1. Describe the demographics of renal cell carcinoma (RCC). how many cases of RCC are diagnosed annually, and how many deaths are attributable to this disease? Is RCC more common in males or females? What is the median age at diagnosis of RCC?
In 2016, an estimated 62,700 cases of RCC were diagnosed, and 14,240 deaths were attributable to the disease. Approximately 63% and 65% of diagnoses and deaths, respectively, occurred in males. The median age at diagnosis is 65.
3. What are the clinical features of collecting duct (bellini duct) carcinoma? What clinical disorder is associated with the medullary variant of collecting duct carcinoma?
Collecting duct carcinoma comprises less than 1% of RCC cases, and has a particularly aggressive phenotype. Medullary RCC represents a variant of collecting duct carcinoma, and was first noted to occur among patients with sickle-cell trait.
4. What are common presenting signs of RCC?
Often, RCC presents as an incidental finding on radiographic imaging of the abdomen. With respect to symptoms, common complaints include hematuria and flank pain. In the setting of metastatic disease, patients may note bone pain, palpable adenopathy, or pulmonary complaints (i.e., shortness of breath secondary to bulky lung disease or pleural effusions).
5. What paraneoplastic syndromes are associated with RCC? What is Stauffer’s syndrome?
Nearly 40% of patients with RCC develop paraneoplastic syndromes. RCC produces a range of ectopic hormones, including parathyroid-like hormone, erythropoietin, insulin, gonadotropins, renin, and placental lactogen. Clinically, this may manifest in a range of symptoms and laboratory abnormalities including, but not limited to, hypertension (24%), hypercalcemia (10% to 15%), and erythrocytosis (4%). Stauffer’s syndrome, which occurs in roughly 6% of patients, implies liver function test abnormalities but absent hepatic metastases. This reversible liver dysfunction is pathognomonic for RCC.
6. What gene is disrupted in the majority of sporadic cases of RCC?
The VHL gene is disrupted in up to 70% of sporadic cases of RCC. In approximately 50% of cases, somatic mutations occur, and in 10% to 20% of cases, the gene is hypermethylated. A consequence of VHL mutation is upregulation of hypoxia-induced genes, leading to increased production of moieties such as vascular endothelial growth factor (VEGF). This, in turn, causes increased tumor angiogenesis.
7. Describe the features of (1) Hereditary papillary renal cell carcinoma, (2) Birt-Hogg-Dubé syndrome, and (3) Hereditary leiomyomatosis/renal cell carcinoma (HLRCC).
Hereditary papillary renal cell carcinoma is characterized by mutations in the MET proto-oncogene, located at 7q31. The mutations are highly penetrant and autosomal dominant. The resulting tumors are classified as papillary type 1 and are often multifocal and bilateral. Birt-Hogg-Dubé syndrome is characterized by the triad of hair follicle hamartomas, lung cysts, and renal neoplasia. The disorder is caused by mutations in the BHD gene, located at 17p11.2. While the disorder is highly penetrant with respect to lung and skin findings (>85%), renal neoplasia only occurs in 25% to 35% of patients. Finally, HLRCC is characterized by mutations in the gene-encoding fumarate hydratase ( FH , located at 1q24-43). The resulting phenotype includes type 2 papillary RCC, along with cutaneous and uterine leiomyomas.
8. What is the staging workup for RCC?
Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that the initial workup for RCC should include a complete history and physical, comprehensive laboratories (including a low-density lipoprotein [LDH] and urinalysis), and abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI). If clinically indicated, an MRI of the brain and bone scan should be ordered. If urothelial carcinoma is suspected, urine cytology or ureteroscopy should be considered.
9. For patients with localized RCC (stage I to III), what treatment is recommended after surgical resection of the tumor? What follow-up exams are recommended after surgical resection?
At present, no adjuvant therapy is recommended for patients with resected RCC. Follow-up (per NCCN guidelines) is guided by risk stratification according to tumor, node, and metastasis (TNM) staging. For example, patients with T1a disease are recommended to receive history and physical and labs every 6 months for 2 years, and annually up to 5 years. Abdominal CT or MRI is recommended within 6 months, and then at least annually. Imaging of the chest is recommended annually for surveillance of metastases. In much higher-risk disease (e.g., stage II or III disease), history and physical is recommended every 3 to 6 months for 3 years, then annually up to 5 years. Baseline CT or MRI of the abdomen is recommended within 3 to 6 months, then every 3 to 6 months for 3 years, and annually up to 5 years. Baseline CT of the chest is recommended on essentially the same frequency. Bone scan is recommended as clinically indicated.
11. What are common sites of metastasis of RCC?
RCC classically spreads to the lung, bone, brain, liver, and adrenal gland. With improvements in systemic therapy, the rates of brain metastasis are steadily increasing. This is because the brain remains a “sanctuary site,” where penetration of systemic therapy is highly variable.
12. What are the two classes of agents used to treat metastatic RCC?
The two broad classes of agents used to treat metastatic RCC include (1) immunotherapy and (2) targeted therapy. Immunotherapy may be divided into the more classical cytokine-based treatments such as interferon-α (IFN-α) and high-dose interleukin-2 (IL-2), and novel checkpoint inhibitors such as nivolumab. Nivolumab inhibits programmed death-1 (PD-1), which sits at the T-cell and antigen presenting cell interface and induces T-cell anergy. Targeted therapies include inhibitors of VEGF, including the monoclonal antibody bevacizumab and the small-molecule tyrosine kinase inhibitors such as sunitinib, pazopanib, sorafenib, and axitinib. Also U.S. Food and Drug Administration (FDA) approved are two inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. Two multikinase inhibitors with affinity for a number of oncogenic drivers are lenvatinib and cabozantinib. Beyond VEGF receptor, lenvatinib inhibits signaling through the fibroblast growth factor receptor (FGFR), while cabozantinib inhibits signaling through MET and AXL.
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