Clear Cell Renal Cell Carcinoma (ccRCC): Imaging Diagnosis, MRI Hallmarks, Differential Diagnosis, and Modern Treatment

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 Imaging Diagnosis, MRI Hallmarks, Differential Diagnosis, and Modern Treatment


Clear cell renal cell carcinoma (clear cell RCC, ccRCC) is the most common malignant tumor of the kidney and a leading cause of cancer-related mortality in urologic oncology. In contemporary clinical practice, ccRCC is increasingly detected incidentally during imaging performed for unrelated indications—often before classic symptoms arise. This early detection has transformed the diagnostic workflow into an imaging-centered pathway, where radiologists and clinicians rely heavily on multiphasic CT and multiparametric MRI to characterize renal masses, stratify malignancy risk, and guide staging and treatment planning.

In this column, I present a representative case of ccRCC discovered on surveillance imaging in an elderly former smoker, with subsequent MRI demonstrating hallmark features including heterogeneous T2 hyperintensity, signal drop on chemical shift imaging consistent with intracellular lipid, restricted diffusion, and early enhancement with washout. We will comprehensively review the pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, diagnostic approach, treatment options, and prognosis of ccRCC using evidence-based, widely cited literature.

Keywords: clear cell renal cell carcinoma, clear cell RCC, renal cell carcinoma MRI, kidney tumor MRI, multiphasic MRI renal mass, renal mass differential diagnosis, RCC imaging features, ccRCC diagnosis, renal tumor staging

1. Case Summary: Incidental Renal Mass Detected on CT Follow-Up

A 73-year-old woman with a history of smoking and prior pulmonary mycobacterial infection presented for imaging surveillance. Non-contrast CT of the chest incidentally demonstrated an abnormality involving the anterior left kidney, prompting further evaluation.

Figure 1. Coronal non-contrast CT. A contour-deforming soft tissue mass is suggested along the anterior mid-to-lower pole of the left kidney, appearing exophytic and new compared with prior imaging, raising suspicion for a renal neoplasm.

Figure 2. Axial abdomen non-contrast CT. An exophytic soft tissue lesion abutting the renal pelvis is identified in the anterior left kidney, causing a focal contour bulge. Non-contrast CT is limited for characterization; MRI is recommended for definitive evaluation.

Given the lesion location near the renal pelvis and need for tissue characterization, multiphasic contrast-enhanced abdominal MRI was appropriately recommended as the next step.

2. Pathophysiology of Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma originates from the epithelial cells of the proximal convoluted tubule. Its hallmark histologic appearance—cells with optically clear cytoplasm—reflects abundant intracellular lipid and glycogen, which are dissolved during tissue processing.

The most important molecular driver in sporadic ccRCC is alteration of the VHL (von Hippel–Lindau) tumor suppressor gene on chromosome 3p. Loss of VHL function leads to accumulation of hypoxia-inducible factors (HIF-1α/HIF-2α), triggering transcriptional upregulation of angiogenic and growth-promoting pathways, including:

  • VEGF (vascular endothelial growth factor)
  • PDGF
  • TGF-α

This explains why ccRCC is typically hypervascular and prone to intratumoral hemorrhage, necrosis, and heterogeneous enhancement patterns.

From an imaging standpoint, this biology translates into:

  • strong early arterial enhancement (especially corticomedullary phase)
  • washout relative to the renal cortex
  • frequent heterogeneity due to necrosis/cystic degeneration

3. Epidemiology and Risk Factors

Renal cell carcinoma accounts for the majority of primary renal malignancies in adults, and ccRCC constitutes up to ~70–80% of RCC subtypes.

Key epidemiologic features:

  • Typical diagnosis age: ~60s–70s
  • Slight male predominance overall
  • Increasing incidence of incidentally detected small renal masses due to widespread imaging

Risk factors strongly linked to RCC include:

  • Smoking (dose-dependent risk)
  • Obesity
  • Hypertension
  • Chronic kidney disease and dialysis-associated acquired cystic disease

Hereditary syndromes:

  • Von Hippel–Lindau disease (classic for ccRCC)
  • Tuberous sclerosis complex (associated with renal tumors, though angiomyolipomas are more typical)

In this case, the patient’s smoking history is clinically relevant and increases baseline RCC risk.

4. Clinical Presentation

Classic triad:

  • hematuria
  • flank pain
  • palpable mass

However, the triad is present in <10% of modern cases, because most tumors are detected before they become symptomatic.

Other possible presentations:

  • constitutional symptoms: weight loss, fever, fatigue
  • paraneoplastic syndromes:
    • hypercalcemia
    • erythrocytosis (EPO production)
    • hepatic dysfunction (Stauffer syndrome)
  • venous thrombosis due to tumor invasion of the renal vein/IVC

ccRCC has a higher tendency than some other subtypes to present with advanced stage or metastasis, making accurate staging critical.

5. Imaging Features: CT and MRI Hallmarks of ccRCC

Why MRI is powerful for renal mass characterization

While multiphasic CT is commonly first-line due to availability and speed, multiparametric MRI provides superior soft tissue contrast and additional functional sequences:

  • chemical shift imaging (in-phase/opposed-phase)
  • diffusion-weighted imaging (DWI/ADC)
  • dynamic contrast enhancement


Figure 3. Axial T2-weighted post-contrast fat-saturated MRI. The lesion demonstrates heterogeneous high T2 signal, consistent with a solid renal tumor containing necrosis/cystic components—an imaging pattern commonly seen in clear cell RCC rather than papillary RCC (typically low T2).

Figure 4. Axial contrast-enhanced MRI (dynamic phase). The mass shows early internal enhancement, reflecting hypervascularity—an important feature favoring clear cell RCC over papillary RCC, which typically enhances weakly and later.

Figure 5. Axial contrast-enhanced MRI (dynamic phase). Continued enhancement pattern with areas of heterogeneity suggests tumor vascularity with possible necrosis/hemorrhage—typical for ccRCC.

Figure 6. Diffusion-weighted imaging (DWI) and ADC map. The lesion demonstrates restricted diffusion (high DWI signal with corresponding low ADC), supporting malignant solid tumor biology due to increased cellularity.


Figure 7. Multiphasic MRI axial series (subtraction images: pre-contrast T1, corticomedullary, nephrographic, excretory phases). The mass demonstrates early hyperenhancement with relative washout, a classic dynamic enhancement signature for clear cell RCC. Subtraction imaging improves the detection of enhancement in lesions with intrinsic T1 hyperintensity.

Chemical shift imaging: intracellular lipid

A particularly valuable imaging clue is signal drop on opposed-phase imaging, indicating intracellular lipid rather than macroscopic fat.

In ccRCC:

  • Intracellular lipid is common
  • signal drop from in-phase → opposed-phase can be present
  • This does not indicate macroscopic fat (which is more typical for classic angiomyolipoma)

6. Differential Diagnosis of a Solid Renal Mass

The imaging differential for a solid renal mass includes both benign and malignant entities:

A) Angiomyolipoma (AML)

  • Classic AML: macroscopic fat → signal loss on fat-sat sequences, very high T1
  • Fat-poor AML: may mimic RCC; often very low T2 due to smooth muscle predominance
  • may show some chemical shift drop, but usually lacks an aggressive enhancement pattern of ccRCC

B) Papillary RCC

  • typically low T2 signal
  • less vascular: weaker enhancement, delayed enhancement
  • may show hemorrhage/hemosiderin with susceptibility artifacts

C) Chromophobe RCC

  • often more homogeneous
  • may show a central scar
  • enhancement patterns can overlap, but generally not as strongly hypervascular as ccRCC

D) Oncocytoma

  • benign but imaging overlap
  • possible central stellate scar
  • segmental enhancement inversionis  described, but not fully reliable

In this case, the combination of:

  • heterogeneous T2 hyperintensity
  • intracellular lipid (chemical shift drop)
  • restricted diffusion
  • early enhancement and washout

strongly supports clear cell RCC.

7. Diagnosis and Staging

Diagnostic approach

  • Initial detection: US/CT
  • Characterization: multiphasic CT or MRI
  • Staging requires evaluation of:
    • tumor size (T stage)
    • perinephric fat invasion
    • Gerota fascia involvement
    • renal vein invasion
    • IVC invasion
    • adrenal invasion
    • nodal disease and metastases

Key staging structures to report

  • ipsilateral renal vein
  • ipsilateral adrenal gland
  • perinephric fat ± Gerota fascia

As described in the case, the lesion did not demonstrate invasion beyond the renal cortex or vascular invasion.

8. Treatment of Clear Cell RCC

Management depends on tumor size, location, patient comorbidity, renal function, and metastatic status.

Localized disease

  • Partial nephrectomy (nephron-sparing):
    • preferred for T1 tumors (<7 cm), especially peripheral
    • preserves renal function
  • Radical nephrectomy:
    • for larger tumors, central tumors, or complex lesions
    • removes kidney ± adrenal ± lymph nodes as needed

Ablation

  • cryoablation or radiofrequency ablation
  • typically for small renal masses in poor surgical candidates

Metastatic disease

Modern systemic therapy has evolved dramatically:

  • VEGF pathway inhibitors (targeted therapy)
  • immune checkpoint inhibitors (ICI)
  • combination regimens are now standard in many settings

9. Prognosis

Prognosis is stage-dependent:

  • Small localized tumors: excellent outcomes
  • Higher stage with venous invasion or metastasis: worse survival

Important prognostic factors:

  • TNM stage
  • tumor grade
  • sarcomatoid features
  • performance status
  • molecular risk profiles (in advanced disease)

Recurrence can occur, often within the first 5 years; surveillance imaging is essential.

Quiz

Question 1. A 73-year-old woman has an exophytic anterior left renal mass on imaging. Multiphasic MRI shows early hyperenhancement in the corticomedullary phase with washout and heterogeneous T2 hyperintensity. Which diagnosis is most likely?

A. Papillary renal cell carcinoma
B. Classic angiomyolipoma
C. Chromophobe renal cell carcinoma
D. Clear cell renal cell carcinoma

answer: D. Explanation: Early strong enhancement and washout with heterogeneous T2 hyperintensity is typical of clear cell RCC, which is hypervascular. Papillary RCC tends to be hypovascular and low T2. Classic AML demonstrates macroscopic fat. Chromophobe RCC is often more homogeneous.

Question 2. Signal drop from in-phase to opposed-phase MRI in a renal mass most strongly indicates:

A. Macroscopic fat
B. Intracellular lipid (microscopic fat)
C. Hemorrhage
D. Calcification

answer: B. Explanation: A chemical-shift imaging signal drop indicates microscopic fat/intracellular lipids, not macroscopic fat. Macroscopic fat is best seen as a high T1 signal, suppressed by fat saturation.

Question 3. For RCC staging, which structures must be carefully evaluated and reported to determine T stage?

A. Ipsilateral renal vein
B. Perinephric fat and Gerota fascia
C. Ipsilateral adrenal gland
D. All of the above

answer: D. Explanation: RCC T staging depends on tumor size and invasion into adjacent structures, including renal vein, perinephric fat/Gerota fascia, adrenal gland, and IVC.

References

[1] C. Beisland, “Incidental detection of renal cell carcinoma,” Scand. J. Urol., vol. 51, no. 3, pp. 178–184, 2017.


[2] C. Lopes Vendrami et al., “Differentiation of solid renal tumors with multiparametric MR imaging,” Radiographics, vol. 37, no. 7, pp. 2026–2042, 2017.


[3] C. S. Ng et al., “Renal cell carcinoma: diagnosis, staging, and surveillance,” AJR Am. J. Roentgenol., vol. 191, no. 4, pp. 1220–1232, 2008.


[4] K. E. Sand et al., “Incidentally detected renal cell carcinomas are highly associated with comorbidity and mortality unrelated to renal cell carcinoma,” Scand. J. Urol., vol. 47, no. 6, pp. 462–471, 2013.


[5] R. H. Uzzo et al., “Renal mass and localized renal cancer: evaluation, management, and follow-up,” J. Urol., clinical guideline literature (widely cited consensus), 2010s.


[6] B. Ljungberg et al., “EAU Guidelines on Renal Cell Carcinoma,” Eur. Assoc. Urol. Guidelines, updated editions (widely referenced).
[7] R. J. Motzer et al., “NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer,” NCCN Guidelines, updated editions.

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