What is the greatest risk factor for renal cell carcinoma, excluding cigarette smoking, in a patient with a history of type 2 diabetes mellitus (T2DM), hyperlipidemia, peripheral arterial disease (PAD), obesity, and a family history of kidney cancer?

Greatest Risk Factor for Renal Cell Carcinoma in This Patient

Obesity is the greatest risk factor for renal cell carcinoma in this patient, aside from cigarette smoking. 1, 2

Clinical Context and Reasoning

This patient presents with a right-sided varicocele that does not decompress when supine, hematuria, proteinuria, and ipsilateral lower extremity edema—a constellation of findings highly suspicious for right-sided renal cell carcinoma with possible renal vein involvement or IVC obstruction. When evaluating his risk factors for RCC, we must rank them by strength of association:

Risk Factor Hierarchy

Obesity (The Answer)

• A 5 kg/m² increase in BMI is strongly associated with RCC development, making obesity one of the three most well-established modifiable risk factors alongside smoking and hypertension. 1
• Central adiposity shows a relative risk of 1.8 (95% CI 1.2-2.5) for RCC, particularly in women, though the association holds across sexes. 1
• The combination of obesity, hypertension, and type 2 diabetes creates a synergistic effect with substantially elevated risk (HR 4.13,95% CI 2.76-6.18) compared to having none of these conditions. 3

Type 2 Diabetes Mellitus

• Type 2 diabetes is independently associated with increased RCC risk (HR 1.60,95% CI 1.19-2.17) after adjusting for BMI, hypertension, and smoking. 3
• However, this association is weaker than obesity's direct effect and may be partially mediated through obesity itself. 3

Family History of Kidney Cancer

• First-degree relatives with kidney cancer confer an OR of 2.5 (95% CI 1.04-5.9) for RCC development. 4
• While statistically significant, this represents a lower magnitude of risk compared to obesity's population-attributable risk. 4
• The majority of RCC cases are sporadic rather than hereditary. 1

Hypertension

• Hypertension is one of the three most well-established risk factors for RCC alongside obesity and smoking. 1, 2
• Higher BMI and hypertension independently increase long-term RCC risk, with blood pressure reduction lowering this risk. 1
• This patient's blood pressure of 146/92 mmHg indicates hypertension, contributing to his overall risk profile. 1

Hyperlipidemia

• Statins have actually been shown to significantly reduce RCC risk by 48% (adjusted OR 0.52,95% CI 0.45-0.60) in large analyses. 1
• Hyperlipidemia itself is not established as an independent RCC risk factor; rather, statin treatment appears protective. 1

Peripheral Arterial Disease

• PAD is not established as an independent risk factor for RCC in the literature. 1, 2
• It likely represents a marker of systemic atherosclerosis and shared risk factors (smoking, diabetes) rather than a direct carcinogenic pathway. 2

Important Clinical Pitfalls

• Do not overlook the cumulative effect of multiple comorbidities. This patient has obesity, hypertension, and type 2 diabetes—the triad that confers a 4-fold increased risk compared to having none of these conditions. 3
• The right-sided varicocele that fails to decompress supine is pathognomonic for right renal vein or IVC obstruction and demands urgent imaging with CT or MRI. 1
• While family history matters, the population-attributable risk from modifiable factors (obesity, smoking, hypertension) far exceeds that of hereditary predisposition in most RCC cases. 1, 4