Dermatology Online Journal

Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after hypofractionated radiotherapy
Hiram A Gay MD¹, Ronaldo Cavalieri MD², Ron R Allison MD¹, James Finley MD³, Walter D Quan Jr MD⁴
Dermatology Online Journal 13 (4): 6

1. Department of Radiation Oncology, The Brody School of Medicine at East Carolina University, Greenville, NC, USA. gayh@ecu.edu 2. Department of Radiation Oncology, Brazilian National Cancer Institute, Rio de Janeiro, RJ, Brazil 3. Department of Pathology and Laboratory Medicine, The Brody School of Medicine at East Carolina University, Greenville, NC, USA 4. Department of Internal Medicine, Division of Hematology/Oncology, The Brody School of Medicine at East Carolina University, Greenville, NC, USA

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Abstract

Cutaneous metastases from renal cell carcinoma (RCC) are uncommon, but may be painful and deforming. A review of the English language literature yields no references regarding the use of radiotherapy in the palliation of cutaneous RCC metastases. We report the first documented case of a patient with a single RCC facial metastatic nodule treated with hypofractionated electron beam radiotherapy followed by administration of sorafenib. The patient achieved a complete resolution of the cutaneous metastasis.

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Renal cell carcinoma (RCC) represents approximately 85 percent of all primary renal neoplasms. Up to one third of patients with RCC present with metastatic disease; lung and bone are the most common sites. Cutaneous metastases from RCC are uncommon, with an incidence of approximately 2.4-6.4 percent [1, 2]. The clinical appearance of cutaneous metastases from RCC has been described as painless or painful nodules, plaques, or pulsatile masses, ranging from flesh-colored to violaceous [3, 4, 5, 6].

Historically, renal cell carcinoma has been regarded as a radio-resistant tumor when treated with radiotherapy using standard fractions of 180-200 cGy. Advances in stereotactic radiotherapy over the past decade have made possible the safer delivery of fewer, but larger doses of radiation, termed hypofractionation, to deeply seated tumors. Stereotactic radiosurgery to metastatic RCC sites in the brain and extracranial sites has resulted in higher than 85 percent local control rates, with approximately one fifth of metastases achieving a complete response [7, 8, 9, 10, 11, 12]. Therefore, the stereotactic literature supports the notion that hypofractionation is more effective than standard fractionation in RCC.

A review of the English-language literature yields no references regarding the use of radiotherapy in the palliation of cutaneous RCC metastases. We report the first documented case of a patient with a single RCC facial metastasis treated with hypofractionated electron beam radiotherapy followed by the administration of sorafenib. The patient achieved a complete resolution of the metastatic nodule.

Clinical synopsis

A 51-year-old man had an 8 month history of weakness, fatigue, and 15 pound weight loss. Prior to admission to the hospital, he experienced several days of hematuria. A CT scan of the abdomen showed a large left renal mass measuring 9.3 x 7.2 cm in the axial plane, replacing the left upper kidney. The scan also showed invasion of the perinephric fat, left renal vein, and inferior vena cava (IVC), at least to the level of the intrahepatic IVC. Moderate adenopathy in the left paraaortic region and left renal hilum were demonstrated. A CT scan of the chest revealed multiple pulmonary metastases. There was significant dilation of the inferior vena cava due to multiple thrombi. A fine needle aspiration (FNA) of the left kidney mass revealed renal cell carcinoma, clear cell type (Fig. 1). Immunoperoxidase studies showed the tumor cells to be positive for vimentin, epithelial membrane antigen, and AE1-3 pancytokeratin. The immunoprofile, Oil Red-O positivity, and morphology were consistent with clear cell renal cell carcinoma. The pathologic slides were reviewed at the Memorial Hospital for Cancer and Allied Diseases in New York, NY and the diagnosis remained unchanged. The patient was deemed unresectable and did not undergo surgery. The patient had completed 4 cycles of IL2 seven months after diagnosis, but further IL2 therapy was discontinued because of side effects during the infusion of the fifth cycle.

Figure 1	Figure 2
Figure 1. PAP stained smear at 250X magnification of the left kidney FNA showing a loosely cohesive group of epithelioid cells with vacuolated and wispy cytoplasm consistent with clear cell carcinoma. Figure 2. FNA of the facial metastasis, showing loosely cohesive groups of cells with pleomorphic nuclei and clear cytoplasm. (PAP stain, 400X magnification).

The patient noticed a left facial preauricular skin nodule that appeared approximately 10 months after diagnosis. The nodule grew slowly and subsequently became painful. The nodule was violaceous, fixed, and pulsatile. An FNA of the nodule showed malignant cells, consistent with metastatic renal cell carcinoma (Fig. 2). The atypical cells were positive for pancytokeratin (AE1/3), vimentin, and EMA. A CT scan of the head revealed the depth of the lesion (Fig. 3). The patient was referred for palliative radiotherapy. At the time of clinical examination, the nodule measured close to 2 cm in diameter at its base. The patient received a palliative hypofractionated course of electron beam radiotherapy consisting of 13 fractions of 375 cGy for a total of 4875 cGy. A custom bolus made from alginate impression material was placed over the lesion to create better dose homogeneity. A planning CT scan with the bolus in place was obtained to help select the electron energy that would cover the tumor and minimize radiation to the left temporal lobe (Fig. 4). The electron field encompassed the lesion with a 2 cm peripheral margin.

Figure 3	Figure 4
Figure 3. Axial CT image showing the skin metastasis (arrow) after 2 fractions, 5 days after starting radiotherapy. The lesion measures 2.2 cm in the superficial to deep axis, 1.4 cm in width, and invades through the platysma muscle. The lesion measured 1.2 cm from the skin surface to the deepest point, with more than half of the tumor being subcutaneus. This illustrates the importance of choosing an adequate electron beam energy. Figure 4. Planning CT scan showing the custom bolus and lesion (dashed white line).

Because of transient mental status changes, an MRI scan of the brain was obtained the day radiotherapy was completed, but there was no evidence of brain metastases or edema. Incidentally, the MRI scan showed that the facial nodule was flush with the skin by the end of treatment (Fig. 5) with effective palliation. Fig. 6 illustrates the visual evolution of the lesion.

One week after completing radiotherapy the patient was started on sorafenib. He received sorafenib intermittently for the next 9 months. At the 2 month follow-up visit the facial metastatatic site was flat and painless, but it was unclear whether there was still some residual disease (Fig. 6, panel D). The next visit was 4 months later and a complete response was evident (Fig. 6, panel E); some hyperpigmentation remained at the irradiated area. The patient died of progressive disease 10 months after the completion of radiotherapy, but had enjoyed durable palliation of his skin lesion.

Figure 5	Figure 6a

Figure 6b	Figure 6c

Figure 6d	Figure 6e
Figure 5. Axial T1 MRI image showing the skin metastasis the last day of treatment (arrowhead). The lesion now measures 1 cm in the superficial to deep axis, and 1.1 cm in width. Note that the lesion is now flush with the skin surface. Figure 6. A. Tumor appearance after 3 fractions, 12 days since the start of treatment. Most of the purplish layer that initially covered the tumor has disappeared, revealing a reddish nodule; B. after 7 fractions, 20 days since the start of treatment; C. 16 days after the completion of treatment; D. 2 months after the completion of treatment; E. 6 months after the completion of treatment.

Discussion

The patient received 375 cGy x 13 fractions over 5 weeks. Taking an α-β ratio of 3 for normal tissue late effects[13] and 10 for tumor response, this hypofractionated regimen is approximately equivalent to 6600 cGy in 200 cGy fractions to the normal tissues and 5600 cGy in 200 cGy fractions to the tumor. Although the equivalent dose to the tumor was lower than the 6000 cGy to 7000 cGy that may be delivered in 200 cGy fractions, it is possible that the shorter treatment course could have overcome tumor repopulation or that damage to the tumor microvasculature may have contributed to the complete response. In this patient, more than half of the tumor volume was subcutaneous and not visible, which highlights the importance of adequate radiation treatment planning.

The fact that sorafenib was started 1 week after the completion of radiotherapy raises the question as to what its role was in the patient's response. The MRI scan of the brain from the last day of treatment showed that the lesion was less than half of its original size, but that there was still subcutaneous tumor. Review of the patient's serial CT scans of the abdomen showed stable disease for at least 2 months after the patient started sorafenib. The next abdominal CT scan, 5 months after the patient started sorafenib, showed progressive abdominal disease.

Sorafenib is a tyrosine kinase inhibitor targeting both tumor cells and the tumor vasculature. Preclinical studies in xenograft models showed that the primary effect of sorafenib was inhibition of tumor growth [14]. Unlike cytotoxic agents, sorafenib's main clinical benefit is hypothesized to be disease stabilization. The results of a phase-II sorafenib trial are consistent with this hypothesis and showed 36 percent of patients achieving ≥ 25 percent tumor shrinkage and 34 percent achieving stable disease. Tumor growth or other evidence of progression at or before week twelve was noted in 25 percent [15]. In this study involving 202 patients and earlier trials involving over 500 patients who received sorafenib, no complete responses were described [16, 17]. This evidence, together with our patient's clinical history, would suggest that the radiotherapy was primarily responsible for the response of the skin metastasis. Whether the concurrent administration of sorafenib and radiotherapy could result in synergism is an interesting hypothesis.

Hypofractionated electron beam radiotherapy can be effective in achieving rapid palliation of cutaneous metastases from renal cell carcinoma. Imaging studies can help the radiation oncologist choose the optimal electron energy, as visual inspection may underestimate the depth of the tumor.

Acknowledgments: We would like to thank Joseph Lurito, MD, Department of Radiology, Pitt County Memorial Hospital, for his review of the diagnostic images and image capture; James Finley, MD, Department of Pathology and Laboratory Medicine, The Brody School of Medicine at East Carolina University, for his review of the pathologic slides and image capture; and Melodee Wolfe, Department of Radiation Oncology, M.S., The Brody School of Medicine at East Carolina University, for her assistance during treatment planning and retrieving the planning CT scan.

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