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research-article2016

IJSXXX10.1177/1066896916634207International Journal of Surgical PathologyCohen et al

Case Report

Metastatic Renal Cell Carcinoma in a Hepatic Hemangioma: A Case Report and Review of the Literature

International Journal of Surgical Pathology 1­–4 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896916634207 ijs.sagepub.com

Joshua Cohen, BA1, Rashna Meunier, MD1, Sarah Jamshed, MD1, Adib R. Karam, MD1, Jennifer Yates, MD1, Xiaofei Wang, MD1, and Jennifer LaFemina, MD, FACS1

Abstract We report the case of 55-year-old female with biopsy-proven clear cell renal cell carcinoma with a suspicious lesion found in the liver who presented for right radical nephrectomy and partial hepatectomy. Histologic evaluation of the hepatic specimen demonstrated metastatic renal cell carcinoma within a hepatic hemangioma. Herein we provide a review of the literature for this uncommon scenario. Keywords renal cell carcinoma, hepatic hemangioma, tumor-to-tumor metastasis, vascular endothelial growth factor (VEGF)

Introduction Clear cell renal cell carcinoma (RCC) accounts for 70% of all cases of RCC. Abundant clear cytoplasm with frequent distant metastases are characteristic.1 The typical sites of distant metastasis are the lungs, bone, liver, and nonregional lymph nodes. These account for approximately 56%, 32%, 8%, and 2% of metastatic lesions, respectively, at the time of nephrectomy. Metastases are found at multiple sites at the time of nephrectomy in about 19% of cases.2 Clear cell RCC has long been known to overexpress vascular endothelial growth factor (VEGF), which is believed to contribute to its tumor pathogenesis and metastasis.3-5 In this article, we report a case of clear cell RCC with a synchronous liver metastasis identified within a hepatic hemangioma.

Case Report A 55-year-old female with a history of renal insufficiency and left sided back pain was found to have a large right renal mass on ultrasound. She subsequently underwent a computed tomography (CT) scan of the abdomen and pelvis to evaluate the newly discovered renal mass, which demonstrated an 11-cm heterogeneously enhancing right renal tumor highly suspicious for RCC. There was also a 1.6-cm indeterminate right lobe liver lesion suspicious for hypervascular metastasis, focal nodular hyperplasia (FNH), or atypical hemangioma along with a left retroperitoneal soft tissue nodule suspicious for distant metastasis (Figure 1). CT-guided biopsy of the left retroperitoneal

nodule confirmed the diagnosis of metastatic clear cell RCC. Gadoxetate disodium–enhanced liver magnetic resonance imaging (MRI) excluded the diagnosis of FNH. Percutaneous CT-guided fine needle aspiration of the liver mass was negative for malignant cells, showing only scant hepatocytes. The patient underwent a right radical nephrectomy, adrenalectomy, retroperitoneal lymph node dissection, and partial hepatectomy of liver segments V and VI. On gross examination of the renal tumor, the mid and lower poles were entirely replaced by an 11.4-cm solid, encapsulated, golden-yellow lesion with focal hemorrhage and central necrosis. The tumor was confined to the kidney without involvement of the renal vein, Gerota’s fascia, or perihilar fat. Microscopic examination revealed classic features of clear cell RCC, including nests of tumor cells with clear cytoplasm, surrounded by prominent intervening blood vessels (Figure 2). The tumor cells had large nuclei with irregular nuclear contours and prominent nucleoli, meriting a Fuhrman nuclear grade of III. Thirteen paracaval lymph nodes were negative for metastasis. The partial hepatectomy specimen consisted of a 1.6 × 1.2 × 1.2 cm tan-pink, ill-defined lesion. Microscopic evaluation of the lesion revealed numerous thin-walled 1

University of Massachusetts Medical School, Worcester, MA, USA

Corresponding Author: Jennifer LaFemina, Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Email: [email protected]

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Figure 1.  (a, b, c) Representative images of preoperative CT scan demonstrating a right renal mass (asterisk), a hyperenhancing lesion in the right lobe of the liver (arrow), and a left retroperitoneal enhancing soft tissue nodule (circle). (d, e, f) Gadoxetate disodium–enhanced liver MRI redemonstrates the hyperenhancing liver lesion (arrow) without enhancement on the hepatobiliary phase image (f) excluding the diagnosis of FNH.

and prominent nucleoli, which were morphologically quite similar to the clear cell RCC cells seen in kidney (Figure 3). PAX8 and RCC immunohistochemical stains highlighted these cells, confirming the diagnosis of metastatic clear cell RCC. The final pathologic stage of the tumor was T2bN0M1. With ablation of the contralateral perinephric nodule, the patient was rendered free of disease.

Discussion

Figure 2.  Clear cell RCC of the kidney, (hematoxylin-eosin, 400×). The tumor cells contain clear cytoplasm, have large nuclei with irregular nuclear contours, and prominent nucleoli.

vascular spaces, lined by a single layer of endothelial cells. CD31 and CD34 immunohistochemical stains highlighted the endothelial cells, confirming a diagnosis of hemangioma. Within the 1.6-cm hemangioma, there was a 0.2-cm focus of cells with clear cytoplasm, large nuclei,

Hepatic metastases are relatively uncommon in clear cell RCC, accounting for approximately 10% of all metastatic lesions. Clear cell RCC often exhibits hematogenous spread, so it is not surprising that a metastatic lesion was found within a vascular tumor.2 However, what is unclear in this setting of tumor-to-tumor metastases is whether the clear cell RCC metastasized to an existing hepatic hemangioma or if the metastatic lesion induced the formation of a hemangioma. Wheeler et al report a case of metastatic clear cell RCC in a site of hepatic FNH.6 It is proposed that increased blood flow through the vascular tumor predisposes these hepatic lesions to hematogenous spread of metastatic clear cell RCC. However, a recent report by Fellegara and Rosai of multiple vascular proliferations of the kidney associated with a clear cell RCC argues that

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Figure 3.  Clear cell RCC metastatic to hepatic hemangioma. A 0.2-cm focus of metastatic clear cell RCC was found within the hepatic hemangioma, hematoxylin-esoin (a, 40×; b, 100×). Tumor cells stained with PAX8 (c) and RCC (d), 100×. CD34 (e) and CD31 (f) highlight the endothelial cells of the hepatic hemangioma, 100×.

these hemangioma-like growths could represent a tumor epiphenomenon wherein the RCC induces vascular proliferation.7 It has been long established that clear cell RCC overexpresses VEGF and its receptor (VEGFR).3,4 Von Hippel-Lindau (VHL) tumor suppressor gene allele deletion has been demonstrated in 84% to 98% of all sporadic RCCs, which has been proposed as the initiating event in most RCC pathogenesis.5 The role of VHL in the normal cell is to bind hypoxia-inducible factors (HIF) and target them for proteolysis. During a hypoxic state, the HIFVHL interaction is broken, leading to stabilization of HIF, which allows for the upregulation of VEGF transcription and ultimately vascular proliferation. With VHL deletions or mutations, HIF genes are constitutively active, leading to the overexpression of VEGF and allowing for vascular proliferation to support the growth of a clear cell RCC.5 VEGF has also long been theorized to be a major contributor in the pathogenesis of a hepatic hemangioma.8,9 Mahajan et al reported the incidental decrease in the size of a cavernous hemangioma in a patient being treated with the VEGF inhibitor bevacizumab for colonic adenocarcinoma. This suggests a possible mechanism that may also be seen within hemangioma pathogenesis.9 While the exact pathogenesis of this tumor-to-tumor phenomenon remains to be elucidated, this case serves as a unique and interesting report of an uncommon entity whereby a patient with metastatic disease was rendered free of disease with multimodality care.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Mai KT, Landry DC, Robertson SJ, et al. A comparative study of metastatic renal cell carcinoma with correlation to subtype and primary tumor. Pathol Res Pract. 2001;197:671-675. 2. Hoffmann NE, Gillett MD, Cheville JC, Lohse CM, Leibovich BC, Blute ML. Differences in organ system of distant metastasis by renal cell carcinoma subtype. J Urol. 2008;179:474-477. 3. Xia G, Kageyama Y, Hayashi T, Kawakami S, Yoshida M, Kihara K. Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma. Cancer. 2001;91:1429-1435. 4. Nicol D, Hii SI, Walsh M, et al. Vascular endothelial growth factor expression. J Urol. 1997;157:1482-1486. 5. Rini BI, Rathmell WK. Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma. Clin Cancer Res. 2007;13:741s-746s. 6. Wheeler YY, Wheeler GL, Diaz-Arias AA, Anders RA. Metastatic renal cell carcinoma within a hepatic focal nodular hyperplasia: a case report and review of the literature. Int J Clin Exp Pathol. 2009;2:190-193.

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7. Fellegara G, Rosai J. Multifocal capillary hemangioma-like vascular proliferation of the kidney associated with clear cell renal cell carcinoma: a case report and review of the literature. Int J Surg Pathol. 2013;21:424-426. 8. Zhang WJ, Ye LY, Wu LQ, et al. Morphologic, phenotypic and functional characteristics of endothelial cells derived

from human hepatic cavernous hemangioma. J Vasc Res. 2006;43:522-532. 9. Mahajan D, Miller C, Hirose K, McCullough A, Yerian L. Incidental reduction in the size of liver hemangioma following use of VEGF inhibitor bevacizumab. J Hepatol. 2008;49:867-870.

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Metastatic Renal Cell Carcinoma in a Hepatic Hemangioma: A Case Report and Review of the Literature.

We report the case of 55-year-old female with biopsy-proven clear cell renal cell carcinoma with a suspicious lesion found in the liver who presented ...
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