- Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults, accounting for about 85–90% of all primary malignant kidney tumors. It originates from the epithelial cells of the renal tubules, which are responsible for filtering blood and forming urine.
- RCC is a heterogeneous disease, encompassing several histological subtypes with distinct genetic, pathological, and clinical characteristics. The major subtypes include clear cell RCC (the most prevalent, about 70–75%), papillary RCC (10–15%), and chromophobe RCC (5–7%), with rarer forms such as collecting duct carcinoma, translocation RCC, and unclassified variants.
- The etiology and risk factors for RCC are multifactorial. Established risk factors include smoking, obesity, hypertension, and chronic kidney disease. A family history of RCC and hereditary syndromes such as von Hippel–Lindau (VHL) disease, hereditary papillary RCC, Birt–Hogg–Dubé syndrome, and tuberous sclerosis complex also significantly increase risk. Occupational exposure to certain toxins, as well as male sex and older age, further contribute to susceptibility.
- At the molecular level, RCC subtypes are driven by different genetic alterations. Clear cell RCC is strongly associated with mutations or inactivation of the VHL gene, leading to stabilization of hypoxia-inducible factors (HIFs) and activation of angiogenic pathways. Papillary RCC often involves mutations in the MET gene, while chromophobe RCC is characterized by multiple chromosomal losses. These distinct molecular mechanisms explain variations in tumor biology, clinical behavior, and therapeutic response across RCC subtypes.
- Clinically, RCC has been called the “internist’s tumor” because of its variable and often silent presentation. Many cases are discovered incidentally during imaging for unrelated conditions. When symptomatic, the classic triad—hematuria (blood in urine), flank pain, and a palpable mass—is observed, though it occurs in fewer than 10% of patients. Other presentations may include unexplained fever, weight loss, hypertension, polycythemia, or paraneoplastic syndromes due to abnormal hormone production. RCC has a notorious tendency to metastasize, with common sites including lungs, bones, liver, and brain, sometimes even after nephrectomy for localized disease.
- Diagnosis typically relies on imaging modalities such as ultrasound, CT scans, and MRI. Biopsy may be used in uncertain cases, though it is not always necessary if imaging findings are typical. Pathological analysis after surgical resection remains the gold standard for confirming subtype and grade. Staging follows the TNM classification, which assesses tumor size and extent, nodal involvement, and presence of distant metastases.
- The management of RCC depends on stage and patient factors. For localized disease, surgical resection remains the cornerstone, with options including radical nephrectomy (removal of the entire kidney) or nephron-sparing surgery (partial nephrectomy). Ablative techniques such as cryoablation or radiofrequency ablation may be considered for small tumors or patients unfit for surgery. In advanced or metastatic disease, systemic therapies are the mainstay. These include targeted therapies against angiogenesis and tyrosine kinase pathways (e.g., sunitinib, pazopanib, cabozantinib) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab, ipilimumab). Combination regimens have improved survival outcomes compared to older cytokine-based therapies.
- The prognosis of RCC varies widely depending on stage, grade, and histological subtype. Localized RCC treated surgically has favorable survival rates, with 5-year survival often exceeding 70–80%. However, advanced or metastatic RCC has historically carried a poor prognosis. Thanks to the advent of immunotherapy and targeted agents, outcomes for advanced disease have improved substantially, though cure remains rare once distant metastases occur.
- In summary, renal cell carcinoma is a biologically diverse and clinically significant malignancy with rising incidence worldwide. Its varied histological subtypes reflect distinct genetic drivers, which increasingly guide diagnosis, prognosis, and therapy. While surgical treatment cures many localized cases, systemic therapies based on molecular and immunologic insights are transforming the landscape for advanced disease. Continued integration of precision medicine promises further improvements in managing this complex cancer.
