What is used to determine the type of renal cell carcinoma?

Determination of Renal Cell Carcinoma Type

The type of renal cell carcinoma is determined primarily by histopathological examination of tissue obtained from either core needle biopsy or nephrectomy specimen, using the World Health Organization (WHO) classification system based on tumor histology, chromosomal alterations, and molecular pathways. 1

Primary Diagnostic Method: Histopathological Assessment

Core needle biopsy or surgical specimen examination provides definitive histological classification with high sensitivity (86-100%) and specificity (98-100%). 1

When Biopsy is Mandatory:

• Before starting systemic treatment in metastatic disease 1
• Prior to ablative therapies 1
• When imaging findings are equivocal and would alter management 2

Key Histological Features Used for Classification:

Clear Cell RCC (70-85% of cases):

• Clear cytoplasm due to glycogen and lipid accumulation 1, 3
• Cells distributed in tubular and solid areas with prominent capillary stroma 1
• Associated with VHL gene mutations and 3p25-26 chromosomal abnormalities 1

Papillary RCC (7-15% of cases):

• Malignant cells arranged around capillary cores (papillae) 1
• Type I: scarce cytoplasm, associated with c-MET mutations 1
• Type II: eosinophilic cytoplasm, associated with SETD2 mutations or FH mutations 1
• Strong expression of α-methylacyl-CoA racemase 1

Chromophobe RCC (5-10% of cases):

• Polygonal cells with clear cytoplasmic membrane delimitation 1
• Pale reticulated cytoplasm with abundant 150-300 nm diameter vesicles 1
• Diffuse positivity for cytokeratin 7 (CK7) distinguishes from oncocytoma 1
• Chromosomal losses in 1,2,6,10,13,17, and 21 1

Molecular Classification (Emerging Standard)

The 2022 WHO classification introduced 11 molecular-defined RCC subgroups that cannot be diagnosed by morphology alone, requiring molecular analysis techniques. 1, 4

Key Molecular Subtypes Requiring Special Testing:

MiT family translocation RCC:

• Must be ruled out in patients <40 years with papillary or complex architecture 1
• Diagnosis requires immunohistochemistry and FISH analysis for TFE3/TFEB rearrangement 1, 4

FH-deficient RCC:

• Associated with hereditary leiomyomatosis and RCC syndrome 1
• Usually type 2 papillary RCC with poor prognosis 1

SDH-deficient RCC:

• Requires specific molecular testing 1

ALK-rearranged RCC:

• Directs use of ALK inhibitors 4

Additional Prognostic Factors Required in Pathology Report

Beyond subtype determination, the following must be documented: 1

• ISUP nucleolar grading system (grades 1-4, applied to clear cell and papillary RCC) 1
• Sarcomatoid and/or rhabdoid differentiation (defines grade 4 tumor) 1
• Presence of necrosis 1
• Microscopic vascular invasion 1
• pTNM staging 1

Molecular Testing for Prognostication and Treatment Selection

Specific gene mutations correlate with prognosis and guide therapy selection in clear cell RCC: 4

• PBRM1 mutations: Associated with stage III features but generally favorable prognosis 4
• BAP1 mutations: Correlated with larger tumor size, higher nuclear grade, and worse cancer-specific survival 4
• SETD2 mutations: Associated with increased tumor aggressiveness 4
• MTOR mutations: Predict sensitivity to mTOR inhibitors (everolimus, temsirolimus) 4

Practical Algorithm for RCC Type Determination

1. Obtain tissue: Core needle biopsy (preferred before systemic therapy) or nephrectomy specimen 1

2. Establish histologic subtype: Priority is clear cell versus non-clear cell and presence of sarcomatoid features 4

3. Apply WHO 2022 classification: Based on morphology, immunohistochemistry, and when available, molecular testing 1, 4

4. Consider molecular testing when:

   • Patient age <40 years (rule out translocation RCC) 1, 4
   • Rare subtypes that cannot be diagnosed morphologically 1, 4
   • Actionable targets needed for treatment selection 4

5. Document all prognostic factors: Grade, necrosis, vascular invasion, sarcomatoid features 1

Common Pitfalls to Avoid

Do not rely solely on imaging to determine RCC subtype – while certain imaging features may suggest specific subtypes, histopathological confirmation is mandatory before systemic treatment. 1

Do not skip biopsy in metastatic disease – even if nephrectomy is planned, pre-treatment biopsy provides critical information for treatment selection and avoids unnecessary surgery in some cases. 1

Do not use outdated Fuhrman grading – the ISUP nucleolar grading system has replaced Fuhrman grading and should be applied only to clear cell and papillary RCC. 1

Tumor seeding from biopsy is exceptional – this should not deter appropriate tissue diagnosis, as complications are rare. 1