A 58-year-old man with a 10-year history of chronic kidney disease presents with hematuria and a 4 cm renal mass on imaging. Histopathology reveals clear cell renal cell carcinoma with Fuhrman nuclear grade 2. Which of the following is NOT a characteristic feature of clear cell RCC?

Question

Accepted Answer

A. Originates from the collecting duct system with sarcomatoid differentiation. ## Clear Cell RCC: Histopathologic Origin and Features

### Correct Answer Rationale

**Key Point:** Clear cell RCC arises from the **proximal convoluted tubule (PCT)** epithelium, NOT from the collecting duct. The collecting duct origin is characteristic of a different renal malignancy — **chromophobe RCC** and **collecting duct carcinoma** — which are distinct entities.

### Pathologic Features of Clear Cell RCC

| Feature | Detail |
|---------|--------|
| **Cell of origin** | Proximal convoluted tubule (PCT) epithelium |
| **Cytoplasmic appearance** | Clear (lipid and glycogen rich) — lipid dissolves in routine processing |
| **Genetic hallmark** | VHL (von Hippel-Lindau) gene loss on chromosome 3p |
| **VHL consequence** | Loss of HIF-1α degradation → HIF accumulation → VEGF/PDGF upregulation |
| **Growth pattern** | Expansile, well-demarcated, golden-yellow color (lipid content) |
| **Sarcomatoid variant** | Rare, high-grade spindle cell pattern; poor prognosis |

### Why Collecting Duct Origin is Wrong

**High-Yield:** Collecting duct carcinoma (Bellini duct carcinoma) is a **separate, aggressive renal malignancy** with:
  - Tubulopapillary or solid architecture
  - High-grade nuclei (Fuhrman 3–4)
  - Often presents at advanced stage
  - Much poorer prognosis than clear cell RCC
  - NOT associated with VHL loss (different molecular profile)

### Molecular Pathogenesis of Clear Cell RCC

1. **VHL inactivation** (80–90% of sporadic cases) → loss of 3p
2. **HIF-1α stabilization** (no proteasomal degradation)
3. **VEGF and PDGF upregulation** → angiogenesis
4. **Glucose and lipid accumulation** → clear cell phenotype

**Clinical Pearl:** Patients with hereditary VHL syndrome have 40–50% lifetime risk of developing bilateral/multifocal clear cell RCC, often at younger age.

[cite:Robbins 10e Ch 20]

Answer

B. Demonstrates loss of chromosome 3p containing VHL tumor suppressor gene

Answer

C. Shows abundant intracytoplasmic lipid and glycogen deposits

Answer

D. Arises from the proximal convoluted tubule epithelium

A 58-year-old man with a 10-year history of chronic kidney disease presents with hematuria and a 4 cm renal mass on imaging. Histopathology reveals clear cell renal cell carcinoma with Fuhrman nuclear grade 2. Which of the following is NOT a characteristic feature of clear cell RCC?

Explanation

Clear Cell RCC: Histopathologic Origin and Features

Correct Answer Rationale

Pathologic Features of Clear Cell RCC

Why Collecting Duct Origin is Wrong

Molecular Pathogenesis of Clear Cell RCC

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Feature	Detail
Cell of origin	Proximal convoluted tubule (PCT) epithelium
Cytoplasmic appearance	Clear (lipid and glycogen rich) — lipid dissolves in routine processing
Genetic hallmark	VHL (von Hippel-Lindau) gene loss on chromosome 3p
VHL consequence	Loss of HIF-1α degradation → HIF accumulation → VEGF/PDGF upregulation
Growth pattern	Expansile, well-demarcated, golden-yellow color (lipid content)
Sarcomatoid variant	Rare, high-grade spindle cell pattern; poor prognosis