What is RCC (Renal Cell Carcinoma)?

Renal Cell Carcinoma (RCC)

RCC is a heterogeneous group of cancers originating from renal tubular epithelial cells, accounting for >90% of kidney cancers, with clear cell RCC being the most common subtype (70-85%) and responsible for most cancer-related deaths. 1, 2

Histological Subtypes

• Clear cell RCC (70-85%): Most common subtype characterized by cells with clear cytoplasm due to glycogen and lipid content, arranged in tubular and solid areas with prominent capillary stroma. Associated with VHL gene mutations. 1, 2

• Papillary RCC (7-15%): Named for the distribution of malignant cells around capillary cores (papillae). Two subtypes:

  • Type I (73% of cases): Cells with scarce cytoplasm
  • Type II (42% of cases): Cells with eosinophilic cytoplasm 1, 2

• Chromophobe RCC (5-10%): Features polygonal cells with clear cytoplasmic membrane delimitation and pale reticulated cytoplasm due to cytoplasmic invaginated vesicles. Associated with Birt-Hogg-Dubé syndrome. 1, 2

• Collecting duct RCC (Bellini tumors) (<1%): Originates from medullary distal nephron or Bellini ducts, displaying high nuclear grade, eosinophilic cytoplasm, tubular arrangement, and desmoplasia. 1, 2

• Other rare subtypes: Include translocation RCC, mucinous tubular and spindle cell carcinoma, tubulocystic RCC, and clear-cell papillary RCC. 1, 2

Molecular and Genetic Characteristics

• Clear cell RCC: Associated with VHL gene mutations or inactivation in the majority of cases, leading to aberrant accumulation of hypoxia-inducible factors (HIFs) and uncontrolled activation of genes regulating angiogenesis, glycolysis, and apoptosis. 3

• Papillary RCC: Type 1 is associated with c-MET mutations, while type 2 is linked to SETD2 mutations, CDKN2A mutations, or TFE3 fusions. 2, 3

• Chromophobe RCC: Shows chromosomal losses in chromosomes 1,2,6,10,13,17, and 21, with TP53 being the most frequently mutated gene. 2, 3

Pathways and Therapeutic Targets

• Hypoxia-inducible pathway: Involved in clear cell and papillary type II RCC. 1
• mTOR signaling pathway: Important in clear cell and papillary type II RCC. 1
• c-Met-RAF-MEK-ERK pathway: Active in papillary type I and translocation RCC. 1
• c-kit-RAF-MEK-ERK pathway: Relevant in chromophobe RCC. 1

Staging

RCC is staged using the UICC TNM classification system (7th edition, 2009): 1

• T1: Tumor ≤7 cm in greatest dimension, limited to the kidney

  • T1a: Tumor ≤4.0 cm
  • T1b: Tumor >4.0 cm but ≤7.0 cm

• T2: Tumor >7.0 cm in greatest dimension, limited to the kidney

  • T2a: Tumor >7 cm but ≤10 cm
  • T2b: Tumor >10 cm, limited to the kidney

• T3: Tumor extends to major veins or peri-nephric tissues but not beyond Gerota fascia

  • T3a: Tumor extends into renal vein or invades peri-renal/renal sinus fat
  • T3b: Tumor extends into vena cava below diaphragm
  • T3c: Tumor extends into vena cava above diaphragm or invades vena cava wall

• T4: Tumor invades beyond Gerota fascia (including ipsilateral adrenal gland) 1

Clinical Presentation and Diagnosis

• Many patients (37-61%) are diagnosed incidentally on abdominal imaging studies, with 70% having stage I disease at diagnosis. 4

• Despite surgical intervention with curative intent, approximately 30% of patients with localized ccRCC eventually develop metastases. 1

Treatment Approaches

• Localized RCC: Surgical resection (partial or radical nephrectomy), ablative techniques, or active surveillance for small masses. 1, 4

  • Partial nephrectomy for masses <4 cm can result in 5-year cancer-specific survival >94%. 4

• Advanced/Metastatic RCC: Combinations of immune checkpoint inhibitors or immune checkpoint inhibitors with tyrosine kinase inhibitors, showing tumor response rates of 42-71% and median overall survival of 46-56 months. 4

• T3 Disease Management: Open radical nephrectomy remains standard of care, with the goal of obtaining negative margins. Systematic adrenalectomy and extensive lymph node dissection are not routinely recommended without evidence of invasion. 5

Risk Assessment

• Risk assessment models for localized tumors include the Stage Size Grade and Necrosis (SSIGN) score and the UCLA Integrated Staging System (UISS). 1

• T3 clear cell RCC is considered high risk with a 5-year metastasis-free survival of approximately 31.2% for patients with a SSIGN score ≥6. 5

Important Clinical Considerations

• Understanding the histological subtype is crucial for treatment planning as different subtypes respond differently to various therapies. 2

• The discovery of molecular pathways has led to targeted therapies for metastatic RCC, particularly those inhibiting VEGF and its receptor VEGFR for clear cell RCC. 3

• Sunitinib, a tyrosine kinase inhibitor, is approved for advanced RCC but can cause serious side effects including severe liver problems. 6