Renal Cancer

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Introduction   

Renal cancer, referred to as kidney cancer, originates in the tissues of the kidneys, which are vital organs responsible for filtering waste from the blood and producing urine within the human body [1]. The most prevalent type of renal cancer is renal cell carcinoma (RCC), accounting for about 90% of cases [2]. Often, multiple tumors may develop in one or both kidneys and can be large by the time of diagnosis. RCC accounts for over 2-3% of all adult malignancies and is the most lethal urologic cancer [3].  

The 5-year survival rate for RCC varies by histologic type and metastatic potential, with clear cell RCC often metastasizing to the lungs and chromophobe RCC spreading to the liver. Based on data from individuals diagnosed with cancers of the kidney (or renal pelvis) between 2013 and 2019, the 5-year relative survival rates are as follows: For localized cancer, the survival rate is 93% [4] [5]. Regional cancer rates drop to 74% [4] [5]. For distant cancer, the survival rate is significantly lower at 17% [4] [5]. When combining all SEER stages, the overall 5-year relative survival rate is 78% [4] [5]. 

Early detection and diagnosis improve prognosis when identifying cancer at a localized stage. The kidneys, two bean-shaped organs located in the middle to lower part of the back on either side of the spine, filter waste and excess fluid from the blood [14]. This waste exits the body as urine through tubes called ureters to the bladder, and then through the urethra. Besides filtering waste, the kidneys regulate blood pressure and maintain adequate red blood cell levels.  

Renal cancer presents with symptoms such as hematuria (blood in the urine), flank pain, and a palpable mass in the abdomen or side [6] [7]. However, many cases are asymptomatic and discovered during imaging studies for other conditions. Treatment options depend on the stage and grade of the cancer and may include surgery, targeted therapy, immunotherapy, and radiation therapy. Advances in understanding the molecular and genetic underpinnings of renal cancer continue to enhance diagnostic and therapeutic strategies, offering hope for improved patient outcomes.  

Case Study: Renal Cell Carcinoma in a 64-Year-Old Male 

A 64-year-old male with a past medical history of nephrolithiasis, voiding dysfunction, hypertension, and a 30-pack-year smoking history presented to the emergency department (ED) with complaints of hematuria. He also reports intermittent flank pain and unintentional weight loss of 15 pounds over the past six months. Physical examination reveals a palpable mass in the right abdominal region. Weeks prior, he presented to a neighboring hospital with the same primary complaint, where doctors found him anemic and required a transfusion. During that visit, doctors discovered a right renal mass and referred him to a urologist, but he failed to follow up. Over time, he experienced widespread weakness, fatigue, and discomfort, along with swelling in his left side and abdominal area. 

On initial presentation to the (ED) and examination, the patient’s vital signs were as follows: blood pressure of 119/77 mmHg, pulse rate of 90 bpm, temperature of 98.6°F, respiratory rate of 17 breaths per minute, and oxygen saturation of 100% on room air. He was afebrile. Physical examination reveals pallor, a soft and distended left midline/lower abdomen, and tenderness to palpation (TTP) in the left flank, with normal bowel sounds. 

The laboratory findings reveal significant abnormalities. The complete blood count (CBC) showed leukocytosis with a white blood cell count of 15,000/µL (normal range: 4,500-11,000/µL), anemia with a hemoglobin level of 9 g/dL (normal range: 13.8-17.2 g/dL), and thrombocytosis with a platelet count of 500,000/µL (normal range: 150,000-450,000/µL). These results suggest an underlying inflammatory process or malignancy. The basic metabolic panel (BMP) shows an elevated creatinine at 2.1 mg/dL (normal range: 0.6-1.2 mg/dL) and blood urea nitrogen (BUN) at 30 mg/dL (normal range: 7-20 mg/dL), indicating renal dysfunction or impairment associated with renal cancer. 

The diagnostic workup began with an initial ultrasonography, which indicated a suspicious mass in the right kidney. This prompted further evaluation with a CT scan, which confirmed the presence of a large, irregularly shaped mass consistent with renal cell carcinoma (RCC). The biopsy identified the mass as clear cell renal cell carcinoma (CCRCC), the most common subtype of RCC. Additional imaging, including a chest CT, revealed metastasis to the lungs. The treatment plan included a radical nephrectomy to remove the affected kidney, adrenal gland, and surrounding tissues. Post-surgery, doctors initiated targeted therapy with sunitinib, a tyrosine kinase inhibitor, to manage metastatic disease [8]. The medical team also included immunotherapy with a T-cell checkpoint inhibitor to enhance the immune response against cancer cells and regular follow-up visits, with abdominal imaging every six months and chest CT scans to monitor lung metastasis [28].  

The primary outcome goals were to prolong progression-free survival and improve overall patient outcomes. Despite the advanced stage of RCC, the combination treatment offered a hopeful prognosis, leveraging recent advancements in RCC management. 

This case highlights the importance of early detection and comprehensive management of renal cell carcinoma (RCC). Well-timed diagnosis, surgical intervention, and advanced therapeutic strategies influence the patient’s prognosis and treatment success. Continued advancements in understanding the molecular and genetic underpinnings of RCC are essential in improving diagnostic accuracy and developing more effective treatment protocols for patients with renal cancer. 

The Cell Growth and Death Cycle 

Cancer arises when cells in the body undergo rapid abnormal growth [9]. The cycle of cell growth and death, also known as the cell cycle, is a series of stages that a cell undergoes to grow, replicate its DNA, and divide. This process ensures the maintenance, growth, and repair of tissues. The cell cycle consists of four main phases: G1 (Gap 1), S (Synthesis), G2 (Gap 2), and M (Mitosis) [10]. Cells can also enter a resting state called G0.  

G1 Phase (Gap 1) 

During G1, the cell grows in size and synthesizes various proteins and organelles [10]. This stage is essential for the cell to get ready for DNA replication. Cells also monitor their environment to ensure conditions are favorable for division. 

S Phase (Synthesis) 

In the S phase, the cell duplicates its DNA, ensuring that each daughter cell will have an identical set of chromosomes [10]. This replication regulates and involves synthesizing new DNA strands based on the existing templates. 

G2 Phase (Gap 2) 

During G2, the cell continues to grow and produces proteins and organelles [10]. G2 examines the duplicated DNA for errors and performs any needed repairs. This phase guarantees that the cell is adequately prepared to proceed to mitosis. 

M Phase (Mitosis) 

Mitosis is the procedure through which a cell splits into two identical daughter cells. This process is composed of several stages: 

Prophase: Chromosomes condense, and the nuclear envelope begins to break down [10]. 

Metaphase: Chromosomes align in the center of the cell [10]. 

Anaphase: The cell pulls sister chromatids apart to opposite ends [10]. 

Telophase: Nuclear envelopes re-form around the separated chromatids, now called chromosomes [10]. 

Cytokinesis: The cytoplasm divides, resulting in two separate daughter cells [10]. 

G0 Phase (Resting-State) 

Cells can enter a resting state called G0, where they are not prepared to divide [10. Some cells, such as nerve cells, may remain in G0 for an extended period. Other cells can re-enter the cell cycle when conditions become favorable. 

Cell Death 

Apoptosis is a regulated process that leads to the elimination of damaged or unnecessary cells [11] [12]. It is essential for maintaining tissue homeostasis and preventing the accumulation of harmful cells. Apoptosis involves a series of biochemical events that lead to characteristic cell changes and eventual death without causing an inflammatory response. Necrosis is an uncontrolled form of cell death that occurs in response to injury or infection [12]. Unlike apoptosis, necrosis often results in inflammation and damage to surrounding tissues. 

The cell life-death cycle is repetitive, but cancer cells continue to grow, often forming a mass known as a tumor. Over time, these cancer cells can invade nearby tissues and spread to other parts of the body, a process called metastasis [13].  

Epidemiology  

The incidence of renal cell carcinoma (RCC) varies across different regions across the globe, with the highest rates observed in the Czech Republic and North America [14][15]. In the United States, 82,000 new cases of RCC occur per year, with 15,000 resulting in death [14]. Worldwide, over 400,000 new cases of RCC arise each year, leading to over 170,000 deaths from kidney cancer [14][15]. RCC occurs about twice as often in males compared to females and affects individuals aged 60 to 80, with a median age at diagnosis of around 64 years [16]. RCC is uncommon for those under 40 and children [17]. 

In the United States, the incidence of renal cancers is lowest among Asian American and Pacific Islander patients compared to other ethnicities [14][15]. The five-year survival rate for Black American patients is similar to that of White American patients, exceeding 75 percent [18]. 

Since 1975, the incidence of renal cell carcinoma (RCC) has increased, though this rise has slowed in recent years [19]. This trend is due to the detection of asymptomatic and early-stage renal cancer cases facilitated by advances in imaging techniques. Physicians detect over half (60%) of RCC cases as incidental findings [20]. 

RCC constitutes over 3% of all adult malignancies and presents with various histological subtypes [21]. The American Cancer Society expects the United States to see 81,610 new cases of kidney cancer in 2024, with 52,380 in men and 29,230 in women [16]. This number includes all types of kidney and renal pelvis cancers. The society also estimates that 14,390 people will die from kidney cancer in 2024, with 9,945 men and 4,940 women [16]. 

The overall 5-year relative survival rate in the United States for patients diagnosed with early-stage RCC is 93% [16][18]. Patients with early-stage disease represent about two-thirds of all diagnosed renal cancer cases [22]. The overall survival rate for kidney and renal pelvis cancers stands at 75% [16][18]. 

RCC, originating from the renal epithelium, includes over 10 histological and molecular subtypes [23]. Recent genomic studies have identified significant mutations and intra-tumor heterogeneity, impacting prognosis and treatment strategies [23]. Surgery can manage localized RCC, while conventional chemotherapy struggles to treat metastatic RCC [24]. However, researchers have made significant advances in treating metastasis with targeted agents and immunotherapies [28]. This overview of RCC covers its biology, focusing on clear cell RCC, and provides updates on clinical guidelines and potential future research directions. RCC, also known as hypernephroma or Grawitz tumor, affects adults aged 50 to 70, with a male-to-female ratio of approximately 2:1 [25]. 

Etiology 

Primary risk factors for RCC include tobacco use and obesity, with half of RCC cases having the potential to be preventable through the control of these factors [26]. Both cigarette smokers and users of pipes and cigars are at elevated risk [26]. Obesity in women is another significant contributor [26]. Studies estimate that eliminating tobacco use and excess body weight could reduce the incidence of kidney cancers by half [27]. 

Other risk factors include high blood pressure, chronic renal failure, and exposure to certain chemicals, specifically chemicals like trichloroethylene [28]. Moderate alcohol consumption (up to about two drinks per day), a diet rich in fruits and vegetables, and long-term consumption of fatty fish are associated with a reduced risk of kidney cancer [29]. 

RCC is a heterogeneous group of neoplasms with distinct histologic, cytogenetic, and imaging characteristics [30]. The three main subtypes are clear cell (70%), papillary (10%), and chromophobe (5%), each with unique radiologic appearances [30]. Less common subtypes include carcinoma of the collecting ducts of Bellini, renal medullary carcinoma, and Xp11.2 translocation carcinoma [21]. 

Genetic factors also play a crucial role in the development of RCC [31]. The VHL gene implicates both sporadic and familial types of clear cell RCC (CCRCC), while mutations in the MET gene characterize familial papillary RCC (PRCC) [31].  

Almost 4% of renal cell cancers arise from rare hereditary conditions, including the following: 

Von Hippel-Lindau (VHL) Syndrome: Associated with cysts and tumors in various organs, including pancreatic neuroendocrine tumors, cerebellar and spinal hemangioblastomas, and multiple bilateral tumor nodules of clear cell RCC [32]. 

Hereditary Leiomyomatosis and Aggressive Papillary Carcinoma Syndrome: An autosomal dominant disease caused by mutations in the FH gene, linked to uterine leiomyomatosis and early metastatic spread of papillary RCC [33]. 

Hereditary Papillary Carcinoma: An autosomal dominant condition characterized by mutations in the MET gene, resulting in bilateral and multiple papillary tumors with various cytogenetic abnormalities [34]. 

Birt-Hogg-Dubé Syndrome: This autosomal dominant disease involves mutations in the BHD gene, presenting a range of renal tumor histologies and associated features such as fibrofolliculomas, trichodiscomas, acrochordons, and pulmonary cysts [35]. 

Tuberous Sclerosis Syndrome: Caused by mutations in the TSC1 and TSC2 genes, leading to multiple bilateral renal angiomyolipomas and CCRCC, along with various extra-renal manifestations [36]. 

Other less common types of kidney cancers include transitional cell carcinoma (also known as urothelial carcinoma), which begins where the ureter and kidney meet (renal pelvis) and resembles bladder cancer; Wilms’ tumor, primarily occurring in children and rare in adults; and renal sarcoma, a rare cancer originating in the blood vessels and connective tissue around the kidneys [37] [38].  

Pathophysiology  

Experts believe renal cell carcinomas (RCCs) originate from the epithelial cells of the nephron [39]. Clear cell renal cell carcinoma (CCRCC) links to the proximal tubular epithelium, papillary renal cell carcinoma (PRCC) to the distal tubular epithelium, and chromophobe RCC (ChRCC) to the intercalated cells of the collecting duct [39].  

In CCRCC, the VHL tumor suppressor gene is the most often mutated [32]. The complete loss of VHL through genetic mechanisms (such as point mutations, indels, and 3p25 loss) and/or epigenetic mechanisms (such as promoter methylation) constitutes the earliest and most crucial oncogenic driving event [32].  

Histopathology  

Renal cell carcinoma (RCC) encompasses several types, identified by a pathologist through microscopic examination of cancer cells. The most common type is clear cell RCC, characterized by pale or clear cells [2]. Papillary RCC, the second most common type, features tumors with tiny fingerlike growths [40]. Chromophobe RCC is a rare form distinguished by larger cells compared to other RCC types [41]. Collecting duct RCC, another rare form, has cancer cells resembling irregular tubes [42]. Unclassified RCC consists of tumors with cells from more than one type of cancer or cells that do not fit into other categories [43]. The Modified 2016 World Health Organization (WHO) classification identifies over 14 types of renal cell carcinomas (RCCs) [44].  

Clear cell RCC (CCRCC) is the most prevalent type, characterized by a yellow-cut surface due to lipid content, with areas of necrosis and hemorrhage [2]. Tumor cells appear rounded or polygonal with clear or pink granular cytoplasm [45]. Papillary RCC (PRCC), accounting for 10-15% of renal cancers, can be multifocal and bilateral, often presenting with central necrosis and hemorrhages [45]. It comprises two subtypes: Type 1, characterized by small cells with basophilic cytoplasm, and Type 2, identified by large cells with eosinophilic cytoplasm [45]. 

Chromophobe RCC (ChRCC), comprising about 5% of RCCs, arises from intercalated cells of collecting ducts and presents with a lobulated orange surface that turns grayish white on formalin fixation [46]. Tumor cells have a transparent, reticulated cytoplasm and thick-walled vasculature [46]. Collecting duct carcinoma, making up about 1% of RCCs, originates from medullary collecting duct cells and features irregular channels lined by atypical epithelium within a prominent fibrotic stroma. Distinguish this type from medullary carcinoma associated with sickle cell trait [47] [48]. 

Differential Diagnosis  

Half of the renal cell carcinomas (RCCs) are incidental findings with the disease is being often asymptomatic [20]. Consider RCC when detecting a renal mass in a radiologic study. Include various conditions in the differential diagnosis that can mimic RCC when a client presents with a renal mass.  

These conditions include [49]: 

• Abscess 
• Angiomyolipoma (benign neoplasm) 
• Renal oncocytoma (benign neoplasm) 
• Renal adenoma (benign neoplasm) 
• Renal lymphoma 
• Renal cyst 
• Renal infarction 
• Sarcoma 
• Metastasis from distant primary lesions, such as metastatic melanoma 

Differential diagnoses based on clinical findings may include [50]: 

• Acute pyelonephritis 
• Bladder cancer 
• Chronic pyelonephritis 
• Non-Hodgkin lymphoma 
• Differential Adult-type Wilms tumor 

Renal cell carcinomas (RCCs) can remain asymptomatic until the disease has progressed. Only 10 to 15% of clients exhibit the “classic triad” of symptoms: flank pain, hematuria, and flank fullness [51]. More than 60% of clients present with asymptomatic hematuria [49]. Other common symptoms include fatigue, weight loss, fever, night sweats, malaise, hypertension, and anemia [49]. Varicocele can occur due to tumor invasion and growth into the renal vein and inferior vena cava, obstructing the testicular vein [52].  

When present, Hypercalcemia indicates either bony metastasis or a paraneoplastic phenomenon [53]. Bone metastasis from RCC is often osteolytic, leading to pathologic fractures, spinal cord compression, and hypercalcemia [54].  

Sharp, excruciating, band-like back pain may result from vertebral collapse and spinal cord compression caused by metastatic disease, aiding in the diagnosis of metastatic renal cell carcinoma [54].  

At the time of diagnosis, one-third of clients with RCC have metastatic disease [55]. Therefore, a thorough physical examination should include an evaluation for metastasis to the lungs (75%), bones (20%), liver (18%), central nervous system (8%), and other areas [56].  

Diagnostic Testing 

The most utilized tests for renal assessment include renal ultrasonography, which is often the initial study [57]. The initial evaluation may also involve a CT excretory urogram. Confirmation requires a staging CT of the abdomen and pelvis. To check for lung metastasis, perform a chest X-ray or CT scan. Use magnetic resonance imaging (MRI) to detect venous invasion and metastatic tumor progression [57]. After confirming renal cell carcinoma (RCC), conduct renal arteriography and venography if suspecting inferior vena cava involvement [57]. Measure bone scan and alkaline phosphatase levels to diagnose or assess bone metastasis and for follow-up [57]. Perform a CT head scan if suspecting cerebral metastasis. Recommend genetic testing for patients suspected of having hereditary disease due age at presentation or a family history of RCC [58]. Use ultrasound or CT-guided percutaneous needle biopsy for suspicious and cystic lesions suspected to be malignant [59]. 

Treatment  

Management and prognosis of RCC depend on tumor staging, grading, and characteristics such as the degree of invasion, venous thromboembolic involvement, and necrosis extent [57]. Treatment varies based on tumor size and location. Treat smaller tumors confined to one kidney pole with partial nephrectomy, while larger tumors may require partial or radical nephrectomy [60]. Targeted therapies, like tyrosine kinase inhibitors, have shown efficacy in improving progression-free survival. Novel immunotherapeutic agents, such as T-cell checkpoint inhibitors, show promise in treating metastatic RCC [61].  

The primary treatment for kidney cancer involves surgery, known as nephrectomy. This procedure removes the kidney and includes distinct types. A radical nephrectomy removes the entire kidney, the adrenal gland, surrounding tissues, and sometimes nearby lymph nodes. A simple nephrectomy removes only. A partial nephrectomy involves removing only the tumor-containing part of the kidney. The remaining kidney can compensate and perform the functions of both kidneys. 

Radiation therapy, which uses high-energy X-rays to destroy cancer cells, is sometimes employed to alleviate pain when kidney cancer metastasizes to the bones. Targeted therapy, which utilizes drugs designed to attack specific components of cancer cells, is often the first-line treatment for advanced kidney cancer due to its mild side effects compared to standard chemotherapy. Examples of first-line drugs include sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, and pazopanib [61]. 

Biological therapy, also known as immunotherapy, leverages the body’s immune system to combat cancer. Chemotherapy, the use of drugs to kill cancer cells, is less effective for kidney cancer due to the cancer’s resistance to these drugs. Arterial embolization is another treatment option that involves injecting small pieces of material through a catheter to block the main renal blood vessel, thus starving the tumor of necessary nutrients and oxygen. This method can shrink the tumor before surgery or relieve pain when surgery is not feasible. 

Accurate Staging for Effective Management of Renal Cell Carcinoma 

Stage 1a: Treat tumors confined to the kidney with curative intent using a nephron-sparing partial nephrectomy. The National Comprehensive Cancer Network (NCCN) recommends an abdominal CT or MRI within six months of starting surveillance, followed by annual imaging [57]. 

Stage 1b: Partial or radical nephrectomy yields similar outcomes. Post-surgery follow-up includes baseline abdominal imaging (CT, MRI, or ultrasound) 3-12 months after surgery, then annually for three years, with chest X-rays also annually for three years [57]. 

Stages 2 and 3: Recommend radical nephrectomy and schedule follow-up imaging at 3 to 6 months post-surgery, then every 3-6 months for three years, and per year up to five years. Perform additional site-specific imaging as needed [57]. 

Stage 4: Systemic targeted molecular therapies, such as tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors (e.g., sunitinib, sorafenib, pazopanib, axitinib) or rapamycin inhibitors (e.g., temsirolimus, everolimus), have replaced immunotherapy (e.g., interferon-α). Nephrectomy followed by immunotherapy improves survival in patients with metastatic RCC compared to using immunotherapy or TKIs alone. Follow-up includes pretreatment imaging (CT or MRI of the chest, abdomen, and pelvis), with repeat imaging every 6 to 16 weeks based on clinical status [57][60][61]. 

Prognosis  

The 5-year relative survival rate for renal cell carcinoma (RCC) stands at 75%. Diagnosing two-thirds of cases at a local stage result in a 93% 5-year relative survival rate. Predict prognosis based on the stage and grade of the cancer [57]. Cancer-specific survival rates range from 85-90% for localized (stage 1 and 2) RCC.  

The International Society of Urological Pathology (ISUP) Grading System, proposed in 2012 and later adopted by the World Health Organization (WHO), includes more objective criteria for tumor grading based on nuclear characteristics [57]. These criteria encompass the degree of tumor invasion, the presence, and extent of venous thromboembolic involvement, adrenal gland involvement, tumor grade, sarcomatoid features if present, lymphovascular invasion, and the extent of necrosis. The ISUP system no longer grades chromophobe RCC. Higher grades correlate with larger tumor sizes and more aggressive tumors. 

Categorize prognostic factors for RCC into three main groups: tumor-related factors, patient-related factors, and laboratory biochemical tests [57]. The integration of these factors into algorithms enhances prognostic accuracy beyond a simple anatomic tumor stage, thereby improving management decisions. Tumor-related factors include stage, tumor size, tumor grade, histologic type, histologic tumor necrosis, and sarcomatoid transformation [57].  

Patient-related factors involve the presence of symptoms (asymptomatic, local symptoms, systemic symptoms), performance status, substantial weight loss, presence of well-defined paraneoplastic syndrome, metastasis-free interval, and history of prior nephrectomy [57]. Laboratory biochemical tests consider elevated LDH levels, hypercalcemia, anemia, thrombocytosis, and elevated ESR or CRP [57]. 

Conclusion

Renal cell carcinoma (RCC), a significant form of kidney cancer, originates in the tissues of the kidneys, essential organs responsible for filtering waste from the blood and producing urine. RCC, accounting for about 90% of kidney cancer cases, is notable for its lethality and prevalence, comprising over 3% of all adult malignancies [2][3]. The most common subtype, clear cell RCC, often metastasizes to the lungs, while chromophobe RCC spreads to the liver. Early detection and diagnosis are crucial, as prognosis improves with early detection. The kidneys’ vital functions, including waste filtration, blood pressure regulation, and red blood cell maintenance, underscore the importance of early intervention in RCC [62].  

Symptoms of RCC can include hematuria, flank pain, and a palpable mass, although many cases are asymptomatic and discovered through imaging studies for other conditions [6][7][20]. Treatment options, determined by the cancer’s stage and grade, range from surgery to targeted therapy, immunotherapy, and radiation therapy. Advances in understanding RCC’s molecular and genetic basis have improved diagnostic therapeutic strategies, enhancing patient outcomes. Despite these advancements, RCC remains challenging to treat, particularly in its metastatic form, highlighting the need for continued research and innovation in therapeutic approaches. 

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