General characteristics of the disease
Renal cell carcinoma originates from the epithelium of the proximal renal tubules and is coded in the ICD as C64. The letter C in the classification denotes malignant oncological diseases in the majority of cases (over 90%), though there are exceptions: for instance, carcinoma in situ, which by definition is not invasive, is coded with the letter D. This same letter is used for benign lesions and incidental findings for which a histological report has not yet been obtained.
Renal cell carcinoma should be distinguished from transitional cell carcinoma of the kidney, which arises from the epithelium of the renal pelvis and calyces. This is a fundamentally different nosology with its own clinical course, and within the scope of this topic, only renal cell carcinoma (C64) is considered.
Epidemiology and risk factors
Renal cell carcinoma is a relatively rare tumor, accounting for about 4–5% of all malignancies. In recent years, an increase in detection rates has been observed, which is likely due to improved diagnostic methods rather than a true rise in incidence.
Risk factors include:
- male sex (although women are also frequently encountered in clinical practice);
- smoking;
- obesity;
- arterial hypertension (hypertensive disease) of various etiologies;
- long-term maintenance hemodialysis — in such patients, the kidneys frequently undergo cystic degeneration, from which a tumor may subsequently develop.
TNM staging system
Renal cell carcinoma, like other solid tumors, is staged using the TNM system:
- T — primary tumor characteristics;
- N — regional lymph node involvement (involvement is either present or absent);
- M — presence of distant metastases.
The most common metastatic sites are the lungs, bones, liver, as well as the contralateral kidney and brain. Lung metastases are detected most frequently because a chest CT is performed almost universally during staging. Brain metastases are detected significantly less often since a brain CT or MRI is not prescribed to all patients as part of the initial workup, although the true incidence of involvement may be comparable. Rare metastatic sites are also possible, including superficial lymph nodes, which requires histological confirmation if another primary tumor is suspected.
Clinical presentation
The symptoms of renal cell carcinoma remain hidden for a long time: the patient may be asymptomatic until the tumor reaches a significant size. As the disease progresses, the following appear:
- pain in the lumbar region;
- hematuria (blood in the urine);
- arterial hypertension;
- paraneoplastic syndrome in advanced disease — weight loss, intoxication, arthralgia, and other general manifestations.
These symptoms are nonspecific and typically appear only in advanced disease; therefore, a significant proportion of tumors are discovered incidentally during examinations for other reasons.
Diagnostics
Most commonly, a renal mass is first detected on an ultrasound performed for other indications. Unlike simple cysts, tumor tissue usually has its own blood supply, which is visible on Doppler ultrasound: a hypervascular and richly supplied mass has a high probability of being a tumor, as tumor growth requires a continuous influx of blood and nutrients.
The gold standard for diagnosis is contrast-enhanced CT of the abdomen and pelvis, used both to confirm the diagnosis and to plan surgical treatment.
To evaluate cystic renal lesions, the Bosniak classification (analogous to the TI-RADS scale for the thyroid gland) is used:
- Bosniak category 1 — simple cyst;
- Bosniak category 2 — minimally complex cyst;
- Bosniak categories 3–4 — high probability of malignancy, with surgical treatment indicated in virtually all cases.
A distinct entity is angiomyolipoma, a benign renal tumor that does not require surgical intervention except for large sizes or clinical symptoms (in such cases, nephron-sparing surgery is performed). PET and MRI have low diagnostic value in renal cell carcinoma and are used in a limited capacity.
Surgical treatment
Surgical intervention remains the primary treatment for localized renal cell carcinoma. The scope of surgery depends on the size and location of the tumor:
- partial nephrectomy (nephron-sparing surgery) — for a small volume of involvement;
- radical nephrectomy (complete removal of the kidney) — for a large volume of involvement;
- thrombectomy — additional removal of tumor thrombi from the renal vessels when they are involved in the process.
The definitive diagnosis is established solely on the basis of histological examination of the surgical specimen, because a mass that appears suspicious for a tumor on imaging may prove to be benign, such as an oncocytoma — a lesion that visually resembles a malignant tumor but is incapable of metastasizing.
Renal biopsy is performed relatively rarely, primarily in elderly patients for whom surgery is contraindicated due to their general condition. In solitary metastases in patients with a solitary kidney, removal of the primary tumor (resection) and the metastasis while preserving renal function is possible, which is preferable to subsequent dialysis. In the absence of indications for radical treatment and in the presence of small, asymptomatic masses in frail patients, active surveillance is used, and in rare cases, ablation.
Systemic therapy for metastatic renal cell carcinoma
Metastatic renal cell carcinoma is characterized by resistance to standard treatments:
- radiation therapy is practically not used, except for palliative irradiation of bone metastases to reduce pain;
- classical chemotherapy is ineffective because renal cell carcinoma cells express multidrug resistance proteins.
The mainstay of treatment is targeted therapy, which targets two key pathways:
- VEGFR (vascular endothelial growth factor receptor) — renal tumors actively stimulate angiogenesis, and drugs in this class (sunitinib, pazopanib, and other tyrosine kinase inhibitors) inhibit the growth of new blood vessels;
- mTOR (mechanistic target of rapamycin) — regulates cell growth; mTOR inhibitors (everolimus) and newer VEGFR inhibitors are administered in tablet form, facilitating long-term therapy.
Therapy is long-term and continuous in nature, aimed at slowing tumor growth rather than achieving a complete cure. Additionally, immunotherapy with immune checkpoint inhibitors—such as nivolumab and pembrolizumab, which target the PD-1 (programmed cell death protein 1) receptor—is used to restore the anti-tumor immune response. Combination regimens are also utilized, including pembrolizumab combined with tyrosine kinase inhibitors. Immunotherapy is less well tolerated by patients than targeted therapy and is accompanied by its own spectrum of side effects.
Key points
- Renal cell carcinoma (C64) develops from the epithelium of the proximal tubules and differs from transitional cell carcinoma of the renal pelvis and calyces.
- The main risk factors are smoking, obesity, arterial hypertension, and long-term hemodialysis.
- The disease is staged using the TNM system; the most frequent metastases are found in the lungs, bones, liver, and brain.
- The clinical presentation remains asymptomatic for a long time, with the majority of tumors being detected incidentally on ultrasound.
- The gold standard for diagnosis is contrast-enhanced CT; cystic lesions are evaluated using the Bosniak classification.
- Surgical treatment (partial or radical nephrectomy) remains the primary method, and the definitive diagnosis is established solely by histology.
- The tumor is resistant to radiation therapy and classical chemotherapy.
- Systemic treatment for metastatic disease includes targeted therapy (VEGFR and mTOR inhibitors) and immunotherapy with PD-1 inhibitors.