Introduction

Renal cell carcinoma (RCC) arises from the renal cortex or the renal tubular epithelial cells. It is classified into clear cell RCC (ccRCC), papillary RCC, and chromophobe RCC, accounting for about 85% of all the primary renal cancers. The other 15% constitutes of transitional cell carcinoma, Wilms tumor or nephroblastoma, tumors of the collecting ducts, and renal sarcomas.[1] They are heterogeneous diseases with different biology, genetics, and behavior. Overall, the incidence has been steadily increasing, and currently, it is the 7th most common cancer among men. Among the genitourinary cancers, RCC has the highest mortality rate. The increase in incidence could be attributed to incidental diagnosis. About 60% of the cases are detected incidentally.

Etiology

Renal cell carcinoma can develop due to genetic or acquired causes. The two most common genetic abnormalities are the Von Hippel–Lindau (VHL) gene and the protein polybromo-1 (PBRM-1) gene. The common acquired causes include long-term dialysis dependence, history of smoking, long-term analgesic use, obesity, hypertension, and diabetes.[2][3] About 95% of the patients with ccRCC have a deletion in the short arm of chromosome 3 (loss of 3p). Screening for this is usually not recommended in healthy individuals.

Screening should be considered in patients with high-risk characteristics such as VHL syndrome, tuberous sclerosis, long-term dialysis dependence (more than 3 years), especially in young patients, family history of RCC, and personal history of irradiation. Following renal transplantation, the risk of kidney cancer is 15 fold in the first three years and increases thereafter due to immunosuppressive therapy.[2] Patients on long-term dialysis acquire cysts without any underlying history of the acquired cystic disease, called acquired cystic kidney disease (ACKD). When compared to the general population, patients with ACKD are at increased risk for papillary RCC.[3] Patients with polycystic kidney disease (PCKD) do not have any increased risk of RCC compared to the general population.

Epidemiology

Renal cell carcinoma is more prevalent in North America and the Czech Republic, with overall male predominance (male: females 2:1).[4] Every year, the number of reported cases in the United States is about 64,000, and the mortality is as high as 14,000. The incidence peaks from 60 to 80 years of age.[5] Overall, the prognosis is worse in the Black population.

Pathophysiology

Mutations in the VHL gene can be transmitted in an autosomal dominant fashion or in a sporadic way. More than 50% of the patients with ccRCC sporadically have VHL gene abnormalities.[6] The double hit theory is that some patients are born with one copy of defective VHL gene, and the second hit is due to the somatic mutation. Normally, VHL is a tumor suppressor gene that regulates the levels of intracellular proteins and hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A and HIF2A).[7][8]

A defective VHL gene results in the interaction among intracellular proteins resulting in the upregulation of messenger RNA (mRNA) encoding for growth factors such as platelet-derived growth factor-beta (PDGFB), vascular endothelial cell growth factor (VEGF), and transforming growth factor-alpha (TGFA). All these growth factors promote the development of these vascular tumors. Under normal oxygen conditions, HIF1A and HIF2A undergo hydroxylation and binds to a protein called pVHL and are degraded. In hypoxemic conditions or the absence of pVHL, HIFA accumulates, leading to the upregulation of mRNA and increased production of the growth factors.[8][9]

Histopathology

ccRCC and papillary RCC arise from proximal tubule epithelial cells, whereas the chromophobe RCC and collecting duct tumors arise from the distal tubules.

History and Physical

Usually, patients are asymptomatic until the malignancy has advanced. The classic symptoms include flank pain, hematuria, and palpable renal mass and are seen in only 9% of the cases. The classical triad is seen in advanced disease.[5] Flank pain is due to the mass effect or stretch of the renal capsule. The hematuria is due to tumor infiltration into the renal medulla and collecting ducts. It can be differentiated from the glomerular bleed by the absence of acanthocytes/ red cell casts on the microscopy. Depending on the extent of bleeding, the patients can complain of passing clots and colicky pain.

On physical examination, an abdominal mass can be palpable, which moves with respiration. The examination of the testes is to evaluate for left-sided varicocele as the left-sided spermatic vein drains into the left renal vein. The five years of life span was better in individuals with an incidental diagnosis of RCC. The common metastatic sites are lungs, bones, and brain. Erythrocytosis can be due to increased erythropoietin and impaired breakdown of hypoxia-inducible factors (HIFs) under normal oxygen concentrations. 

Patients with tuberous sclerosis present with benign tumors in various organs including, kidneys, liver, lung, brain, heart, eyes, and skin. It is characterized by ash-leaf spots, shagreen patches, hamartomas, and angiomyolipomas, whereas, VHL is characterized by hemangioblastomas and benign and malignant tumors. Bilateral RCCs are more common in patients with papillary RCC, underlying history of VHL disease, and tuberous sclerosis.

Evaluation

Higher rates of diagnosis of renal cell carcinoma are due to an incidental diagnosis. A thorough history, physical examination, including a testicular exam, is needed. Imaging studies, including ultrasound (US) or computed tomography (CT), are indicated. The US is a good test for the evaluation of simple and complex cysts. Bosniak classification guides us in managing renal cysts. CT with intravenous contrast is a better study than the US. Magnetic resonance imaging (MRI) is better for evaluating the extent of the disease when there is a contraindication to use the contrast or the inconclusive US or CT scan. The choice of test for metastatic RCC is MRI or a positron emission tomography (PET-CT). CT urography is better in evaluating the collecting system. 

Bosniak classification of renal cysts:

• Category I- Non-enhancing cyst - A benign cyst is characterized by a smooth border without any calcification or echoes in the cyst (anechoic). It has a thin wall without any septations or calcification or solid component. No risk of malignancy and no follow-up is needed.
• Category II- Less than 3 cm benign cyst with few thin septations or fine calcification. No, follow up needed.
• Category IIF- Greater than 3 cm benign cyst with few thin septations or fine calcification. "F" refers to follow-up with imaging in 6 months.
• Category III- Cysts with irregular walls or thick septations with cystic masses. Enhancement is seen. About 60% of the cysts have the risk of malignant transformation.
• Category IV and category III and solid mass or nodules or necrotic contents. Malignancy risk is around 90%.

Treatment / Management

Stages 1 to 3 are characterized as localized, and stage 4 is advanced disease. The treatment for localized disease is surgery with curative intent. Radical nephrectomy or partial nephrectomy is preferred depending upon the extent of the disease, patient's comorbidities, and underlying renal function. Cryotherapy and radiofrequency ablation are reserved for unresectable or nonsurgical candidates presenting with a small renal mass. Tyrosine kinase inhibitors (sunitinib and pazopanib) are used in metastatic ccRCC as they act by inhibiting VEGFR. The mammalian target of rapamycin (mTOR inhibitors) everolimus and temsirolimus have been approved for metastatic ccRCC.[6] mTOR inhibitor, along with lenvatinib (VEGFR inhibitor), is used as a second-line agent in metastatic ccRCC. The use of selective HIF2 blockers is under investigation.

Differential Diagnosis

• Simple cyst
• Angiomyolipoma
• Metastatic lesion
• Renal infarction
• Acquired cystic kidney disease (ACKD)

Medical Oncology

Following surgical resection, there is no clear role for chemotherapy or immunotherapy in renal cell carcinoma. Tyrosine kinase inhibitors (sunitinib and pazopanib), mTOR inhibitors (everolimus and temsirolimus) have been approved for metastatic ccRCC. mTOR inhibitor, along with lenvatinib (VEGFR inhibitor), is used as a second-line agent in metastatic ccRCC.

Staging

TNM Staging per American Joint Committee on Cancer[7]

• TX- Unable to assess the primary
• T0- Without any evidence of the primary
• T1- Localization to the kidney, less than 7 cm (T1a is less than 4 cm, and T1b is greater than 4 cm, but less than 7 cm)
• T2- Localization to the kidney, greater than 7 cm (T2a is less than 10 cm, and T2b is greater than 10 cm)
• T3- Invasion of the tumor into the blood vessels and perinephric region, but not beyond Gerota's fascia (T3a- when there is no spread beyond the Gerota's fascia: T3b- involves infra diaphragmatic vena cava; T3c- Invasion of the supradiaphragmatic vena cava or the vena cava wall)
• T4- Invasion of the tumor beyond Gerota's fascia into the ipsilateral adrenal gland

• NX- Unable to assess the regional lymph nodes
• N0- No evidence of regional lymph node involvement
• N1- When there is evidence of regional lymph nodes involvement 

• M0- No evidence of metastasis
• M1- Evidence of widespread metastasis

Prognosis

The prognosis of metastatic ccRCC is poor, with a median survival of about 13 months and 5-year survival under 10%.[8] With the newer therapies, the overall survival has improved. Post-surgical resection, active surveillance is done to monitor for the development of additional RCCs. Carbonic anhydrase IX (CA-IX) is used for prognosis in advanced RCC.

Complications

Paraneoplastic symptoms including hypercalcemia, erythrocytosis, hepatic dysfunction, secondary AA amyloidosis, and symptoms suggestive of polymyalgia rheumatica (PMR) are common complications.

Consultations

• Urology
• Nephrology
• Oncology
• Genetics

Deterrence and Patient Education

The only evidence for prevention includes a diet rich in fruit and vegetables and high vitamin D levels.[9] Serial monitoring of renal cysts is highly recommended, as about 30% of these lesions do not change their characteristics. About 35% of the cysts can grow faster, and the other 35% of the cysts grow at a slower rate of 4 to 5 mm over 1 year.[10] Lesions less than 3 cm need to be monitored, whereas lesions that grow at a faster rate need surgical intervention despite being less than 3 cm.[11]

Pearls and Other Issues

It has been shown that about 40% of patients with renal cell carcinoma die, signifying the importance of additional studies and treatment modalities.[11]

Enhancing Healthcare Team Outcomes

Renal cell carcinoma (RCC) arises from the renal cortex or the renal tubular epithelial cells. Overall, the incidence has been steadily increasing, and currently, it is the seventh most common cancer among men. Among the genitourinary cancers, RCC has the highest mortality rate. The prognosis of metastatic ccRCC is poor, with a median survival of about 13 months and 5-year survival under 10%. However, with newer therapies, overall survival has improved. Usually, the patients are asymptomatic until the malignancy has advanced, which is the biggest challenge for early diagnosis. The classic symptoms include flank pain, hematuria, and palpable renal mass is seen in only 9% of the cases. Higher rates of diagnosis of RCC are due to an incidental diagnosis. The treatment involves an interprofessional team consisting of a urologist, medical oncologist, nephrologist, and a genetic counselor. Patients with a family history should be educated about the possibility of acquiring cancer.