Perspective Chapter: An Update on Renal Cell Carcinoma

Abstract

Incidence and mortality of renal cell carcinoma (RCC) significantly vary worldwide. While RCC incidence has been increasing, its mortality rate has been decreasing. Smoking, obesity, hypertension, chronic kidney disease (CKD), ethnicity, location, and other environmental factors are reported to be associated with RCC. With the use of the improved diagnostic methods, including ultrasound, contrast-enhanced ultrasound (CEUS), computed tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT scan, the detection rate of RCC has significantly increased over the past decade. We have witnessed innovation in surgical techniques and robotic platforms with integration of imaging approaches, and urologists are now able to maximize functional and oncologic outcomes in nephron preservation and complication-free recovery. Thus, the paradigm in the surgical treatment of RCC has transformed and will continue to change in the future. In addition, targeted therapy, immunotherapy, and combination therapy are adopted to treat patients with advanced RCC. In recent years, the combination of immune checkpoint inhibition and antiangiogenic therapy is a very attractive combined therapeutic strategy for advanced/metastatic RCCs. Biomarkers, including epigenetic markers for RCC, have been increasing, which will be helpful to discover new therapeutic targets and related inhibitors for the treatment of advanced RCC.

1. Introduction

Kidney cancer has been known to have distinct histological types with different genetic profiles. The most common type is renal cell carcinoma (RCC), representing more than 90% of all kidney cancers [1]. RCC is consisted of a few subtypes. The most common subtype is clear cell renal cell carcinoma (ccRCC), followed by papillary RCC (pRCC, type I and type II), chromophobe RCC (cRCC), collecting duct carcinoma (CDC), etc. Kidney cancer is the sixth most common malignant disease in men and tenth in women. It accounts for 5% of male and 3% female malignancies [2, 3]. The RCC incidence is constantly rising as well. In urology, kidney cancer is the third most common malignant disease. While kidney cancer occurs mostly in North American and European, the incidence of renal cancer is relatively lower in Asian [4]. Based on the global cancer statistics in 2020 [5, 6], there were an estimated 431,300 people diagnosed with kidney cancer and approximately 179,400 deaths worldwide in 2020. It was recently estimated that there were 81,800 new kidney cancer cases and 14,890 deaths in the United States in 2023 [7]. Diagnosis of RCC at early stages is crucial in treating patients and improving survival rates. With the application of improved diagnostic techniques such as cross-section abdominal imaging [8], the detection rate of RCC has increased in recent years [9]. Choosing the best therapeutic strategy is essential for improving the outcome of patients with RCC.

2. Epidemiology of RCC

RCC is the most lethal urogenital cancer, accounting for 2–3% of all cancers. The incidence of RCC is continuously rising worldwide, and it is higher in developed countries compared to developing countries, and higher in men than women (male to female ratio is 1.5:1). The mortality rate of RCC is 30–40% and is higher in men compared to women [3]. The majority of RCC patients are aged over 60 years. Since the advance in diagnostic methods and public consciousness of the importance of periodic health screening, the number of RCC patients diagnosed in the early stages keeps increasing. Thus, the incidence of RCC has been rising as well in the past three decades [9]. Even though, the mortality rate of RCC has been constantly decreasing, especially in developed countries, due to early therapy and progress of the therapeutic strategies [10]. However, despite the improvement in disease control and increased survival rate, metastases are often observed in many RCC patients [11]. As reported, 30–50% of patients with local RCC progress to metastasis. In addition, metastasis was observed in 20–30% of the RCC patients at the early stage of diagnosis, and nearly 40% of the patients with localized RCC tumors presented distant metastases even after surgery. The most common distant metastatic sites are the lungs, bones (vertebrae, proximal part of the femur, pelvic bones), lymphatic nodes brain, liver, the opposite kidney, and suprarenal glands [12]. The patients with RCC metastases suffer from pain, nerve compression, hypercalcemia, and pathological fractures. The occurrence of metastases often worsens the patients’ prognosis [13]. The median survival for patients with RCC metastases is approximately 8 months and the mortality rate is 50% during the first year, and 10% for 5 years survival [10, 13, 14].

3. Risk factors associated with RCC

While age and gender are strongly associated with increased RCC incidence, hypertension, smoking, obesity, ethnicity, location, and history of using tobacco products increase the risk of RCC as well [3]. It was reported that smoking could increase the risk by about 54% in men and 22% in women. Smoking time and the daily number of cigarettes are directly associated with kidney cancer incidence for both men and women. In addition, some minor risk factors that may be related to RCC include acquired renal cystic disease, chronic kidney disease (CKD), end-stage renal disease (ESRD), exposure to cadmium and trichloroethylene, consumption of red and processed meat, chronic use of palliatives, type-2 diabetes, vitamin D level, viral hepatitis, increased triglycerides, decreased physical activity, and genetic syndromes [15]. Patients with renal insufficiency and in the terminal stage of the disease are four times more likely to develop kidney cancer. Measures of preventing RCC include smoking cessation, and reducing of the body mass index (BMI), etc.

4. Pathophysiology of RCC

Since RCC is a heterogeneous cancer that may stem from different type of renal cells, histological subtyping of RCC may exert a crucial impact on the choice of therapeutic strategies and prognosis. Based on the histological features, RCC is divided into 16 subtypes, including clear cell RCC, pRCC (type I and II), cRCC, collecting duct RCC, multilocular cystic RCC, medullary carcinoma, mucinous tubular, spindle cell carcinoma, neuroblastoma-associated RCC, Xp11.2 translocations—TFE3 carcinoma, hereditary cancer syndromes, and unclassified lesion [16]. Of them, clear cell RCC is the most common subtype of RCC and accounts for 75–85%. The second most common one is pRCC that constitutes 10–15%. cRCC ranked third and represents 3–5% of kidney cancers. Both clear cell carcinoma and pRCC are thought to stem from the proximal tubule, while chromophore RCC originates from the distal connecting tubules (DCT) and collecting duct system, especially the intercalated cells [17]. While most clear cell RCCs are sporadic, approximately 5% of the clear cell RCC is hereditary, and usually related to hereditary syndromes such as Von Hippel–Lindau disease (VHL) and tuberous sclerosis (TS). Clear cell RCC tends to metastasize to the lymph nodes, the lungs, the liver, and bones. Clear cell RCC has poorer prognosis compared to pRCC and cRCC. On the basis of histological and genetic differences, pRCC is further divided into two subtypes: type I and type II. The type I pRCC cannot be distinguished from type II through routine imaging techniques. Papillary type I can be detected at an early stage, and thus has a better prognosis compared to type II. cRCC is commonly observed in patients aged more than 60, and less aggressive compared to clear cell RCC. Therefore, cRCC has the best prognosis among all RCCs [4].

5. Genetics of RCC

The first categorization of kidney cancer based on molecular genetics was conducted by Heidelberg in 1997, and it was adopted in the WHO tumor classification of 2004, 2012 Vancouver ISUP [18], and the latest RCC classification of the WHO (2016) [16]. RCC has various genetic alterations, including gene mutations, epigenetic modifications, and chromosomal aberrations. While genetic alterations can cause both sporadic and hereditary types, patients with familial history (hereditary) represent only 3% of all kidney cancer cases. An increased number of RCC-related genes were identified in the past decades. Considering its high genetic heterogeneity, RCC can be caused by mutations in many genes and chromosomal abnormalities. Each subtype of RCC has its corresponding affected genes [19]. Clear cell RCC-related genes include VHL, PBRM1, BAP1, STED2, JARID1c, FLCN, and c-MYC. VHL mutations account for approximately 60% of clear cell RCC [20]. In addition, exome-sequencing has revealed that PBRM1, SETD2, BAP1, and JARID1c are associated with RCC as well (PBRM1, 40%, SETD2, 12%, BAP1,10%, and KDM5C,5%) [21]. Combinational mutations of the above genes were also detected in many clear cell RCCs. With the advent of new genetic tools, more RCC-related genes/biomarkers might be uncovered. pRCC is divided into two types: Type I and Type II. Although pRCC type I and type II are morphologically similar, they are cytologically different. Compare to pRCC II, pRCC type I has a low-grade tendency and better prognosis [22]. pRCC I is often caused by overexpression of the MET gene on chromosome 7q31, while pRCC II is less correlated to MET overexpression but associated with alterations in FH, CDKN2A, SETD2, BAP1, PBRM1, FLCN, NRF2-ARE, TERT, TFE3, and increased expression of NF2 [23, 24]. cRCC is a relatively rare type of RCC that originates from the distal convoluted tubule. cRCC is associated with mutations in PTEN, TP53, mTOR, c-kit, FAAH2, PDHB, PDXD1, ZNF765, PRKAG2, ARID1A, and ABHD3. Of them, PTEN mutation is the most common event in cRCC [25]. In addition, mutations in FLCN appear to cause all types of RCC in Flcn knockout mouse models [26, 27].

Chromosomal aberration is also a common feature in RCC [28]. In clear cell RCC, the loss of the short arm of chromosome 3 is the most frequently occurred event, which is related to the loss of the VHL gene located on 3p [28, 29]. Other chromosomal aberrations include loss of chromosome Y, gaining 5q31, 8q, 4p, 14q, 9p, and trisomy of chromosome 7. Patients with gaining of 4p, 9p, and 14q have poor prognosis while gaining 5q31 is connected with prolonged survival in high-grade clear cell RCC. Deletion of the Y chromosome usually leads to clear cell RCC with distant metastasis. In addition, gaining chromosome 8q can cause metastasis of clear cell RCC, which may be associated with overexpression of C-MYC. For chromosomal abnormity, pRCC type I is also different from papillary type II. Trisomy of chromosomes (e.g., 3q, 7, 8, 12, 16, 17, 20) commonly appears in type I pRCC. In addition, loss of chromosome Y is an important feature of papillary type II in men. In contrast, gaining a chromosome 8q and losing 1p and 9p are frequently observed in RCC papillary type II. cRCC is also associated with chromosome aberrations, including loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 [20]. Losing copies of chromosomes 1, 2, 6, 10, 13, and 17 are more commonly observed in the classical type of cRCC than the eosinophilic type [30]. In addition, gaining chromosome copies (e.g., 4, 7, 11, 12, 14q, and 18q) is related to cRCC as well [31].

6. Clinical diagnosis of RCC

Since small RCC masses are usually asymptomatic, the majority of RCCs are accidentally detected by routine imaging for various medical screening purposes [32]. Patients diagnosed with RCC based on the symptoms account for only 30%, and approximately 20–30% of the patients present metastasis at the time of diagnosis. Flank pain, hematuria, and abdominal mass are usually considered as the classic symptoms for RCC diagnosis, but these symptoms are observed in only 4–17% of the cases. Other symptoms for diagnosis include fever, abdominal pain, anemia-induced fatigue, weight loss, bone pain, and cough caused by metastasis of cancer cells or lower limb edema, peripheral lymphadenopathy (LAP), and varicocele caused by inferior vena cava (IVC) or renal thrombosis [33]. Once signs and symptoms appear, further laboratory investigation should be performed. The laboratory investigation includes renal function tests, complete blood cell count (CBC), liver function tests, urinary analysis, thyroid function tests, and examination of the level of calcium, lactate dehydrogenase, and alkaline phosphatase.

Various preclinical imaging modalities are valuable tools for detecting renal masses. These imaging modalities include ultrasound, CEUS, computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, etc. Many renal masses and benign cystic kidney lesions can be easily detected with ultrasound [34]. In addition, as an inexpensive and accurate imaging approach, contrast-enhanced ultrasound (CEUS) has been adopted to evaluate indeterminate renal lesions, though it may not effectively discriminate between malignant and benign renal masses. For more accurately identifying malignant masses, CT scan or MRI is required [35]. In some cases, both CT and MRI should be performed by contrast because contrast absorption is a key factor in determining malignant masses [36]. For small lesions (1–2 cm) and in cases of renal insufficiency, pregnant women, and patients allergic to contrast material, MRI should be conducted [37]. The primary purpose of imaging is to inspect the characteristics of the affected mass, identify possible abdominal metastases, mass expansion, and venous involvement for staging. PET scan, is not a standard scan strategy, is very helpful in the diagnosis and follow-up of RCC. Thus, routine use of PET/CT is also recommended [38]. Other imaging approaches, including advanced MRI techniques or the combination use of iodine PET and CT, may be performed to determine renal masses [39]. In addition, biopsy and histopathology are required to carry out in suspected masses before further treatment.

7. Treatment and management of RCC

To date, surgery is still an essential treatment for RCC, and RE nephrectomy has been regarded as the standard of care for the management of renal tumors. For small renal lesions and surgery-induced chronic kidney disorders, active surveillance of nephron surgery and minimally invasive approaches have been adopted to limit the invasion and loss of kidney function in clinical [40]. RCC patients with severe comorbidities, elderly patients with small tumors ≤4 cm, or patients with a short life expectancy are recommended for active surveillance [41]. In some cases, active surveillance is also suggested to monitor the rate of the large tumor’s growth. In addition, imaging can be performed for active surveillance in the first half year, and then, every 6 months at 2–3 years, and later, annually [42]. In addition, for treating small randomly detected tumors, minimally invasive procedures should be used. Cryotherapy (CRYO) and radiofrequency ablations (RFA) were suggested for patients with only one kidney or for those unable to undergo major surgery.

7.1 Nephron preservation surgery

While radical nephrectomy is the removal of the entire kidney and is suitable for patients with larger renal tumors (T2, >7 cm), nephron-sparing partial nephrectomy only removes the small localized renal tumor (T1, <7 cm) and preserves the parenchyma. Thus, in most cases including locally advanced and metastatic diseases, nephron-sparing partial nephrectomy is recommended except for those that technically impossible to be removed due to their unfavorable location.

The advent and improvement of robot-assisted surgical approaches and robotic platforms have helped to close the technical gap and allow for greater adoption of the laparoscopic approach and nephron-sparing surgery, leading to a revolution for surgical management of RCC in recent decades [43, 44]. As the use of robotic platforms combined with imaging techniques in surgery, larger, higher stage, and more complex renal lesions can now be treated in a minimally invasive fashion, which leads to decreased morbidity, shortened patients’ hospitalization, and less side effects [45, 46]. Robot-assisted surgery has continued to evolve and has been playing an ever-expanding role in the treatment of RCC worldwide [45]. Laparoscopic partial nephrectomy and robot-assisted partial nephrectomy are becoming the standard treatment for patients eligible for nephron-sparing surgery. While the nephron-sparing surgery has been endorsed as the gold standard treatment of T1a tumors ≤4 cm in size and T1b lesions in the United States and Europe when technically possible with experienced surgeons [41, 47], robot-assisted partial nephrectomy has been adopted for treatment of cT2 RCC [48]. While new robotic platforms such as single-port (SP) robotic surgical system and multiport robotic surgical systems are currently under development, the popular da Vinci platform has significantly expanded the laparoscopic paradigm spectrum in the surgical treatment of RCC [49, 50, 51].

7.2 Cytokine treatment of metastatic disease

Before targeted therapy, patients with metastatic clear cell RCC were previously treated with immunosuppressive agents such as INFα and IL2, namely systemic therapy. In 1990s, systemic therapy with a high-dose IL2 turned into a commonly used modality for various cancer patients with metastasis. However, complete response was only observed in <10% of patients treated with a longer high dose of IL-2. It simultaneously caused severe toxic effects. Thus, high-dose IL2 treatment is not recommended for patients with metastatic RCC unless the patients are young and in very good conditions with low tumor volume [52].

Aldesleukin and INFα (along with Bevacizumab) are the only safe modulating drugs that are approved in selected metastatic RCC. INFα is adopted to treat RCC patients in various formulas with a response rate of 10–15% and a response time of 4 months. Patients who benefit from INF treatment were then subjected to nephrectomy. Although INFα treatment shows some efficacy in the treatment of patients with metastatic RCC, it is not suggested for treating RCC patients as a single drug.

7.3 Targeted therapy and immunotherapy of metastatic RCC

In the past decades, the most significant advance in the therapeutic strategy of metastatic RCC has been the development of treatments that specifically target the RCC-related biological pathways and related biomarkers [53, 54]. In the 1990s, cytokines, such as IFNα and IL-2, were used to treat metastatic clear cell RCC (Figure 1). In the 2000s, targeted therapies that target the VEGF/PDGFR/mTOR pathways replaced the cytokine therapies. In the targeted therapies, tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of metastatic RCC, which was used as the first line and the second line treatment options. To date, five TKIs (e.g., cabozantinib, axitinib, pazopanib, sorafenib, and sunitinib) have been approved internationally for the targeted therapy of metastatic RCC (Figure 1). Cabozantinib targets the tyrosine-protein kinase receptor UFO and the MET receptor tyrosine kinase. Pazopanib targets the VEGFR, while axitinib inhibits VEGFR with improved specificity, sorafenib an multi-kinase inhibitor, inhibits RAF-1, B-RAF, VEGFR-2, VEGFR-3, PDGF-β, KIT, and FLT-3. Sunitinib targets VEGFR2(Flk-1) and PDGFR-β. Whereas, lenvatinib suppresses VEGFRs and fibroblast growth factor receptors [55, 56]. In addition, temsirolimus and everolimus, two mTOR inhibitors, have been approved for the treatment of advanced RCC as well. Bevacizumab, an anti-VEGF monoclonal antibody, is approved for the treatment of advanced RCC when it is used in combination with INF. In 2015, nivolumab, an anti-PD-1 immune checkpoint inhibitor that prevents signaling through programmed cell death 1, has been approved for the first immunotherapy agent of metastatic RCC [57]. Later, ipilimumab, an anti-CTLA-4 monoclonal antibody, in combination with nivolumab was approved for the first-line treatment of advanced RCC [20, 58]. Recently, increasing attention has been paid to the combination therapy. The latest combination therapy strategies such as axitinib–avelumab (target VEGF and immune checkpoints) [59, 60], axitinib–pembrolizumab (target VEGFR) in combination with PD-L1 and PD-1, respectively, have been used to treat metastatic RCC. To date, immune checkpoint inhibition plus antiangiogenic therapy constitutes a very promising combined therapeutic strategy for advanced/metastatic RCCs.

Figure 1.

Development of approved anti-RCC agents.

In addition, some epigenetic markers have been proposed as promising epigenetic RCC markers based on DNA methylation, ncRNA expression, and histone modification [61, 62, 63]. Many epigenetic markers and epigenetic modifiers are likely candidates for clinical use, but further validation is needed [63, 64]. The development of epigenetic therapies, either alone or in combination with antiangiogenic agents and/or immune-checkpoint inhibitors, is a hopeful therapeutic strategy for RCC.

8. Conclusion

RCC accounts for 4%of all malignant tumors. In urology, RCC is the third most common malignant tumor. Risk factors include positive family history, smoking, obesity, high blood pressure, etc. Although most cases of RCC are diagnosed accidentally, the improvement in diagnostic approaches has increased the detection rate over the past decades. Many RCC-related genes and predictive biomarkers are being identified and may further improve the diagnosis of RCC. In addition, choosing the best therapeutic strategy is critical to improve the outcome of RCC. The tumor size, the stage of the disorder, and the surgeon’s experience are the determinant impact factors in the choice of the optimal treatment approach. While the open surgery is still reserved for locally advanced diseases, it is gradually displaced by robotic-assisted partial nephrectomy. Although the optimal first-line treatment, including targeted therapy, immunotherapy, or combined therapy for metastatic RCC may differ by clinical risk group and efficacy endpoint, the first-line treatment landscape for metastatic RCC is rapidly evolving. Thus, knowledge of the latest advances in the diagnosis and management of RCC could assist the related researchers, physicians, and nephrologists, to better diagnose and treat RCC.