Renal Cell Carcinoma for ABIM

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Renal Cell Carcinoma for the American Board of Internal Medicine Exam

Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 85% of cases. It arises from the epithelial cells of the renal tubules and most commonly occurs in adults. RCC can present in various histologic subtypes, with clear cell carcinoma being the most prevalent.

RCC primarily affects individuals aged 60-70 years, with a higher prevalence in men. Risk factors include:
Smoking: Strong association, particularly with long-term smoking.
Obesity: Increased risk due to metabolic changes, particularly in women.
Hypertension: Both treated and untreated hypertension are risk factors.
Occupational Exposures: Chemicals such as trichloroethylene.
Genetic Predispositions:
Von Hippel-Lindau (VHL) disease: An autosomal dominant disorder associated with a higher risk of clear cell RCC due to mutations in the VHL gene.
Hereditary leiomyomatosis and Birt-Hogg-Dubé syndrome are also associated with increased RCC risk.
End-stage Renal Disease (ESRD): Long-standing dialysis and acquired renal cystic disease increase RCC risk.

RCC arises from the proximal renal tubular epithelium and can be divided into various histologic subtypes:
Clear Cell RCC: Accounts for 75-85% of cases, characterized by clear or granular cytoplasm due to lipid and glycogen accumulation.
Papillary RCC: Comprises about 10-15% of cases, with two subtypes (type 1 and type 2). Associated with hereditary and sporadic forms.
Chromophobe RCC: Rare, accounting for 5% of cases, with pale eosinophilic cells. It generally has a better prognosis than clear cell RCC.
Collecting Duct Carcinoma: A rare and aggressive subtype with a poor prognosis.
RCC commonly invades local structures, including the renal vein, which can lead to the extension of tumor thrombus into the inferior vena cava (IVC). Hematogenous spread is common, with metastases often found in the lungs, bones, liver, and brain.

RCC is often asymptomatic in its early stages and may be incidentally discovered on imaging for unrelated conditions. Classic symptoms, known as the triad of hematuria, flank pain, and a palpable abdominal mass, are only seen in a minority of patients and usually signify advanced disease.
Hematuria: Most common symptom, often gross and intermittent.
Flank Pain: Results from tumor growth and renal capsule distension.
Palpable Mass: Can be felt in advanced cases due to large tumor size.
Paraneoplastic Syndromes: Occur in about 20% of patients and include:
Hypercalcemia: Due to tumor production of parathyroid hormone-related peptide (PTHrP).
Polycythemia: Caused by ectopic erythropoietin production by the tumor.
Hypertension: Due to increased renin production.
Stauffer Syndrome: A reversible, non-metastatic liver dysfunction associated with RCC.

Imaging:
Ultrasound: Often the initial test for hematuria, it can identify solid renal masses but is less sensitive for small tumors.
CT Scan (Abdomen/Pelvis): The gold standard for diagnosing and staging RCC. Non-contrast and contrast-enhanced phases help differentiate solid from cystic lesions and evaluate tumor invasion into the renal vein or IVC.
MRI: Useful in evaluating venous involvement (e.g., IVC thrombus) or when radiation exposure needs to be minimized (e.g., in pregnant women).
Biopsy: Not routinely performed for typical radiologic presentations of RCC, but it may be used in cases of indeterminate lesions or when metastasis is suspected without a clear renal primary tumor.
Lab Tests: May show nonspecific findings such as elevated erythrocyte sedimentation rate (ESR), anemia, or polycythemia. Hypercalcemia or abnormal liver function tests may indicate paraneoplastic syndromes.

RCC is staged according to the TNM system (Tumor, Node, Metastasis), which evaluates tumor size and spread to lymph nodes and distant organs.
Stage I: Tumor confined to the kidney, ≤7 cm.
Stage II: Tumor >7 cm but still confined to the kidney.
Stage III: Tumor invasion of local structures such as the renal vein or perinephric tissues, but no distant metastasis.
Stage IV: Distant metastasis or invasion of adjacent organs (e.g., beyond Gerota’s fascia).

Surgical Treatment:
Radical Nephrectomy: The treatment of choice for localized RCC, involving removal of the kidney, adrenal gland, and surrounding fat. It is indicated for large tumors or those invading local structures.
Partial Nephrectomy: Preferred for small tumors (<4 cm) or patients with solitary kidneys or poor renal function. It preserves renal tissue while removing the tumor.
Cytoreductive Nephrectomy: May be performed in patients with metastatic disease to reduce tumor burden before systemic therapy.
Ablative Therapies:
Radiofrequency Ablation (RFA) and Cryoablation are options for patients who are poor surgical candidates due to comorbidities or for small tumors.
Systemic Therapy:
Targeted Therapy: Tyrosine kinase inhibitors (e.g., sunitinib, pazopanib) and mTOR inhibitors (e.g., everolimus, temsirolimus) are the mainstay for advanced or metastatic RCC. These therapies inhibit angiogenesis and tumor growth.
Immune Checkpoint Inhibitors: Drugs such as nivolumab and pembrolizumab (PD-1 inhibitors) are increasingly used for metastatic RCC, particularly in combination with targeted therapies.
Cytokine Therapy: High-dose interleukin-2 (IL-2) was historically used but is now less common due to significant toxicity.
Radiation Therapy: Generally reserved for palliation of symptoms in patients with metastatic disease (e.g., bone pain).

Prognosis depends on the stage at diagnosis. Five-year survival rates range from 90-95% for localized disease (stage I) to 10-20% for metastatic disease (stage IV).
Key prognostic factors include tumor stage, histologic subtype, performance status, and response to therapy.

Key Points

Renal cell carcinoma (RCC) is the most common kidney cancer, with clear cell carcinoma being the predominant subtype.
Risk factors for RCC include smoking, obesity, hypertension, and genetic syndromes like Von Hippel-Lindau disease.
Clinical presentation often includes hematuria, flank pain, and palpable mass, but many cases are detected incidentally. Paraneoplastic syndromes, including hypercalcemia and polycythemia, may occur.
Diagnosis is primarily based on imaging (CT or MRI), with biopsy reserved for indeterminate cases.
Treatment depends on the stage. Surgery (radical or partial nephrectomy) is the mainstay for localized disease, while targeted therapies (tyrosine kinase inhibitors, immune checkpoint inhibitors) and systemic treatments are used for advanced or metastatic RCC.
Prognosis is favorable for early-stage disease but poor for metastatic RCC. Five-year survival ranges from 90% in stage I to 10-20% in stage IV disease.