What are the different types of kidney cancer?

Types of Kidney Cancer

Renal cell carcinoma comprises three major histological subtypes—clear cell (70-85%), papillary (7-15%), and chromophobe (5-10%)—with each demonstrating distinct molecular characteristics, clinical behavior, and treatment responses that directly impact patient outcomes. 1

Major Histological Subtypes

Clear Cell Renal Cell Carcinoma (ccRCC)

Clear cell RCC is the most common subtype, accounting for 70-85% of all renal cell carcinomas in adults. 1

• The hallmark microscopic feature is the clear cytoplasmic appearance caused by glycogen and lipid accumulation, which dissolves during routine histological processing. 1, 2
• Tumor cells are arranged in tubular and solid patterns with prominent capillary stroma, reflecting the highly vascularized nature of these tumors. 1, 2
• Molecularly, ccRCC is associated with VHL gene mutations and chromosomal abnormalities at 3p25-26 in 34-56% of sporadic cases. 1, 3
• The multilocular cystic variant represents a low-aggressivity subtype composed entirely of numerous cysts lined by clear cells. 1, 2

Papillary Renal Cell Carcinoma (pRCC)

Papillary RCC accounts for 7-15% of cases and is named for the distribution of malignant cells around capillary cores (papillae). 1, 3

• The 2022 WHO classification no longer divides papillary RCC into type 1 and type 2 subtypes due to poor interobserver reproducibility and lack of proven clinical significance. 1
• Extensive necrosis is common in papillary RCC but is not an adverse prognostic factor, unlike in clear cell RCC. 1
• Molecularly, papillary RCC type 1 is associated with c-MET mutations, trisomy/tetrasomy 7, trisomy 17, and loss of chromosome Y. 1, 3
• WHO/ISUP grade and tumor architecture, rather than classic tumor types, better predict outcomes. 1

Chromophobe Renal Cell Carcinoma

Chromophobe RCC represents 5-10% of cases and features polygonal cells with clear cytoplasmic membrane delimitation. 1, 3

• The pale reticulated cytoplasm results from abundant cytoplasmic invaginated 150-300 nm diameter vesicles. 1
• Molecularly characterized by chromosomal losses in chromosomes 1,2,6,10,13,17, and 21, with association to Birt-Hogg-Dubé syndrome. 1, 3
• c-kit expression is a typical feature of chromophobe cells. 1

Rare Histological Subtypes

Collecting Duct Carcinoma (Bellini Tumors)

Collecting duct RCC accounts for less than 1% of cases and originates from the medullary distal nephron or Bellini ducts. 1, 3

• Characterized by high nuclear grade, eosinophilic cytoplasm, predominant tubular arrangement, desmoplasia, and expression of high-molecular-weight cytokeratins. 1
• Medullary RCC is considered an undifferentiated variant of collecting duct carcinoma. 1

Translocation RCC

Translocation RCC is a rare entity mainly observed in children or young adults, characterized by specific chromosomal translocations. 1

• Most commonly involves translocation of Xp11.2 with gene-fusion TFE3, or less frequently translocation t(6;11)(p21;q12) with fusion TFEB. 1
• The 2022 WHO classification introduced molecular-driven approaches for these subtypes that cannot be diagnosed by morphology alone. 1, 4

Additional Rare Variants

Several other rare histological variants have been recognized, each with distinct features: 1

• Mucinous tubular and spindle cell carcinoma represents a distinct entity with characteristic morphology. 1
• Tubulocystic RCC is composed of packed tubules and cysts lined by cuboidal or hobnail cells with abundant eosinophilic cytoplasm and may represent a subset of papillary RCC. 1
• Clear-cell papillary RCC is often associated with end-stage renal disease. 1

Critical Clinical Considerations

Sarcomatoid Differentiation

Sarcomatoid features can occur in all RCC subtypes and do not represent a distinct entity, but denote high-grade and very aggressive tumors. 1, 5

• Sarcomatoid and/or rhabdoid differentiation defines a grade 4 tumor regardless of the cell of origin. 3
• This variant can account for approximately one in six cases of advanced kidney cancer and carries a poor prognosis. 5

Molecular Classification Impact

The 2022 WHO classification introduced 11 subgroups of molecular-defined RCC that cannot be diagnosed by morphology alone, requiring molecular testing for accurate diagnosis. 1, 4

• Key molecular subtypes with therapeutic implications include eosinophilic solid and cystic RCC, ALK-rearranged RCC, TFEB-altered RCC, SMARCB1-deficient medullary RCC, and FH-deficient RCC. 4
• Molecular classification is recommended but not yet mandated due to limited availability and lack of actionable targets for most identified mutations. 4

Prognostic Implications

Different RCC subtypes demonstrate distinct clinical behavior and prognosis, with clear cell and papillary type II generally showing worse outcomes than chromophobe and papillary type I. 1

• Papillary RCC type I has significantly lower risk of death compared to clear cell RCC and papillary type II in the nonmetastatic setting. 1
• Each subtype responds differently to systemic therapy, making accurate histological classification essential for treatment planning. 1, 6, 7