What are the biomarkers for renal cell carcinoma (RCC)?

Cancer Biomarkers for Renal Cell Carcinoma

Diagnostic Biomarkers

For clear cell RCC (ccRCC), PAX8 and carbonic anhydrase IX (CAIX) are the primary diagnostic markers recommended for histological evaluation. 1

Immunohistochemical Markers

• CAIX shows diffuse membranous positivity in 94% of clear cell RCCs and is the most characteristic diagnostic marker for this subtype 2, 3
• PAX8 is commonly used alongside CAIX for confirming ccRCC diagnosis 1
• Cytokeratin 7 (CK7) is typically absent or focal in ccRCC, though rare cases may show diffuse staining 2
• c-kit expression is a typical feature of chromophobe RCC 2
• α-methylacyl-CoA racemase shows strong expression in papillary RCC 2

Hereditary Syndrome Markers

• Loss of FH (fumarate hydratase) expression is highly specific (but imperfectly sensitive) for FH-deficient RCC 2
• Positive 2SC staining is highly sensitive (but imperfectly specific) for FH-deficient RCC 2
• Loss of SDHB expression is highly specific for succinate dehydrogenase deficient RCC 2
• Loss of both SDHA and SDHB indicates SDHA mutation-associated tumors 2
• Use a low threshold for FH, 2SC, and SDHB immunohistochemistry in any difficult-to-classify renal carcinoma, particularly in younger patients 2

Prognostic Biomarkers

Clinical Prognostic Systems

The International Metastatic RCC Database Consortium (IMDC) system is the gold standard for risk assessment in metastatic disease. 1

The IMDC system includes six factors: 1

• Karnofsky performance status <80%
• Hemoglobin below the lower limit of normal
• Time from diagnosis to treatment <1 year
• Corrected calcium above the upper limit of normal
• Platelets above the upper limit of normal
• Neutrophils above the upper limit of normal

This system is applicable in subsequent lines of therapy and in non-clear cell histology 1

Molecular Prognostic Markers

BAP1 and PBRM1 mutations provide independent prognostic information, with BAP1-mutant tumors having significantly worse outcomes than PBRM1-mutant tumors. 2

• BAP1 mutations correlate with larger tumor sizes, higher nuclear grade, and worse cancer-specific survival 4
• PBRM1 mutations (present in 29-41% of ccRCC) are associated with stage III pathological features but generally indicate more favorable prognosis than BAP1 mutations 2, 4
• SETD2 mutations (8-12% of ccRCC) are implicated in tumor progression 4
• VHL mutation status alone has no effect on clinical outcome as it is the founding event of ccRCC 4

Chromosomal Alterations

• 3p loss of heterozygosity is nearly universal in ccRCC and constitutes an early genetic event 4
• Tumor progression is associated with losses of 9p and 14q, and gain of 5q 2
• Gain of chromosomal regions 7q, 8q, and 20q, and losses of 9p, 9q, and 14q are associated with poor survival 2

Immunotherapy-Related Biomarkers

PD-L1 tumor expression has a negative prognostic role when elevated, though its predictive value remains controversial. 2, 1

• PD-L1 can identify patients who benefit from combination immunotherapy 1
• Discrepancies in PD-L1 expression between primary tumor and metastases limit its utility 2, 1
• Additional potential biomarkers include tumor mutation burden, CD8+ T-cell density, and gene expression signatures 2

CAIX as a Prognostic Marker

• Low CAIX staining (≤85%) is an independent poor prognostic factor for survival in metastatic RCC, with a hazard ratio of 3.10 3
• Overall CAIX expression decreases with development of metastasis 3
• CAIX significantly substratifies patients with metastatic disease when analyzed by T stage, Fuhrman grade, nodal involvement, and performance status 3

Subtype-Specific Molecular Markers

Clear Cell RCC

• VHL gene mutations or inactivation present in the vast majority of sporadic ccRCC cases 4
• Loss of VHL leads to aberrant HIF accumulation, resulting in uncontrolled activation of angiogenesis, glycolysis, and apoptosis genes 4

Papillary RCC

• Type 1: c-MET mutations 2, 4
• Type 2: SETD2 mutations, CDKN2A mutations, or TFE3 fusions 5, 4
• NRF2-ARE pathway activation associated with type 2 papillary RCC 4

Chromophobe RCC

• TP53 is the most frequently mutated gene (32%) 5
• Chromosomal losses in chromosomes 1,2,6,10,13,17, and 21 2, 5

Common Pitfalls

• Not performing biopsy before ablative treatments can lead to treatment of benign lesions, as up to 30% of T1a masses are benign 1
• Relying solely on PD-L1 expression is problematic due to discrepancies between primary tumor and metastases, different tests and cut-offs used, and heterogeneity of expression 2, 1
• Failing to compare metastatic tissue with primary histology when diagnosing metastatic ccRCC, particularly when diagnostic material from the primary tumor is not available 1
• Not using low threshold for hereditary syndrome markers (FH, 2SC, SDHB) in difficult-to-classify renal carcinomas, especially in younger patients 2