What are the histologic subtypes of renal cell carcinoma and their characteristic microscopic features and clinical behavior?

Renal Cell Carcinoma Histology

Renal cell carcinoma comprises five major histologic subtypes—clear cell (70-85%), papillary (7-15%), chromophobe (5-10%), collecting duct (<1%), and translocation RCC—each with distinct microscopic features, molecular profiles, and clinical behaviors that directly impact treatment selection and prognosis. 1, 2

Major Histologic Subtypes and Microscopic Features

Clear Cell RCC (70-85% of cases)

• Microscopic hallmark: Cells with clear cytoplasm due to abundant glycogen and lipid accumulation, arranged in tubular and solid growth patterns with a prominent capillary stroma 1
• Molecular signature: VHL gene mutations with chromosomal loss at 3p25-26 in 34-56% of sporadic cases 1
• Immunohistochemistry: CD10-positive (86-94%), CAIX-positive (94%), CK7-negative or focal, vimentin-positive 2, 3
• Clinical behavior: Generally worse overall survival compared to chromophobe and papillary type I 2
• Multilocular cystic variant: Composed entirely of cysts lined by clear cells; represents a low-aggressivity variant 1

Papillary RCC (7-15% of cases)

• Microscopic hallmark: Malignant cells arranged around capillary cores (papillae) in 50-70% of the tumor 1
• Historical subtypes (no longer recommended): Type I with scarce cytoplasm (73% of cases) and Type II with eosinophilic cytoplasm (42% of cases); the 2022 WHO classification eliminated this subdivision due to poor inter-observer reproducibility 1, 2
• Molecular signature: Type I associated with c-MET mutations; Type II with fumarate-hydratase or SETD2 mutations 1, 2
• Immunohistochemistry: Strong α-methylacyl-CoA racemase expression; CD10-positive in 63-93% 1, 2, 3
• Clinical behavior: Type I has significantly lower risk of death than clear cell RCC; Type II has worse prognosis similar to clear cell 2

Chromophobe RCC (5-10% of cases)

• Microscopic hallmark: Polygonal cells with sharply defined cytoplasmic membranes (plant cell appearance); pale reticulated cytoplasm containing abundant 150-300 nm diameter invaginated vesicles 1
• Molecular signature: Chromosomal losses in 1,2,6,10,13,17, and 21; associated with Birt-Hogg-Dubé syndrome 1, 2
• Immunohistochemistry: Diffuse CK7-positivity (81.5%), c-kit (CD117) expression, CD10-negative, CAIX-negative 1, 2, 3
• Clinical behavior: More favorable prognosis than clear cell RCC 2
• Critical differential: Chromophobe RCC shows diffuse CK7 and c-kit positivity, whereas oncocytoma lacks these markers 3

Collecting Duct Carcinoma (<1% of cases)

• Microscopic hallmark: High nuclear grade cells with eosinophilic cytoplasm, predominant tubular arrangement, desmoplasia, and expression of high-molecular-weight cytokeratins 1
• Origin: Medullary distal nephron or Bellini ducts 1, 2
• Molecular signature: Chromosomal losses in 1q, 6p, 13q, 14,15, 21q, and 22 1
• Clinical behavior: Aggressive with poor prognosis 4
• Medullary RCC: Considered an undifferentiated variant of collecting duct carcinoma 1

Translocation RCC (Rare, primarily pediatric/young adults)

• Microscopic hallmark: Cannot be diagnosed by morphology alone; requires molecular confirmation 2, 5
• Molecular signature: Xp11.2-TFE3 gene fusion or t(6;11)(p21;q12)-TFEB fusion 1, 2
• Diagnostic requirement: Both immunohistochemistry and fluorescence in-situ hybridization (FISH) mandatory for patients ≤40 years with papillary or complex architecture 2, 3, 5
• Clinical behavior: Primarily affects children and young adults 1, 2

Molecular Pathways and Therapeutic Implications

Understanding the molecular pathway of each subtype is critical because it determines treatment response:

• Hypoxia-inducible pathway: Clear cell and papillary type II (via fumarate-hydratase gene) 1
• mTOR signaling pathway: Clear cell and papillary type II 1
• c-Met-RAF-MEK-ERK pathway: Papillary type I and translocation RCC 1
• c-kit-RAF-MEK-ERK pathway: Chromophobe 1

Grading and Prognostic Features

• ISUP nucleolar grading system (grades 1-4): Provides accurate prognostic information for clear cell and papillary RCC 2, 5
• Sarcomatoid or rhabdoid differentiation: Automatically defines grade 4 tumor regardless of underlying histology; paradoxically shows increased sensitivity to immune checkpoint inhibitors 2, 5, 6
• Required documentation: Necrosis, microscopic vascular invasion, and pTNM stage must be reported for all specimens 5

2022 WHO Classification Updates

The 2022 WHO classification introduced 11 molecular-defined RCC subgroups that cannot be diagnosed by morphology alone, requiring molecular testing (immunohistochemistry, FISH, or next-generation sequencing) for accurate classification. 2, 5

• FH-deficient RCC: Loss of fumarate hydratase expression; associated with hereditary leiomyomatosis-RCC syndrome; poor prognosis 3, 5
• SDH-deficient RCC: Loss of SDHB expression; requires dedicated molecular assays 3, 5
• ALK-rearranged RCC: Identification directs use of ALK-targeted inhibitors 5

Diagnostic Approach and Common Pitfalls

• Core needle biopsy: Provides histopathological confirmation with 86-100% sensitivity and 98-100% specificity; mandatory before ablative therapies and systemic treatment in metastatic disease 1, 5
• Never rely on imaging alone to determine RCC subtype; histopathology is required before systemic therapy 5
• Do not omit molecular testing in younger patients (<40 years) or difficult-to-classify tumors; use low threshold for hereditary syndrome markers (FH, 2-SC, SDHB) 3, 5
• Tumor seeding from biopsy is rare and should not preclude tissue diagnosis 5
• Do not use outdated Fuhrman grading; ISUP nucleolar grading is the current standard 5

Prognostic Genomics in Clear Cell RCC

• PBRM1 mutations: Associated with stage III features but generally favorable prognosis 2, 3, 5
• BAP1 mutations: Correlate with larger tumors, higher nuclear grade, and significantly worse cancer-specific survival 2, 3, 5
• SETD2 mutations: Implicated in tumor progression and increased aggressiveness 2, 3, 5
• MTOR mutations: Predict sensitivity to mTOR inhibitors (everolimus, temsirolimus) 5