The presence of cutaneous metastasis is a late manifestation of disseminated disease. Prognosis is poor, with a mean survival of about 6–9 months after cutaneous lesions are found.4–6 Prognostic indicators of short survival in RCC include a serum lactate dehydrogenase level higher than 1.5 times the upper limits of normal and paraneoplastic syndromes (anemia, hypercalcemia with corrected serum calcium levels higher than 10 mg/dL, hepatic dysfunction). Karnofsky performance score of 70 or less, two or more metastases, and less than 1 year from the time of diagnosis to the start of therapy also portend poor outcomes.7 Thrombocytosis, if present, is also a rare but ominous sign of poor prognosis in RCC.8,9
Treatment options include surgical resection of early localized disease, with radical nephrectomy of primary renal tumors and metastasectomy of isolated oligometastatic sites. There are ongoing studies to determine whether neoadjuvant systemic therapy prior to radical nephrectomy in patients with advanced RCC improves overall survival; however, data using older regimens have not shown this effect. In patients who have undergone a complete resection of their tumor, neither adjuvant chemotherapy nor radiotherapy has shown any benefit in terms of decrease in relapse or improvement in survival.2 With nonresectable disease, treatment options are limited to systemic therapy and supportive care.
Clear cell type RCC overexpresses receptors related to angiogenesis, and this has been the main therapeutic target. First-line systemic therapy includes multikinase inhibitors (MKIs), such as sorafenib, pazopanib (Votrient), and sunitinib (Sutent), which inhibit tumor invasion and metastasis by decreasing tumor vascularity and inducing tumor necrosis. MKIs target tyrosine kinase receptors, including vascular endothelial growth factor (VEGF) receptor-2 and platelet-derived growth factor receptor.
Other agents such as everolimus (Afinitor) and temsirolimus (Torisel), which are specific mTOR (mammalian target of rapamycin) inhibitors, also inhibit angiogenesis and are used in patients with a poor prognosis. Biologic agents, such as interferon-(INF-) and interleukin-2 (aldesleukin, Proleukin), were frontline treatment options in the past; however, with the development of the MKIs and mTOR inhibitors, they have fallen out of favor as first-line therapy.
It has been shown that patients with metastatic RCC treated with sunitinib versus INF- have a better quality of life, longer progression-free survival (11 months vs 5 months), and a higher objective response rate (31% vs 6%).10 A subsequent follow-up study showed that patients who were on sunitinib had longer overall survival (26.4 months vs 21.8 months).10
The AVOREN (Avastin and Roferon in Renal Cell Carcinoma) trial also showed that the addition of bevacizumab (Avastin), a VEGF inhibitor, to IFN- improved progression-free survival by 89%, although there was no statistically significant increase in overall survival.11 This combination is currently recommended as another treatment option for patients with relapsed or medically unresectable stage IV clear cell type RCC.11 Although the combination of MKIs with VEGF inhibitors is a promising option in phase I studies, it has shown no synergistic effect and has significantly more toxicity. However, all available agents have various toxicity profiles and, at most, prolong survival for a few months. Supportive care, including palliative radiation, metastasectomy, and bisphosphonates for metastatic bone disease, is still an integral part of treatment.
Cutaneous metastases from RCC can pose a diagnostic dilemma, as they can mimic other dermatologic lesions. Renal malignancies should be included in the differential diagnosis, since cutaneous lesions may be the first manifestations of disease. A high index of suspicion and a confirmatory biopsy are crucial to the diagnosis.
- Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 2002;11:37–42. 2.
- National Comprehensive Cancer Network. (2011). Kidney Cancer. Accessed at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 3.
- DeKernion, JB. Real numbers. In: Walsh PC, Gittes RF, Perlmutter AD, eds. Campbell’s Urology. Philadelphia, PA: WB Saunders; 1986:1294. 4.
- Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021–1026. 5.
- Dorairajan LN, Hemal AK, Aron M, et al. Cutaneous metastases in renal cell carcinoma. Urol Int 1999;63;164–167. 6.
- Koga S, Tsuda S, Nishikido M, et al. Renal cell carcinoma metastatic to the skin. Anticancer Res 2000;20:1939–1940. 7.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–2281. 8.
- Symbas NP, Townsend MF, El-Galley R, et al. Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma. BJU Int 2000;86:203. 9.
- O’Keefe, SC, Marshall FF, Issa MM, et al. Thrombocytosis is associated with a significant increase in the cancer specific death rate after radical nephrectomy. J Urol 2002;168:1378. 10.
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alpha in metastatic renal cell carcinoma. N Engl J Med 2007;356:115–124. 11.
- Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 2007;370:2103–2111.