Renal Cell Carcinoma

History

Renal cell carcinomas, the most common form of kidney cancer or renal cancer, develop in the lining of the tubules.¹ Approximately 90% of all kidney cancers are renal cell carcinoma.² Alternative names for this malignancy include renal cell cancer, renal adenocarcinoma, and hypernephroma.³ There are three main histological subtypes of renal cell carcinoma, itself a type of kidney cancer. The most common is clear cell carcinoma (75%), followed by papillary renal cell carcinoma (15 to 20%), and chromophobe renal cell carcinoma (5%).⁴

Renal Cell Carcinoma Epidemiology

Renal cell carcinomas account for approximately 3% of all cancer cases worldwide.² In recent decades, the incidence has increased by about 2% each year. The incidence is highest in Western countries, particularly the Czech Republic and Lithuania. In 2022, an estimated 79,000 new cases of renal cell cancer will be diagnosed in the United States. In the same year, 13,920 patients are expected to die of renal cell cancer.³ Renal cell cancer is nearly twice as prevalent in men than women. Black men are more at risk than men of other races. The majority of patients are diagnosed between the ages of 60 and 70.⁴

Renal Cell Carcinoma Risk Factors & Etiology

The precise cause or causes of renal cell cancer, a type of kidney cancer, have not been identified, but there are several known risk factors which are highlighted in Table 1.

Table 1. Renal Cell Carcinoma Risk Factors

Risk Factors	Association
Tobacco Use5	Research indicates that tobacco use is linked to an increased risk of developing renal cell carcinoma. The risk of having advanced renal cell carcinoma at the time of diagnosis may be associated with heavy tobacco use.5
Prolonged misuse of certain pain medications5	Chronic, excessive consumption of pain medications including acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs is linked to renal failure, and has been shown to raise one’s risk of developing renal carcinoma and other instances of kidney cancer.
Kidney disease5	Chronic kidney disease and acquired cystic disease of the kidney are associated with an increased risk of developing renal cell carcinoma. Estimates suggest that patients with acquired polycystic kidney disease who are undergoing dialysis face a 30 times higher risk of developing renal cell carcinoma. Around 6% of those who require chronic dialysis will develop renal cell cancer in their lifetime.
Obesity or excessive body weight5	Renal cell carcinoma is more common in obese or overweight individuals, and the relative risk of developing this type of kidney cancer seems to rise in accordance with increasing body mass index. However, excessive weight may be associated with early-stage renal cell carcinoma or better outcomes in some patients with renal cell carcinoma, potentially due to inactivity of the fatty acid synthase gene.
Hypertension5	Hypertension is a well-known risk factor for renal cell carcinoma, but the underlying mechanisms responsible for this link have yet to be proven. The association seems to remain strong with or without the use of antihypertensives.
Occupational exposures5	People who are chronically exposed to certain carcinogenic chemicals in the workplace may be more likely to develop renal cell carcinoma. These compounds include cadmium, asbestos, and trichloroethylene, a byproduct of petroleum. Exposure to these chemicals are thought to trigger mutations in certain genes that play a role in the development of renal cell carcinoma.
Genetic conditions and family history	Estimates suggest that around 5 to 8% of all kidney cancer is hereditary.2 However, recent research has suggested that genetic syndromes may be responsible for a higher percentage of cases than previously thought. A hereditary case of kidney cancer is suspected in patients who are younger than 47 at the time of diagnosis, have multiple renal masses, or have a family history of kidney cancer.2 Several genetic syndromes have been linked to renal cell carcinoma, including:6 von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, hereditary leiomyomatosis and renal cell carcinoma, BAP1 tumor predisposition syndrome, hereditary paraganglioma/ pheochromocytoma syndrome, non-polyposis colorectal cancer syndrome, hyperparathyroidism-jaw tumor syndrome, phosphatase and tensin homolog hamartoma syndrome, and constitutional chromosome 3 translocation.

Renal Cell Carcinoma Prognosis

While the prognosis can vary depending on patient-specific factors, it is largely based on the stage of the renal cell cancer or the extent of spread.³ Stage-specific survival rates vary depending on the study. With the increased use of abdominal CT and ultrasonography for evaluation of an unrelated problem, renal cell carcinoma tends to be diagnosed at a relatively early stage, and about 75% of all affected patients live for at least 5 years after their diagnosis.³

Most recent studies have identified a 5-year survival rate of more than 90% for patients with stage 1 renal cell carcinoma,⁷ and over 50% of stage I renal cell cancers can be cured with current renal cell carcinoma treatment options.³ Stage 2 has been associated with 5-year survival rates between 75 and 95%.⁷ When stage 3 tumors are resected, the 5-year survival rate has been shown to range from 59 to 70%.⁸

The prognosis decreases significantly for metastatic renal cell carcinoma, although some patients do well after surgical resection.³ The introduction of new renal cell carcinoma treatment options in recent years has improved outcomes. Recent studies have shown that patients with stage 4 renal cell carcinoma who receive immunotherapy have a median overall survival of over 2 years, while those who receive targeted therapy have a median overall survival of almost 5 years.⁷

Renal Cell Carcinoma Diagnosis & Presentation

Renal cell carcinoma is asymptomatic in over half of all patients.⁴ Asymptomatic cases are typically detected incidentally, after imaging scans are performed for another purpose. Incidental diagnoses of renal cell carcinoma have increased due to the more routine utilization of imaging techniques, such as CT scans.⁶ The rise of incidental diagnoses has consequently led to a decrease in symptom-led diagnoses.

The “triad” symptoms, including hematuria, flank pain, and a palpable abdominal mass, are the characteristic presentation of symptomatic renal cell carcinoma.⁴ However, this presentation has become increasingly uncommon, occurring in only 6 to 10% of cases, and is often indicative of advanced renal cell carcinoma.² Other potential symptoms may include:⁴

• Paraneoplastic disease, indicated by hypertension, hypercalcemia, and polycythemia (found in about 20% of cases)
• Right-sided varicocele (nonreducing/isolated)
• Bilateral edema in the lower extremities
• Bone pain, adenopathy, fever, weight loss, pulmonary symptoms, anemia (suggestive of metastatic renal cell carcinoma)^4,6

Imaging tests, particularly CT imaging, is crucial to diagnosing renal cell carcinoma.⁶ All scans should be completed with and without contrast. The initial diagnostic workup will include an abdominal CT (with or without the pelvis) and a chest-x-ray, along with a meticulous physical exam and medical history and laboratory tests. The proper abdominal imaging techniques, combined with clinical and physical findings, can result in a relatively certain diagnosis. As such, performing a biopsy prior to surgery to confirm the diagnosis may not be necessary.

After diagnosis, patients with renal cell carcinoma should be referred to a cancer geneticist for genetic disease evaluation if they are younger than 47, have multiple renal masses, or have a family history of kidney cancer as these factors are associated with hereditary kidney cancer.^2,6 An estimated 5 to 8% of all kidney cancer is linked to inherited genetic mutations. Identifying a genetic underpinning is instrumental in directing management and care.⁶

Imaging tests and other diagnostic techniques will also be needed to stage renal cell carcinoma using the Tumor Node Metastasis (TNM) classification system. The definitions of the TNM system and the staging of a primary tumor are shown below in Table 2 from the European Association of Urology.²

Table 2. Tumor Node Metastasis (TNM) Classification System

Category	Classifications
Primary tumor	TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor is 7 cm or less in greatest dimension, limited to the kidney T1a: Tumor is 4 cm or less T1b: Tumor > 4 cm but less than or equal to 7 cm T2: Tumor > 7 cm in greatest dimension, limited to the kidney T2a: Tumor > 7 cm but less than or equal to 10 cm T2b: Tumors > 10 cm, limited to the kidney T3: Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia T3a: Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system or invades perirenal and/or renal sinus fat, but not beyond Gerota fascia T3b: Tumor grossly extends into the vena cava (VC) below diaphragm T3c: Tumor grossly extends into vena cava above the diaphragm or invades the wall of the VC T4: Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)
Regional lymph nodes	NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in regional lymph nodes
Distant metastasis	M0: No distant metastasis M1: Distant metastasis
TNM stage grouping	Stage I: T1, N0, M0 Stage II: T2, N0, M0 Stage III: T3, N0, M0; T1, T2, T3, N1, M0 Stage IV: T4, Any N, M0; Any T, Any N, M1

Physical Examination Findings in Renal Cell Cancer

Physical examination is a preliminary step in diagnosing renal cell carcinoma.² A physical exam is useful in determining whether and which imaging tests may be indicated. Physical findings that may warrant a further renal cell carcinoma diagnostic workup include apalpable mass in the abdomen, a palpable cervical lymphadenopathy, and right-sided varicocele (nonreducing/isolated) with bilateral lower extremity edema.²

Diagnostic Workup for Renal Cell Cancer

The diagnostic workup for renal cell carcinoma includes the following:

• Physical exam
• Medical history, including family history
• Referral to genetic evaluation, if patient is eligible (has a family history of renal cell carcinoma, is younger than 47, or has multiple renal masses)⁶
• Laboratory tests ⁶
  • Complete blood count (CBC)
  • Serum corrected calcium
  • Serum creatinine
  • Liver function tests
  • Urinalysis
  • Lactate dehydrogenase 
  • C-reactive protein⁴
  • Hemoglobin⁴
  • Erythrocyte sedimentation rate⁴
  • Alkaline phosphatase⁴
• Initial imaging tests⁶
  • Abdominal CT scan with or without pelvic CT (preferred) or abdominal MRI
  • Ultrasound
  • Chest CT (preferred) or chest X-ray
• Supplemental tests (if clinically indicated):⁶
  • Abdominal MRI (to examine the inferior vena cava or for staging, if CT results are indeterminate)
  • Bone scan, if clinical complaints or laboratory findings (elevated serum alkaline phosphatase) are suggestive of bone metastases
  • CT or MRI of the brain, if other findings are suggestive of brain metastases)
  • Urine cytology, ureteroscopy, or percutaneous biopsy if a central renal mass is present (to rule out urothelial carcinoma)
  • Needle biopsy before surgery, if imaging findings are indeterminate, lesions are small, or when necessary to rule out differential diagnoses (not indicated in frail patients, those with comorbidities, or for cystic renal masses that do not have significant solid components in imaging)²

Differential Diagnosis

If imaging findings reveal indeterminate renal masses, the differential diagnosis may include cysts, malignant tumors (lymphomas, sarcomas, and metastases), benign tumors (renal adenomas, angiomyolipomas, oncocytomas), and inflammatory masses due to infection, infarction, or trauma.⁴

Management

Management and treatment of renal cell carcinoma is mostly guided by stage. The standard renal cell cancer treatment options by stage are outlined below.

Stage 1 Renal Cell Carcinoma

The primary treatment option for Stage 1 renal cell carcinoma is surgical resection (nephrectomy).³ In many cases, surgery is curative for Stage 1 renal cell tumors. For patients who cannot undergo surgery, the options are palliative and include external-beam radiation therapy and arterial embolization.³

There are different types of nephrectomy. Partial nephrectomy (also called nephron-sparing surgery) and radical nephrectomy are the main ones. For earlier-stage renal cell carcinoma, partial nephrectomy may be preferred because it has been shown to produce good outcomes while potentially preserving kidney function.⁶ However, the evidence is mixed, and some surgeons may prefer radical nephrectomy.³ Radical nephrectomy is often a better option for renal cell tumours that have grown into the vena cava. This procedure involves removing the kidney, adrenal gland, perirenal fat, Gerota fascia, and sometimes, nearby lymph nodes. Both operations can be performed as open surgery, laparoscopic surgery, or robotic-assisted surgery.⁶

If the cancer is bilateral, surgical options may include bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, or bilateral nephrectomy with dialysis or transplantation.³ When possible and done successfully, the former option may be preferable as it is likely to yield a higher quality of life.

In some cases, active surveillance may be an option.⁶ For early-stage renal cell carcinoma, active surveillance involves monitoring tumor progression through abdominal imaging and postponing renal cell carcinoma treatment until it is necessary. Patients who are older or have small tumors may be eligible.⁶

Stage 2 Renal Cell Carcinoma

For stage 2 renal cell carcinoma, radical nephrectomy is the primary renal cell cancer treatment option and comes with high cure rates.³ While selected patients may be eligible for non-radical nephrectomy, stage 2 tumors tend to require the more comprehensive, radical surgery. For high-risk patients, adjuvant pembrolizumab may be given after radical resection as it may extend disease-free survival in these patients.³

In some cases, external-beam radiation therapy can be given before or after resection. However, it is not clear whether the addition of radiation improves outcomes. Patients who cannot undergo surgery may be given arterial embolization as a palliative treatment.³

Stage 3 Renal Cell Carcinoma

For stage 3 renal cell carcinoma, the potentially curative treatment options are radical nephrectomy, preoperative embolization and radical nephrectomy, and radical nephrectomy with adjuvant systemic therapy with pembrolizumab or sunitinib.³ The decision between these treatment options depends on a variety of factors, including the TNM classification within stage 3.

In general, the primary renal cell carcinoma treatment option is radical nephrectomy. Surgery may be more or less extensive depending on the characteristics of the tumor. For example, patients with T3a, N0, M0 disease will generally require a standard radical nephrectomy to remove the kidney, adrenal gland, perirenal fat, Gerota fascia, and most often, a lymph node dissection and lymphadenectomy of nearby lymph nodes. However, patients with T3b, N0, M0 disease will typically require a more extensive surgery that may involve removing the renal vein, caval thrombus, and parts of the vena cava.³

Adjuvant systemic therapy with pembrolizumab or sunitinib may extend relapse-free survival in some patients but has not been shown to extend overall survival.³ The efficacy of preoperative or postoperative external-beam radiation therapy has not been proven, but it may be useful in patients with larger or more invasive tumors.

If this type of kidney cancer is bilateral, surgical options may include bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, or bilateral nephrectomy with dialysis or transplantation.³ When possible and done successfully, the former option may be preferable as it is likely to yield a higher quality of life.

If the tumor is classified as T1 to T3, N1, MO, surgery is rarely curative.³ For patients who cannot undergo surgery, the options are palliative and include external-beam radiation therapy, arterial embolization, and palliative nephrectomy.

Renal Cell Carcinoma Stage 4 and Recurrence

The treatment options for stage 4 or recurrent renal cell carcinoma can be broken down into first-, second-, third-, and fourth-line therapies.³ Stage 4 renal cell carcinoma is incurable in most cases. Renal cell cancers that recur, relapse, or don’t respond to treatment generally come with similarly poor outcomes.

Table 3. First-line therapies for stage 4 or recurrent renal cell carcinoma³

Renal Cell Carcinoma Treatment Category	Specific Therapies
Immunotherapies	Ipilimumab plus nivolumab
Combined immune checkpoint inhibitors and antiangiogenic targeted therapy	Pembrolizumab plus axitinib Pembrolizumab plus lenvatinib Nivolumab plus cabozantinib Avelumab plus axitinib
Local therapies	Cytoreductive nephrectomy Radical nephrectomy
Anti-vascular endothelial growth factor (VEGF) and multitargeted tyrosine kinase inhibitors	Sunitinib Pazopanib Cabozantinib Sorafenib Bevacizumab
Mammalian target of rapamycin (mTOR) inhibitors	Temsirolimus
Cytokine therapies	Interferon-alpha IL-2
Palliative options	External beam radiation therapy

Table 4. Second-line therapies for stage 4 or recurrent renal cell carcinoma³

Renal Cell Carcinoma Treatment Category	Specific Therapies
Immunotherapies	Nivolumab (second to sunitinib, pazopanib, sorafenib, and/or axitinib)
Combined therapy with multitargeted TKIs and mTOR inhibitors	Lenvatinib plus everolimus (second to sunitinib, pazopanib, cabozantinib, axitinib, or sorafenib)
Anti-vascular endothelial growth factor (VEGF) and multitargeted tyrosine kinase inhibitors (TKIs)	Cabozantinib (second to sunitinib, pazopanib, sorafenib, or axitinib) Axitinib Sorafenib
Mammalian target of rapamycin (mTOR) inhibitors	Everolimus (second to sunitinib and/or sorafenib)
Palliative options	External-beam radiation therapy

Third- and fourth-line therapies for stage 4 or recurrent renal cell cancer include anti-vascular endothelial growth factor, such as tivozanib, or any first- or second-line treatment therapies.

Monitoring Side Effects, Adverse Events, Drug-Drug Interactions

The management of renal cell cancer depends on stage and individual factors. When making renal cell cancer treatment selections, health care providers must weigh the proposed efficacy of a therapy with the potential risks and quality of life impacts.

For early-stage renal cell carcinoma, treatment is largely focused on surgery.⁶ The potential risks of nephrectomy depend on the extent of the surgery and patient-specific factors. In general, adverse events related to surgery for renal cell carcinoma include injuring internal organs, including the spleen, pancreas, and bowels; blood vessel damage in the aorta or vena cava; pneumothorax; incisional hernia; abdominal urine leakage; and kidney failure.⁸

Later-stage renal cell cancers may be treated with a wide-range of therapies, including first-, second-, third-, and fourth-line options. Each therapy comes with potential risks. The risks and potential side effects of some of these options are outlined below:

• Immunotherapy
  • Adjuvant pembrolizumab³
    • Adjuvant pembrolizumab, alongside radical nephrectomy, may be used as a treatment option for Stage 2 high-risk patients or Stage 3 patients.
    • In a clinical trial of adjuvant pembrolizumab, 32% of patients experienced grade 3 or higher adverse events including diarrhea, fatigue, and rash, and 20% reported serious adverse events.

• Combined therapy with multitargeted TKIs and mTOR inhibitors
  • Lenvatinib plus everolimus³
    • Lenvatinib is a multitargeted tyrosine kinase inhibitor, while everolimus is an mTOR inhibitor. Together, these drugs can be used as a second-line therapy for stage 4 renal cell carcinoma.
    • In a clinical trial of 153 patients with late-stage renal cell carcinoma who were previously treated with antiangiogenic therapy, 71% of patients given lenvatinib-plus-everolimus reported grade 3 or higher adverse events including diarrhea, hypertension, fatigue, loss of appetite, vomiting, and cough.

Table 5. Risks and Side Effects of Combined Immune Checkpoint Inhibitors and Antiangiogenic Targeted Therapies³

Combined Immune Checkpoint Inhibitors and Antiangiogenic Targeted Therapy	Associated Risks and Side Effects
Pembrolizumab plus axitinib3	In a clinical trial of 861 patients with metastatic renal cell carcinoma and no prior systemic treatment, 75.8% of patients given pembrolizumab plus axitinib reported grade 3 or higher adverse events.
Pembrolizumab plus lenvatinib3	In a clinical trial of 1609 patients with metastatic renal cell carcinoma and no prior systemic treatment, 82.4% of patients given pembrolizumab plus lenvatinib reported grade 3 or higher adverse events. The most common serious toxicities included hypertension, diarrhea, and weight loss.
Nivolumab plus cabozantinib3	In a clinical trial of 651 individuals with metastatic renal cell carcinoma and no prior systemic treatment, 75.3% of patients given nivolumab plus cabozantinib reported grade 3 or higher adverse events. These included hypertension, hyponatremia, diarrhea, elevated lipase, and hypophosphatemia.Approximately one-fifth of patients (19.7%) given nivolumab plus cabozantinib had to discontinue at least one of the drugs.

Table 6. Risks and Side Effects of Anti-Vascular Endothelial Growth Factor (VEGF) and Multitargeted Tyrosine Kinase Inhibitors³

Anti-VEGF and multitargeted tyrosine kinase inhibitors	Associated Risks and Side Effects
Sunitinib	A tyrosine kinase inhibitor that can be used along with nephrectomy as a treatment option stage 3 renal cell carcinoma. In a clinical trial of 615 individuals with high-risk, locoregional renal cell cancer who had undergone nephrectomy, 34% of patients who received sunitinib required dose reductions, while 46% required dose interruptions, and 28% discontinued the drug. Nearly half of patients (48%) experienced grade 3 adverse events and 12% had grade 4 adverse events including palmar-plantar erythrodysesthesia, hypertension, fatigue, neutropenia, thrombocytopenia, and mucosal inflammation.
Pazopanib	A multikinase inhibitor that may be used as a first-line therapy for stage 4 renal cell carcinoma. In a clinical trial of 1110 individuals with advanced renal cell carcinoma who were given pazopanib and sunitinib separately, each for a period of 4 weeks, 70% of patients preferred pazopanib over sunitinib, compared to 22% who preferred sunitinib. Physicians reported a similar split with 61% preferring pazopanib and 22% preferring sunitinib. Pazopanib was reported to cause less fatigue and better overall quality of life than sunitinib by those who preferred pazopanib. Sunitinib was reported to cause less diarrhea and better quality of life than pazopanib by those who preferred sunitinib.
Cabozantinib	A tyrosine kinase inhibitor that may be used on its own or in combination with immune checkpoint inhibitors as a first- or second-line treatment for stage 4 renal cell carcinoma. In a clinical trial of 658 individuals previously treated with a tyrosine kinase inhibitor, 68% of those who received cabozantinib reported grade 3 or 4 adverse events including hypertension, diarrhea, and fatigue, and 60% were given a dose reduction.
Everolimus	An mTor inhibitor that can be used on its own or in combination with lenvatinib as a second-line therapy for stage 4 renal cell cancer. In a clinical trial of 658 individuals previously treated with a tyrosine kinase inhibitor, 58% of patients receiving everolimus reported grade 3 or 4 adverse events including anemia, fatigue, and hyperglycemia, and 25% were given a dose reduction.

Renal Cell Carcinoma Complications

The potential complications related to renal cell cancer treatment strategies and therapies are discussed above. However, the underlying disease itself can also cause complications which may include hypertension, hypercalcemia, erythrocytosis, liver and spleen problems, and metastases.¹

Renal Cell Carcinoma Treatment Guidelines

For comprehensive renal cell carcinoma treatment guidelines, the National Cancer Institute (NCI), National Comprehensive Cancer Network (NCCN), and American Urological Association (AUA) all have widely available documentation available to clinicians.^3,5,9

References

1. MedlinePlus. Renal cell carcinoma. U.S. National Library of Medicine. Reviewed February 6, 2020. Accessed July 29, 2022.

2. Ljungberg B, Albiges L, Bedke J, et al. EAU guidelines on renal cell carcinoma. Updated March 2022. Accessed July 29, 2022.

3. National Cancer Institute. Renal cell cancer treatment (PDQ®)–Health professional version. Updated July 18, 2022. Accessed July 29, 2022.

4. Gray RE, Harris GT. Renal cell carcinoma: Diagnosis and management. Am Fam Physician. 2019;99(3):179-184.

5. Atkins M, Barony Z, Choueiri T. Epidemiology, pathology, and pathogenesis of renal cell carcinoma. UpToDate. Updated June 3, 2022. Accessed July 29, 2022.

6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Kidney Cancer. June 17, 2022. Accessed July 29, 2022. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

7. Choueiri T. Prognostic factors in patients with renal cell carcinoma. UpToDate. Updated November 19, 2021. Accessed July 29, 2022.

8. Surgery for kidney cancer. February 1, 2020. Accessed July 29, 2022.

9. Campbell SC, Clark PE, Chang SS, et al. Renal mass and localized renal cancer: Evaluation, management, and follow-up: AUA Guideline Part I. J Urol. 2021;206.

Author Bio

Serena McNiff is a journalist covering health and science. Her work has appeared on HealthDay, CNBC, WebMD, U.S. News and more.