Rare case of renal cell carcinoma presenting as a cutaneous horn

Louise Zhou, MD, Taren Ohman, MD, and Robert Zaiden, Jr., MD

Department of Medicine, University of Florida College of Medicine, Jacksonville, FL

Cutaneous metastases are a rare and generally late manifestation of renal cell carcinoma (RCC). Because they can mimic other dermatologic lesions, they may pose a diagnostic challenge if there is not a high degree of suspicion of their underlying cause.

Case presentation

A 61-year-old man presented with a right leg mass initially noted as a pimple-like lesion that enlarged rapidly over 2 weeks. This lesion was extremely painful to touch, and the patient had also noticed the appearance of adjacent leg varicosities. He denied any recent trauma or insect bites. Review of systems revealed an unintentional 30-lb weight loss in the past 6 months as well as progressive dyspnea on exertion and intermittent chest pain for 4 months prior to presentation. The patient had a history of smoking half a pack of cigarettes a day for 12 years; however, he quit 10 years ago.

Physical examination showed a large, 3.7 cm × 3.5 cm × 2 cm, malodorous, moist, exophytic friable mass located on the lateral aspect of his right lower extremity, 5 inches above the lateral malleolus (Figure 1). The lesion was smooth yet firm, yellow-tan to purplish-black without any surrounding erythema. It was slightly gelatinous and bled easily with minor trauma. Prominent dilated veins spanned the length of the patient’s right leg, from his groin to his foot. There was no appreciable lymphadenopathy or abdominal mass.

Laboratory data were significant for anemia, with a hemoglobin level of 5.8 g/dL and hematocrit of 18.9%; thrombocytosis, with a platelet count of 447,000 cells/mm3; and hypercalcemia, with a corrected serum calcium level of 11.5 mg/dL. The patient was hospitalized for packed red blood cell transfusions and further workup of his leg mass.

A biopsy revealed the mass to be metastatic clear cell RCC (Figure 2). A CT scan of the chest, abdomen, and pelvis showed a large, 9.2 cm × 11 cm, heterogeneously enhancing mass with necrotic components arising from the mid and inferior poles of the right kidney (Figure 3). Multiple necrotic mediastinal and bilateral hilar lymph nodes; numerous scattered pulmonary nodules; innumerable enhancing hepatic masses; and lytic lesions in the thoracic, lumbar, and iliac bones were also noted. A CT scan of the brain was negative.

The patient’s hospital course was subsequently complicated by the onset of persistent hematuria, despite continuous bladder irrigation. He was started on sorafenib (Nexavar), and a follow-up appointment was scheduled with oncology upon discharge; however, the patient decided to enroll in inpatient hospice instead.

Discussion

RCC comprises 90% of primary renal neoplasms, and 85% of them are clear cell type.1 RCC represents 2%–3% of all cancer diagnoses; however, rates have steadily increased by 2% each year in the past 65 years, with unknown cause.2 Smoking and obesity are known risk factors. As the use of imaging modalities, such as ultrasonography and CT scans of the abdomen and pelvis, has become more prevalent, the frequency of incidental detection of RCC has increased also.Fewer than 9% of patients with RCC present with the classic triad of hematuria, flank pain, and palpable abdominal mass.3 Indeed, its presentation can be so varied and nonspecific that it is deservedly called the internist’s tumor.

Cutaneous metastases

Most RCCs are clinically silent in their natural course, and their presence may not be discovered until the disease is either locally advanced and unresectable or metastatic. The most common sites of metastasis are the lungs, liver, brain, bones, and adrenal gland.3 Cutaneous metastases are relatively rare, with an incidence of 3.4%.4 The most common sites for cutaneous metastases are the head and neck region followed by the trunk, whereas in our patient, the lesion was located more distally on the leg.

Given the high vascularity of RCC, distant skin metastasis is believed to occur via hematogeneous spread. Cutaneous lesions can be flesh-colored but may also appear erythematous to violaceous, due to hemosiderin deposits in the dermis from its high vascularity. Lesions can be multiple but may infrequently present as solitary masses. Histologically, these lesions involve the dermis, with occasional extension into the subcutis. A grenz zone, a thin layer of superficial dermis separating the lesion from the epidermis, is usually present.

Due to the depth of invasion seen in these lesions, it is preferable to do an excisional or punch biopsy over a superficial shave biopsy so that dermal involvement is not missed. Cutaneous metastases are highly vascular, and a significant amount of bleeding may occur during biopsy. Most RCC cutaneous metastases are histologically consistent in appearance with clear cell adenocarcinoma. Other diagnostic techniques include immunohistochemical staining for vimentin and keratin.

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

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.

Conclusion

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.

References 1.

1. Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 2002;11:37–42.
2.
2. National Comprehensive Cancer Network. (2011). Kidney Cancer. Accessed at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
3.
3. DeKernion, JB. Real numbers. In: Walsh PC, Gittes RF, Perlmutter AD, eds. Campbell’s Urology. Philadelphia, PA: WB Saunders; 1986:1294.
4.
4. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021–1026.
5.
5. Dorairajan LN, Hemal AK, Aron M, et al. Cutaneous metastases in renal cell carcinoma. Urol Int 1999;63;164–167.
6.
6. Koga S, Tsuda S, Nishikido M, et al. Renal cell carcinoma metastatic to the skin. Anticancer Res 2000;20:1939–1940.
7.
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.
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.
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.
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.
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.

ABOUT THE AUTHORS

Affiliations: Dr. Zhou is a medical resident; Dr. Ohman is a fellow in medical oncology in the Department of Medicine; and Dr. Zaiden is Assistant Professor of Medicine, Division of Hematology and Medical Oncology, University of Florida College of Medicine, Jacksonville, FL.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 A 3.7 cm × 3.5 cm × 2 cm exophytic, violaceous, friable mass on the lateral aspect of the lower extremity.

FIGURE 2 Photomicrograph of a skin biopsy reveals classic histology for clear cell renal cell carcinoma.

FIGURE 3 A CT scan of the chest, abdomen, and pelvis shows a large, heterogeneously enhancing mass in the mid and inferior poles of the right kidney, borderline prominent spleen, and peripherally enhancing lesions in the liver, consistent with metastatic disease.

Louise Zhou, MD, Taren Ohman, MD, and Robert Zaiden, Jr., MD

Department of Medicine, University of Florida College of Medicine, Jacksonville, FL

Cutaneous metastases are a rare and generally late manifestation of renal cell carcinoma (RCC). Because they can mimic other dermatologic lesions, they may pose a diagnostic challenge if there is not a high degree of suspicion of their underlying cause.

Case presentation

A 61-year-old man presented with a right leg mass initially noted as a pimple-like lesion that enlarged rapidly over 2 weeks. This lesion was extremely painful to touch, and the patient had also noticed the appearance of adjacent leg varicosities. He denied any recent trauma or insect bites. Review of systems revealed an unintentional 30-lb weight loss in the past 6 months as well as progressive dyspnea on exertion and intermittent chest pain for 4 months prior to presentation. The patient had a history of smoking half a pack of cigarettes a day for 12 years; however, he quit 10 years ago.

Physical examination showed a large, 3.7 cm × 3.5 cm × 2 cm, malodorous, moist, exophytic friable mass located on the lateral aspect of his right lower extremity, 5 inches above the lateral malleolus (Figure 1). The lesion was smooth yet firm, yellow-tan to purplish-black without any surrounding erythema. It was slightly gelatinous and bled easily with minor trauma. Prominent dilated veins spanned the length of the patient’s right leg, from his groin to his foot. There was no appreciable lymphadenopathy or abdominal mass.

Laboratory data were significant for anemia, with a hemoglobin level of 5.8 g/dL and hematocrit of 18.9%; thrombocytosis, with a platelet count of 447,000 cells/mm3; and hypercalcemia, with a corrected serum calcium level of 11.5 mg/dL. The patient was hospitalized for packed red blood cell transfusions and further workup of his leg mass.

A biopsy revealed the mass to be metastatic clear cell RCC (Figure 2). A CT scan of the chest, abdomen, and pelvis showed a large, 9.2 cm × 11 cm, heterogeneously enhancing mass with necrotic components arising from the mid and inferior poles of the right kidney (Figure 3). Multiple necrotic mediastinal and bilateral hilar lymph nodes; numerous scattered pulmonary nodules; innumerable enhancing hepatic masses; and lytic lesions in the thoracic, lumbar, and iliac bones were also noted. A CT scan of the brain was negative.

The patient’s hospital course was subsequently complicated by the onset of persistent hematuria, despite continuous bladder irrigation. He was started on sorafenib (Nexavar), and a follow-up appointment was scheduled with oncology upon discharge; however, the patient decided to enroll in inpatient hospice instead.

Discussion

RCC comprises 90% of primary renal neoplasms, and 85% of them are clear cell type.1 RCC represents 2%–3% of all cancer diagnoses; however, rates have steadily increased by 2% each year in the past 65 years, with unknown cause.2 Smoking and obesity are known risk factors. As the use of imaging modalities, such as ultrasonography and CT scans of the abdomen and pelvis, has become more prevalent, the frequency of incidental detection of RCC has increased also.Fewer than 9% of patients with RCC present with the classic triad of hematuria, flank pain, and palpable abdominal mass.3 Indeed, its presentation can be so varied and nonspecific that it is deservedly called the internist’s tumor.

Cutaneous metastases

Most RCCs are clinically silent in their natural course, and their presence may not be discovered until the disease is either locally advanced and unresectable or metastatic. The most common sites of metastasis are the lungs, liver, brain, bones, and adrenal gland.3 Cutaneous metastases are relatively rare, with an incidence of 3.4%.4 The most common sites for cutaneous metastases are the head and neck region followed by the trunk, whereas in our patient, the lesion was located more distally on the leg.

Given the high vascularity of RCC, distant skin metastasis is believed to occur via hematogeneous spread. Cutaneous lesions can be flesh-colored but may also appear erythematous to violaceous, due to hemosiderin deposits in the dermis from its high vascularity. Lesions can be multiple but may infrequently present as solitary masses. Histologically, these lesions involve the dermis, with occasional extension into the subcutis. A grenz zone, a thin layer of superficial dermis separating the lesion from the epidermis, is usually present.

Due to the depth of invasion seen in these lesions, it is preferable to do an excisional or punch biopsy over a superficial shave biopsy so that dermal involvement is not missed. Cutaneous metastases are highly vascular, and a significant amount of bleeding may occur during biopsy. Most RCC cutaneous metastases are histologically consistent in appearance with clear cell adenocarcinoma. Other diagnostic techniques include immunohistochemical staining for vimentin and keratin.

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

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.

Conclusion

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.

References 1.

1. Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 2002;11:37–42.
2.
2. National Comprehensive Cancer Network. (2011). Kidney Cancer. Accessed at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
3.
3. DeKernion, JB. Real numbers. In: Walsh PC, Gittes RF, Perlmutter AD, eds. Campbell’s Urology. Philadelphia, PA: WB Saunders; 1986:1294.
4.
4. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021–1026.
5.
5. Dorairajan LN, Hemal AK, Aron M, et al. Cutaneous metastases in renal cell carcinoma. Urol Int 1999;63;164–167.
6.
6. Koga S, Tsuda S, Nishikido M, et al. Renal cell carcinoma metastatic to the skin. Anticancer Res 2000;20:1939–1940.
7.
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.
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.
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.
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.
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.

ABOUT THE AUTHORS

Affiliations: Dr. Zhou is a medical resident; Dr. Ohman is a fellow in medical oncology in the Department of Medicine; and Dr. Zaiden is Assistant Professor of Medicine, Division of Hematology and Medical Oncology, University of Florida College of Medicine, Jacksonville, FL.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 A 3.7 cm × 3.5 cm × 2 cm exophytic, violaceous, friable mass on the lateral aspect of the lower extremity.

FIGURE 2 Photomicrograph of a skin biopsy reveals classic histology for clear cell renal cell carcinoma.

FIGURE 3 A CT scan of the chest, abdomen, and pelvis shows a large, heterogeneously enhancing mass in the mid and inferior poles of the right kidney, borderline prominent spleen, and peripherally enhancing lesions in the liver, consistent with metastatic disease.

Louise Zhou, MD, Taren Ohman, MD, and Robert Zaiden, Jr., MD

Department of Medicine, University of Florida College of Medicine, Jacksonville, FL

Cutaneous metastases are a rare and generally late manifestation of renal cell carcinoma (RCC). Because they can mimic other dermatologic lesions, they may pose a diagnostic challenge if there is not a high degree of suspicion of their underlying cause.

Case presentation

A 61-year-old man presented with a right leg mass initially noted as a pimple-like lesion that enlarged rapidly over 2 weeks. This lesion was extremely painful to touch, and the patient had also noticed the appearance of adjacent leg varicosities. He denied any recent trauma or insect bites. Review of systems revealed an unintentional 30-lb weight loss in the past 6 months as well as progressive dyspnea on exertion and intermittent chest pain for 4 months prior to presentation. The patient had a history of smoking half a pack of cigarettes a day for 12 years; however, he quit 10 years ago.

Physical examination showed a large, 3.7 cm × 3.5 cm × 2 cm, malodorous, moist, exophytic friable mass located on the lateral aspect of his right lower extremity, 5 inches above the lateral malleolus (Figure 1). The lesion was smooth yet firm, yellow-tan to purplish-black without any surrounding erythema. It was slightly gelatinous and bled easily with minor trauma. Prominent dilated veins spanned the length of the patient’s right leg, from his groin to his foot. There was no appreciable lymphadenopathy or abdominal mass.

Laboratory data were significant for anemia, with a hemoglobin level of 5.8 g/dL and hematocrit of 18.9%; thrombocytosis, with a platelet count of 447,000 cells/mm3; and hypercalcemia, with a corrected serum calcium level of 11.5 mg/dL. The patient was hospitalized for packed red blood cell transfusions and further workup of his leg mass.

A biopsy revealed the mass to be metastatic clear cell RCC (Figure 2). A CT scan of the chest, abdomen, and pelvis showed a large, 9.2 cm × 11 cm, heterogeneously enhancing mass with necrotic components arising from the mid and inferior poles of the right kidney (Figure 3). Multiple necrotic mediastinal and bilateral hilar lymph nodes; numerous scattered pulmonary nodules; innumerable enhancing hepatic masses; and lytic lesions in the thoracic, lumbar, and iliac bones were also noted. A CT scan of the brain was negative.

The patient’s hospital course was subsequently complicated by the onset of persistent hematuria, despite continuous bladder irrigation. He was started on sorafenib (Nexavar), and a follow-up appointment was scheduled with oncology upon discharge; however, the patient decided to enroll in inpatient hospice instead.

Discussion

RCC comprises 90% of primary renal neoplasms, and 85% of them are clear cell type.1 RCC represents 2%–3% of all cancer diagnoses; however, rates have steadily increased by 2% each year in the past 65 years, with unknown cause.2 Smoking and obesity are known risk factors. As the use of imaging modalities, such as ultrasonography and CT scans of the abdomen and pelvis, has become more prevalent, the frequency of incidental detection of RCC has increased also.Fewer than 9% of patients with RCC present with the classic triad of hematuria, flank pain, and palpable abdominal mass.3 Indeed, its presentation can be so varied and nonspecific that it is deservedly called the internist’s tumor.

Cutaneous metastases

Most RCCs are clinically silent in their natural course, and their presence may not be discovered until the disease is either locally advanced and unresectable or metastatic. The most common sites of metastasis are the lungs, liver, brain, bones, and adrenal gland.3 Cutaneous metastases are relatively rare, with an incidence of 3.4%.4 The most common sites for cutaneous metastases are the head and neck region followed by the trunk, whereas in our patient, the lesion was located more distally on the leg.

Given the high vascularity of RCC, distant skin metastasis is believed to occur via hematogeneous spread. Cutaneous lesions can be flesh-colored but may also appear erythematous to violaceous, due to hemosiderin deposits in the dermis from its high vascularity. Lesions can be multiple but may infrequently present as solitary masses. Histologically, these lesions involve the dermis, with occasional extension into the subcutis. A grenz zone, a thin layer of superficial dermis separating the lesion from the epidermis, is usually present.

Due to the depth of invasion seen in these lesions, it is preferable to do an excisional or punch biopsy over a superficial shave biopsy so that dermal involvement is not missed. Cutaneous metastases are highly vascular, and a significant amount of bleeding may occur during biopsy. Most RCC cutaneous metastases are histologically consistent in appearance with clear cell adenocarcinoma. Other diagnostic techniques include immunohistochemical staining for vimentin and keratin.

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

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.

Conclusion

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.

References 1.

1. Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 2002;11:37–42.
2.
2. National Comprehensive Cancer Network. (2011). Kidney Cancer. Accessed at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
3.
3. DeKernion, JB. Real numbers. In: Walsh PC, Gittes RF, Perlmutter AD, eds. Campbell’s Urology. Philadelphia, PA: WB Saunders; 1986:1294.
4.
4. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021–1026.
5.
5. Dorairajan LN, Hemal AK, Aron M, et al. Cutaneous metastases in renal cell carcinoma. Urol Int 1999;63;164–167.
6.
6. Koga S, Tsuda S, Nishikido M, et al. Renal cell carcinoma metastatic to the skin. Anticancer Res 2000;20:1939–1940.
7.
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.
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.
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.
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.
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.

ABOUT THE AUTHORS

Affiliations: Dr. Zhou is a medical resident; Dr. Ohman is a fellow in medical oncology in the Department of Medicine; and Dr. Zaiden is Assistant Professor of Medicine, Division of Hematology and Medical Oncology, University of Florida College of Medicine, Jacksonville, FL.

Conflicts of interest: The authors have nothing to disclose.

FIGURE 1 A 3.7 cm × 3.5 cm × 2 cm exophytic, violaceous, friable mass on the lateral aspect of the lower extremity.

FIGURE 2 Photomicrograph of a skin biopsy reveals classic histology for clear cell renal cell carcinoma.

FIGURE 3 A CT scan of the chest, abdomen, and pelvis shows a large, heterogeneously enhancing mass in the mid and inferior poles of the right kidney, borderline prominent spleen, and peripherally enhancing lesions in the liver, consistent with metastatic disease.