Pathophysiology
Summary
Renal cell carcinoma (RCC) is the most common renal cancer, primarily affecting men between 60-70 years old. Risk factors include hypertension, smoking, & obesity. RCC often stems from the PCT and has several subtypes, the most frequent being clear cell RCC. Clear cell RCC is notable for its high lipid and glycogen content and is usually associated with Von Hippel Lindau (VHL) gene mutations. VHL mutations also underlie familial VHL syndrome, which increases the risk for multiple tumors. In both sporadic and hereditary forms of VHL syndrome, a 'two-hit' model of gene mutation applies: one allele carries a pre-existing germline mutation, and cancer manifests when a somatic mutation occurs in the second allele.
RCC is frequently asymptomatic when the tumor is small. When symptoms do manifest, they commonly include flank pain and painless hematuria. Paraneoplastic syndromes associated with RCC include polycythemia (ectopic EPO), hypercalcemia (PTHrP), Cushing syndrome (ACTH-like hormone), and renin production. The tumor may also extend into the IVC, causing edema and hepatic dysfunction. Varicocele can occur if the left renal vein is obstructed. Metastasis frequently happens early in the disease course, spreading hematogenously, most commonly to the lungs and bones.
In children, the most common renal cancer is nephroblastoma (Wilms tumor), which arises from the metanephric mesenchyme and typically presents before age 10 as an abdominal mass. These tumors are associated with mutations in the WT1 or WT2 genes, which also follow a ‘two-hit’ model. Nephroblastomas are linked with genetic cancer syndromes such as WAGR syndrome and Denys-Drash syndrome, both of which involve WT-1 gene abnormalities, as well as Beckwith-Wiedemann syndrome, which stems from mutations in the WT2 locus. For benign renal tumors, renal angiomyolipoma is most prevalent, particularly among patients with tuberous sclerosis.
Lesson Outline
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FAQs
RCC frequently manifests as flank pain, painless hematuria, and a palpable abdominal mass. Additionally, it can present with paraneoplastic syndromes, including polycythemia due to ectopic erythropoietin production, hypercalcemia from parathyroid-related peptide (PTHrP) production, and Cushing syndrome from ectopic ACTH-like hormone production. Diagnosis is usually established through medical imaging techniques such as ultrasound or CT scans, and definitive diagnosis is confirmed via biopsy.
Clear cell RCC is most often caused by mutations in the von Hippel Lindau (VHL) gene located on chromosome 3. This occurs in both sporadic and hereditary forms of the disease. VHL functions as a tumor suppressor gene, meaning that cancer develops only if both alleles are mutated. In cases of VHL syndrome, one allele carries an inherited germline mutation, and cancer arises if the second allele acquires a somatic mutation during the individual's lifetime, knows as the ‘two-hit’ hypothesis.
Nephroblastoma, also known as Wilms tumor, is the most prevalent primary renal cancer in children, and most commonly arise sporadically. Nephroblastomas typically arise from the metanephric blastema, one of the two embryonic tissues responsible for kidney development, and are most commonly diagnosed in children under the age of 10. They are typically solitary, unilateral, and encapsulated, presenting as an asymptomatic abdominal mass. Some cases may also exhibit hypertension due to excess renin production.
Wilms tumors are often linked to loss-of-function mutations in the WT1 or WT2 genes, both located on chromosome 11.These tumors may be linked to genetic cancer syndromes such as WAGR syndrome and Denys-Drash syndrome, both of which involve WT-1 gene abnormalities, as well as Beckwith-Wiedemann syndrome, which stems from mutations in the WT2 locus. Similar to VHL syndrome in RCC, these syndromes follow the ‘two-hit' model, where one allele has an inherited germline mutation and cancer occurs if the second allele develops a somatic mutation.
Several risk factors are implicated in the development of RCC, including hypertension, obesity, and smoking. Additionally, lifestyle factors related to energy balance and metabolism, such as diet, physical activity, and body composition, are emerging as potential contributors to RCC risk.
