks) or nivolumab 480 mg intravenous over 30 min (repeat cycle every 4 weeks) for a maximum of 35 cycles.
Outcome and follow-up
After initial treatment with curative surgery, the patient was symptomatically and radiographically disease free at 3 months and 6 months, respectively. The patient’s oxygen requirements progressively increased after a biopsy-proven recurrence, which was likely secondary to metastatic disease in the lungs. The patient developed severe acute respiratory distress while on supplemental oxygen approximately 2 months after that recurrence and 3 weeks after the oncology visit; this required intubation. He passed away in the intensive care unit from respiratory failure, which, in the absence of lab or imaging findings indicating another aetiology, was likely due to worsening metastatic disease in the lungs.
Discussion
The incidence of ccRCC has steadily increased over the last two decades. The risk factors for ccRCC development are the same as those for RCC, and they include cigarette smoking, obesity, hypertension, renal transplant, acquired cystic disease and VHL syndrome.8 However, the classic triad of flank pain, haematuria and flank mass is relatively rare. Radical nephrectomy is considered curative for non-metastatic ccRCCs. However, the recurrence rate of ccRCC after curative surgery remains high during the first 5 years. The median recurrence time after nephrectomy is 38 months for T1 tumours, 32 months for T2 tumours and 17 months for T3 tumours. Surveillance protocols following nephrectomy recommend laboratory tests every 6 months starting 1 month after nephrectomy, a chest radiograph every 6 months starting at 6 months after nephrectomy, and an abdominal CT scan at 12, 24 and 48 months after nephrectomy.2 Advanced ccRCC treatment remains a clinical challenge because of its ability to mediate immune dysfunction and intrinsic radiobiological properties that provide radio resistance.9 10 However, owing to recent advancements, several treatment options for advanced ccRCC have become available, with the ultimate goal of a complete cure. Recent advances in high-throughput genomic sequencing have led to the discovery of RCC-related genomic alterations that cause the malignant transformation of somatic cells. These genomic alterations may have clinical significance as prognostic markers and may aid in the treatment regimen optimisation in both primary and metastatic RCC.
Genomic alterations in ccRCC and their role as predictive and prognostic biomarkers
Functional loss of the VHL tumour suppressor gene is strongly associated with the development and pathogenesis of both hereditary and sporadic ccRCCs through the dysregulation of the hypoxia inducible factor (HIF) pathway. Consequently, ccRCC is highly vascular because of the dysregulation of angiogenesis. Loss of function mutations in other tumour suppressor genes, such as Polybromo1 (PBRM1), SET domain containing 2 (SETD2), and breast cancer gene 1-associated protein 1 (BAP1), have also been linked to the pathogenesis of non-metastatic ccRCCs.4 However, preliminary retrospective studies have linked loss of function mutations in tumour suppressor genes, such as VHL, PBRM1, SETD2, BAP1, lysine demethylase 5C (KDM5C) and TERT promoter mutations, to the development of metastatic ccRCC.11 12 These studies have also linked TERT and BAP1 promoter mutations that are mutually exclusive to poor prognoses. Furthermore, TERT mutations may also be linked to an aggressive disease course, with reported median overall survival rates of 29.6 months for TERT mutants and 52.6 months for wildtype TERT tumours.11 13 Several studies have explored the role of these mutations as predictive biomarkers in patients with metastatic RCC, and it was discovered that patients with PBRM1 mutations benefited from both vascular endothelial growth factor (VEGF)-directed therapy and immunotherapy.14–17 However, there are currently limited data on the roles of other mutations as predictive biomarkers and the roles of VHL, PBRM1, SETD2, BAP1, KDM5C and TERT mutations as prognostic biomarkers.
Treatment strategies
Conventional cytotoxic therapies have been shown to be ineffective in all RCC subtypes. Conversely, systemic interferon-gamma and interleukin 2 therapies have been limited in their usage because of their severe and widespread toxicities. This, combined with an improved understanding of the molecular biology of ccRCC, has resulted in drastic changes in the treatment landscape, including the development of molecularly targeted agents that target the VHL–HIF pathway. These agents inhibit tumour hypervascularity associated with the loss of function mutations in the four tumour suppressor genes by targeting the VEGF receptor.1 7 18 This antiangiogenic tyrosine kinase inhibitor (TKI) therapy has been the mainstay of treatment for several years. However, recent studies have revealed that the loss of VHL function alone is insufficient for HIF activation. Moreover, the development of ccRCC requires the occurrence of a second driving event, such as the loss of PBRM1. The concurrent loss of VHL and PBRM1 was shown to activate the signal transducer and activator of transcription 3 (STAT3) pathway in murine models, making tumours susceptible to immune regulation.19 The discovery of these oncogenic signalling pathways, as well as their interactions with tumour microenvironments and intrinsic signalling in tumours, ushered in immune checkpoint inhibitor therapies/immunotherapies. Additionally, cancer genome atlas comprehensive genetic analyses have revealed alterations in mammalian target of rapamycin (mTOR), phosphatase and tensin homolog, and phosphatidylinositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha in a subset of patients with ccRCC.20 This knowledge revealed that ccRCC progression can be inhibited by targeting the mTOR pathway with everolimus and temsirolimus.
Although immunotherapy induces long-lasting responses through the generation of anti-tumour memory cells, it requires a long time to achieve potent cytotoxicity. In contrast, targeted therapies can induce rapid tumour regression. Targeted therapies assist immunotherapy in consolidating anti-tumour responses by targeting multiple antigens through the generation of large antigenic debris from triggered tumour cell death, thereby increasing their potency.16 21 22 Thus, targeted therapies and immunotherapies work synergistically by targeting complementary pathways. Moreover, they can be administered at lower doses when used in combination than when used alone, limiting systemic cytotoxicity. Several studies have explored the synergistic effects of combination therapies in the treatment of metastatic ccRCC. These studies discovered that the combination of these therapies increased anti-tumour activity and improved outcomes and overall survival rates in patients with metastatic ccRCC. Clinical trials, such as CheckMate 214, Keynote 426, and Javelin Renal 101, compared the efficacy of VEGF-directed targeted therapy combined with immunotherapy and doublet immunotherapy to that of sunitinib (TKI), the gold standard first-line option for patients with mRCC. This resulted in the approval of three combination therapies independent of PDL-1 expression, which include ipilimumab–nivolumab (doublet immunotherapy with a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor and a programmed cell death protein 1 (PD-1) inhibitor), pembrolizumab–axitinib (a PD-1 inhibitor plus TKI), and avelumab– axitinib (a PDL-1 inhibitor plus TKI).23 However, the data on PDL-1 expression as predictive biomarker of immunotherapy, best regimen, best duration, comparative efficacies, long-term toxicities, and quality of life are still limited and require further investigation. The lack of a head-to-head comparison between the three approved treatment regimens and the significant differences in the patient populations of these studies also create a significant clinical challenge in determining the best regimen for patients. However, indirect analysis of data from these trials suggests that VEGF-directed targeted therapy and immune checkpoint inhibitor combination therapy (pembrolizumab and axitinib) are enhanced in terms of overall response, progression-free survival, and overall survival rates, regardless of international metastatic RCC database consortium risk, thus offsetting the chronic toxicity associated with targeted therapies.24 25
In the clinical setting, treatment regimens are currently chosen based on side effect profiles, perceived treatment benefits, and oncologist/patient preference rather than clinically validated regimens. Doublet immunotherapy had the longest follow-up data, and patients were kept on nivolumab monotherapy after four cycles, with no risk of chronic toxicities reported in the targeted therapies. However, poor-risk patients with significant tumour burden, such as our patient, may benefit from targeted therapy and immunotherapy combination because targeted therapy works almost immediately to induce rapid tumour regression, providing a favourable window for immunotherapy to achieve its maximal potential. In conclusion, our case demonstrated that choosing the best combination regimen is crucial for achieving clinically significant favourable outcomes in patients with metastatic ccRC.
Patient’s perspective
I want to undergo treatment to have some more time to do things I enjoy and proceed with my wedding in 3 months as planned. After my first treatment, I did not have any symptoms and was able to lead a relatively normal life. So, I am hoping this treatment will help reduce the symptoms I am experiencing and buy me some more time. I realize I may not benefit from the treatment but I want to give it a shot
Learning points
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Radical nephrectomy and/or inferior vena cava thrombectomy remain the standard treatment for non-metastatic clear cell RCC (ccRCC).
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Cytoreductive nephrectomy and/or metastasectomy with or without adjuvant therapy remain the standard of care in limited metastatic ccRCC.
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Systemic therapy with a combination of vascular endothelial growth factor (VEGF)-directed targeted therapy and immunotherapy or doublet immunotherapy is now the first line of treatment for metastatic ccRCC.
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VEGF-directed targeted therapies that can induce rapid tumour regression provide a favourable window for immune checkpoint inhibitor therapy to achieve clinically significant and long-lasting antitumour responses.
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Combination therapy using VEGF-directed targeted therapies and immune checkpoint inhibitors may provide favourable outcomes in patients with high tumour burden in poor-risk metastatic ccRCC.
Ethics statements
Patient consent for publication
Acknowledgments
The authors would like to thank Dr Hau Bui for helpful discussions.
Footnotes
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Contributors PG performed literature search, drafted, formatted and reviewed the manuscript. She was involved with patient care as an inpatient, and sought his consent for publication. MA suggested pertinent modifications and approved the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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