Renal cell carcinoma

Renal cell carcinoma (RCC), which originates from the renal tubular epithelium, is the most common renal malignancy in adults. Most cases are sporadic, but some hereditary disorders are also associated with the development of RCC. Major risk factors for RCC include smoking, acquired cystic disease of the kidney, nephrolithiasis, and long-term acetaminophen use. In the majority of cases, RCC is diagnosed following an incidental finding on imaging, and most patients are asymptomatic. Rarely, patients may present with the classic triad of flank pain, hematuria, and a palpable abdominal mass. Patients may also present with anemia, weight loss, and/or paraneoplastic manifestations such as hypercalcemia and hypertension. The primary imaging modality is an abdominal ultrasound, or CT or MRI with contrast. Most RCC tumors are resistant to radiotherapy and classical chemotherapeutic agents. Surgical resection is first-line treatment in nonmetastatic disease, and immunotherapy and targeted therapy, e.g., vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors, are used in metastatic RCC. Patients with early-stage RCC with tumor growth limited to the kidney have a very good prognosis.

• Prevalence: most common malignancy of the renal parenchyma (70% of renal cancers in adults are renal cell carcinoma)
• Incidence [1]
  • In 2020, an estimated 73,750 new cases will be diagnosed in the US.
  • ♂ > ♀ (∼ 2:1)
  • Peak incidence between 55 and 74 years
  • Median age at diagnosis: 64 years

Epidemiological data refers to the US, unless otherwise specified.

Overview

• Most renal cell carcinomas (RCCs) occur sporadically.
• Approx. 4% of renal cell carcinomas are associated with hereditary factors.
• Both forms show structural alterations of the short arm of chromosome 3 (3p) and subsequent alterations of the VHL gene.

Risk factors for sporadic RCC [2][3]

• Lifestyle
  • Smoking
  • Obesity
• Associated conditions
  • Sickle cell disease
  • Acquired cystic kidney disease [4]
  • Renal pelvic stones
  • Hypertension
  • Immunodeficiency
  • Chronic hepatitis C infection
• Substance exposure
  • Occupational exposure to:
    • Cadmium
    • Asbestos
    • Petroleum by-products such as trichloroethylene (a degreasing agent)
  • Chemotherapeutic agents (e.g., cisplatin) during childhood
  • Chronic analgesic use (acetaminophen, aspirin)

Hereditary renal cell carcinomas [3]

• Von Hippel-Lindau syndrome: Approx. 40% of patients with VHL syndrome develop renal cell carcinomas (usually clear cell RCC).
• Tuberous sclerosis
  • ∼ 5% of people with tuberous sclerosis develop renal cell carcinomas (usually clear cell RCC).
  • RCC that is associated with tuberous sclerosis occurs more commonly in women.
• Birt-Hogg-Dube syndrome
  • Inherited autosomal dominant condition caused by a mutation in the folliculin (FLCN) gene on chromosome 17
  • Characterized by the following symptoms:
    • Skin lesions: fibrofolliculomas, benign hamartomatous tumors of hair follicles
    • Lung cysts
    • Renal cell carcinoma (usually chromophobic RCC or oncocytic RCC)
• Hereditary leiomyomatosis and renal cancer syndrome (HLRCC)
  • Autosomal dominant condition caused by a mutated fumarate dehydrogenase gene located on chromosome 1
  • Characterized by cutaneous and uterine leiomyomas
  • 15% develop type 2 papillary RCC
• Hereditary papillary renal cell carcinoma (HPRCC)
  • Autosomal dominant condition with a high penetrance
  • Caused by activating mutations of the MET proto-oncogene located on the long arm of chromosome 7
  • Usually associated with type 1 papillary RCC
• Succinate dehydrogenase deficiency: autosomal dominant condition associated with pheochromocytomas, extra-adrenal paragangliomas, and renal cell carcinoma.

Hereditary renal cell carcinomas are autosomal dominant and tend to affect patients at a younger age than sporadic renal cell carcinomas.

• Overview
  • Usually asymptomatic in the early stages
  • Patients become symptomatic when the tumor has reached a large size (usually > 10 cm) and/or if metastases are present.
• Constitutional symptoms
  • Weight loss, fatigue
  • Fever, night sweats
  • Anemia
• Symptoms caused by primary tumor
  • Hematuria
  • Flank pain
  • Palpable renal mass
• Symptoms of local spread and metastatic disease: see “Complications” below

The classical triad of renal cell carcinoma consists of hematuria, flank pain, and a palpable flank mass. However, only 10–15% of patients present with all three components of the triad and > 25% present with one or more atypical symptoms related to paraneoplastic syndromes and/or disseminated disease. [5]

TNM classification (8^th Edition, 2017)

AJCC staging (8^th Edition, 2017)

Approach [6][7]

Most renal masses are detected incidentally on imaging performed for another indication or to evaluate nonspecific symptoms.

• Obtain additional imaging in patients with an indeterminate mass. [8]
  • Preferred: CT or MRI abdomen (with IV contrast)
  • Alternative: ultrasound abdomen (with IV contrast)
• Pursue workup based on imaging findings (e.g., repeat imaging for Bosniak IIF cystic mass).

Hematuria may be the initial presentation of RCC. Patients ≥ 35 years of age with asymptomatic microhematuria, and all patients with gross hematuria in the absence of a UTI, should be referred to urology. [7]

Imaging

• Overview: Most renal masses are detected incidentally on imaging performed for another indication or to evaluate nonspecific symptoms.
• Indications
  • Characterization of lesions (e.g., size, regular or irregular walls).
  • Identification of lymph node and/or renal vein involvement. [9][10]
• Modalities and characteristic findings: Abdominal CT, MRI, or ultrasound (with IV contrast) are first-line modalities. ; [6][8]
  • CT abdomen (with IV contrast; multiphase renal protocol)
    • Lesion(s) with thickened irregular walls, calcification, and variable enhancement [10][11][12]
    • Distorted renal outline
  • MRI abdomen (with IV contrast; multiphase renal protocol) [8][9]
    • May be preferred for the assessment of small lesions (< 1.5 cm) and Bosniak IIF or III cystic renal masses
    • Can provide additional information on IVC invasion if findings are unclear on a CT scan [9]
  • Ultrasound abdomen (with IV contrast)
    • Preferred study in patients with contraindications to iodinated contrast for CT and gadolinium-based contrast for MRI.
    • Can identify renal lesion(s) with variable echogenicity [10]

Metastatic evaluation

These may be considered in consultation with a urologist.

• CT or MRI chest (with IV contrast): indicated in patients with large tumors [15][16]
  • May reveal pulmonary cannonball metastases [17]
  • Other common metastatic sites: bone, lymph nodes, liver [18]
• Bone scan: may be indicated in patients with bone pain and/or ↑ ALP [9]
• CT or MRI head: indicated in patients with neurological signs or symptoms [15]
• Other modalities: Metastases may be an incidental finding on initial imaging, e.g., abdominal ultrasound.

Laboratory studies and urinalysis

• Urinalysis
  • Can show frank and microscopic hematuria [19]
  • Measure albumin:creatinine ratio if proteinuria is detected. [6]
• Laboratory studies [6][14][19]
  • CBC
    • Abnormal hemoglobin levels
    • ↑ WBC and/or ↑ platelets [20][21][22]
  • CMP
    • Hypercalcemia
    • ↑ AST, ALT, and/or ALP
    • ↑ BUN:creatinine ratio

Further investigations

• Renal mass biopsy: only required if it may alter the management or is requested by the patient. [6][23]
• Split renal function [9]

Refer patients ≤ 46 years of age with renal malignancy and those with multifocal or bilateral renal masses or other findings suggestive of familial RCC for genetic counseling. [6]

Renal cell carcinomas are adenocarcinomas that usually arise from the epithelial cells of the proximal convoluted tubule.

Rule of 3: A mutation in the VHL (von Hippel-Lindau) gene on chromosome 3 causes RCC (renal cell carcinoma).

Malignant renal masses

• Renal cell carcinoma
• Metastasis from extrarenal tumors
• Urothelial carcinoma of the renal pelvis (∼ 8% of renal tumors)
• Other rare primary malignancies
  • Lymphomas
  • Soft tissue sarcomas
  • Neuroendocrine neoplasms

All renal masses > 1 cm in size are presumed to be renal cell carcinoma and treated as such.

Benign renal masses

Angiomyolipoma [26]

• Definition: benign renal tumors that arise from perivascular epithelioid cells and consist of blood vessels, smooth muscle, and mature fat cells
• Epidemiology
  • Most common benign renal tumor
  • Sex: ♀ > ♂ (4:1)
• Etiology
  • Sporadic
  • Associated with the following syndromes:
    • Tuberous sclerosis (TSC)
    • Sporadic lymphangioleiomyomatosis
• Clinical features
  • Mostly asymptomatic
  • Large angiomyolipomas may present with the following symptoms:
    • Hematuria
    • Retroperitoneal hemorrhage
    • Impaired renal function
  • Symptoms of tuberous sclerosis may be present.
• Diagnostics
  • Abdominal ultrasound: round, well-circumscribed, highly echogenic (similar echogenicity to renal pelvis) renal tumor often located near the renal capsule
  • Abdominal CT
    • Tumor with macroscopic fat deposits
    • No calcification
• Pathology
  • Classic angiomyolipomas: slow growing tumors
  • Epithelioid angiomyolipomas
    • Greater number of epithelioid cells
    • Acidophilic and granular cytoplasm
    • Less fat than classic type
• Treatment: Surgical resection of the tumor is indicated for angiomyolipomas that measure > 4 cm in diameter.

Oncocytoma

• Definition: benign epithelial tumor arising from the intercalated tubular cells in the collecting duct
• Clinical features
  • Painless hematuria
  • Abdominal mass
  • Flank pain
• Pathology
  • Macroscopy: smooth, clearly defined brown tumor with central radial scar
  • Microscopy
    • Large acidophilic cells
    • Excessive amount of mitochondria → acidophilic, granular cytoplasm without perinuclear clearing (unlike chromophobe RCC)
• Treatment
  • Often resected in order to exclude RCC
  • Surveillance
  • Nephrectomy in case of increase in tumor size
• Prognosis: Oncocytomas are not invasive, but they may transform into a malignant oncocytic RCC.

Others

• Renal abscess
• Renal cysts (e.g., polycystic kidney disease)
• Metanephric adenoma
• Granulomatous renal disease (e.g., renal tuberculosis, xanthogranulomatous pyelonephritis)

The differential diagnoses listed here are not exhaustive.

Approach

• Local or locoregional disease: curative treatment intent ; [19][27]
  • Standard of care: nephrectomy (partial or radical) [6]
  • Consider adrenalectomy, lymph node dissection, and adjuvant therapy with sunitinib. [6]
• Metastatic disease: mostly palliative treatment intent but may be curative for patients with a solitary metastasis or oligometastatic disease [9] [19]
  • Targeted and/or immunotherapy
  • In selected patients, surgery (i.e., cytoreductive nephrectomy, metastasectomy) or other local therapies (e.g., embolization) [28]
• Consider active surveillance for patients with: [23]
  • Solid masses < 2 cm
  • Complex masses that are predominantly cystic
  • Limited life expectancy
  • High surgical risk

Surgery [6]

The following applies to patients with solid renal masses or renal cysts with Bosniak classification III or IV. The approach may be open, robotic, or laparoscopic.

• Partial nephrectomy: Only the mass and some surrounding renal tissue are removed; the rest of the kidney is spared. [6]
  • Absolute indications: patients with a T1a renal mass , a solitary kidney, bilateral masses, familial RCC, preexisting chronic kidney disease, or proteinuria [27]
  • Relative indications: patients who are young and/or have a longer life expectancy, multifocal masses, or comorbidities that impact renal function
• Radical nephrectomy
  • Removal of the entire kidney along with the adrenal gland and surrounding perinephric fat, with or without lymph node dissection
  • Preferred in patients with increased oncological risk [6]

Medical therapy [19][28]

• Regimens vary (e.g., axitinib combined with pembrolizumab) and are determined by risk level. [28][30]

Other

• Radiochemotherapy
  • Radiation therapy is not typically used because RCC is usually radioresistant. [28][31]
  • Conventional chemotherapy is not used to treat RCC because RCC is highly resistant to most chemotherapeutic agents. [19]
• Local therapies [6][27]
  • Thermal ablation (e.g., cryoablation): may be appropriate for patients with tumors ≤ 3 cm and/or high surgical risk
  • Embolization of the primary tumor and/or metastases: for symptom control in patients with nonresectable disease [9]

Many RCC tumors are also resistant to chemotherapy due to the expression of multidrug resistance protein 1 (MDR-1) by tumor cells. [9][32]

Complications caused by paraneoplastic syndromes

• Secondary hypercortisolism: due to ectopic ACTH release
• Secondary polycythemia: due to ectopic erythropoietin (EPO) secretion
• Hypertension: due to the release of renin
• Hypercalcemia: due to the release of PTHrP (parathyroid hormone-related protein)
• Leukemoid reaction: due to bone marrow stimulation
• Limbic encephalitis [33]
  • Memory loss
  • Psychosis
  • Depression

Paraneoplastic RCC: Polycythemia (EPO), Renin (hypertension), hyperCalcemia (PTHrP) and hyperCortisolism (ACTH).

Complications caused by local spread

• Varicocele
  • Rare, classically associated with left-sided RCC
  • Malignant cells grow inside the left renal vein and occlude the ostium of the left gonadal vein.
• Budd-Chiari syndrome: caused by involvement of the IVC
  • Lower limb edema
  • Ascites
  • Hepatic dysfunction

Complications caused by metastatic disease

• Overview
  • Spread beyond the renal capsule affects the lymph nodes of the renal hilum and para-aortic nodes.
  • Hematogenous spread occurs via renal vein and IVC.
• Pulmonary metastases: most common site of metastases
  • Hemoptysis
  • Dyspnea
• Bone metastases: second most common site of metastases
  • Bone pain
  • Pathological fractures

Reactive amyloidosis [34]

• Epidemiology: RCC accounts for 25 to 42% of all reported AA amyloidosis cases caused by solid organ malignancies.
• Clinical features
  • Nephrotic syndrome [35][36]
  • Primary adrenal insufficiency
  • Hepatosplenomegaly
  • Malabsorption

We list the most important complications. The selection is not exhaustive.

Survival of kidney cancer patients

• Overall prognosis is determined by the anatomic extent of the disease (stage of cancer at diagnosis) and the histopathology of the tumor.
• Targeted therapies have significantly prolonged survival time.
• Early stage RCC with tumor growth limited to the kidney generally has a good prognosis.

Increased awareness and screening (e.g., ultrasound) of high-risk patients in recent years has led to earlier tumor detection and improved the prognosis of RCC.

Motzer score [38]

Overview

• Used to determine prognosis of patients with stage IV (distant) disease
• A point is assigned for each of the following criteria.
• Based on the resulting score, the prognosis of the metastatic RCC patient is estimated.
• High scores are associated with a poorer prognosis.

Instrument

Interpretation