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In the United States in 2018, there were an estimated 65,340 new cases of upper tract renal masses leading to 14,970 estimated deaths, representing 2–3% of all cancer cases (Siegel et al, 2018). The incidence is twice as high in men as women. While the incidence of renal cell carcinoma is increasing worldwide, with the highest rates in more developed countries, the age-standardized mortality rates appear to be stabilizing overall and in fact decreasing in western/northern Europe, the United States, and Australia (Znaor et al, 2015). The overall increase in incidence is driven primarily by the increasing availability and use of imaging.

Clinical Presentation

A. Signs and Symptoms

The classically described triad of gross hematuria, flank pain, and a palpable mass occurs in only 7–10% of patients and is frequently a manifestation of advanced disease. Gross or microscopic hematuria can be seen in up to 60% of patients presenting with renal cell carcinoma (RCC). Patients presenting with hematuria should also be evaluated with cystoscopy to rule out urothelial carcinoma. Patients may also present with dyspnea, cough, and bone pain that are typically symptoms secondary to metastases. However, with increasing use of imaging, approximately 60–70% of renal tumors are detected incidentally (Herts et al, 2018; Novara et al, 2010).

B. Paraneoplastic Syndromes

Renal cell carcinoma is associated with a wide spectrum of paraneoplastic syndromes, including polycythemia, thrombocytosis, hypercalcemia, cachexia, pyrexia, hypertension, and hepatic dysfunction, which may be driven by VEGF expression (Ding et al, 2013). While these manifestations are reported in 10–40% of patients with RCC, this may be overestimated because of publication bias (Hegemann et al, 2018). Paraneoplastic symptoms are not associated with increasing disease stage and should be regarded as a diagnosis of exclusion (Kim et al, 2003).

Hypercalcemia is the most common paraneoplastic complication in renal cell carcinoma, and has been reported to occur in up to 13% of patients with RCC (Kim et al, 2003). Hypercalcemia may be due to production of a parathyroid hormone-related peptide (PTHrP) that mimics the function of parathyroid hormone (Papworth et al, 2005; Goldner, 2016). RCC is the most common cause of paraneoplastic erythrocytosis, which is reported to occur in 3–10% of patients with this tumor (Sufrin et al, 1989). In 1961, Stauffer described a reversible syndrome of hepatic dysfunction in the absence of hepatic metastases associated with RCC (Stauffer, 1961). Hepatic function abnormalities include elevation of alkaline phosphatase and bilirubin, hypoalbuminemia, prolonged prothrombin time, and hypergammaglobulinemia. Stauffer’s syndrome tends to occur in association with fever, fatigue, and weight loss and typically resolves after tumor resection. The reported incidence of Stauffer’s syndrome varies from 3% to 20% (Gold et al, 1996).

C. Laboratory Findings

In addition to the laboratory abnormalities associated with the various RCC paraneoplastic syndromes, anemia, microscopic hematuria, ...

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