Metastatic Renal Cell Carcinoma to the Pancreas A Review Shaun Kian Hong Cheng, MB, ChB; Khoon Leong Chuah, MBBS, FRCPA

 The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas. (Arch Pathol Lab Med. 2016;140:598–602; doi: 10.5858/ arpa.2015-0135-RS)

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linically, secondary neoplasms affecting the pancreas are uncommon, accounting from 2% to 5% of all malignancies in the pancreas.1 The more common distant metastases affecting the pancreas include renal cell carcinoma, melanomas, colorectal carcinomas, lung carcinomas, breast carcinomas, and sarcomas.2 During the last few years, attention has been paid to metastatic renal cell carcinoma affecting the pancreas.3 Unlike other forms of nonrenal malignancies affecting the pancreas secondarily, which are often associated with widespread systemic disease, renal cell carcinoma may spread to the pancreas as the only secondary site (ie, the most common primary cancer site), causing an isolated pancreatic metastasis in the kidney.1–3 In light of advances made in pancreatic surgery, surgical resection of isolated renal cell carcinoma of the pancreas is an attractive form of therapy in treating this group of patients with only Accepted for publication June 15, 2015. From the Department of Pathology, Tan Tock Seng Hospital, Singapore. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Khoon Leong Chuah, Department of Pathology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore (email: [email protected]). 598 Arch Pathol Lab Med—Vol 140, June 2016

pancreatic metastasis from a renal cell carcinoma. Consequently, an accurate histologic diagnosis of renal cell carcinoma spreading secondarily to the pancreas is paramount in proper management, especially in the absence of a clinically relevant history. In this review, we discuss the clinicopathologic findings and important histologic differential diagnoses of renal cell carcinoma, particularly the more common clear cell renal cell carcinoma (CCRCC), involving the pancreas. CLINICAL FEATURES In terms of clinical presentation,3 approximately 55% of patients with renal cell carcinoma affecting the pancreas are asymptomatic, and the disease may only manifest after a long period.2 Isolated pancreatic disease is often discovered during routine surveillance imaging for primary lesions or as an incidental finding on imaging performed for other reasons.1 In fact, the discovery of a pancreatic tumor originating from a renal primary tumor may be the first clinical manifestation of renal cell carcinoma in the patient.4 Among those with clinical manifestations, the more common findings include those of weight loss and abdominal pain. Other symptoms include jaundice and gastrointestinal bleeding. Without a significant clinical history, it is often impossible to segregate metastatic clear cell renal carcinoma to the pancreas from a primary pancreatic tumor based on clinical and radiologic findings.2 There is a slight male predominance in terms of sex of patients affected by the disease, and the mean age of the patient is about 65 years and the median age is 66.4 years.3 In terms of manifestation of the pancreatic disease following a diagnosis of renal cell carcinoma, most studies disclose mean time intervals of greater than 10 years during which the patient may be disease free.1 In fact, a period of as long as 32.7 years has been reported.1 Hence, long-term follow-up for renal cell carcinoma is essential in patient management. Whether the incidence of metastatic renal cell carcinoma to the pancreas is increased in syndromic diseases predisposing to the development of renal cell carcinoma is not clear. For example, in von Hippel–Lindau syndrome,5 it appears that the incidence of pancreatic involvement by renal cell carcinoma is less than the general population, whereas in the setting of Birt–Hogg–Dube syndrome,6 the scant data suggest that incidence may be the same as that in the general population. Uniquely, multiple pancreatic lesions are more frequently noted in patients with renal cell carcinoma compared with Renal Cell Carcinoma and Pancreas—Cheng & Chuah

other primary tumors.1 Multifocal pancreatic disease in patients with pancreatic involvement by renal cell carcinoma may range from 20% to as high as 45%. Therefore, surgical management of such patients must take this possibility into account. PATHOLOGIC FINDINGS Grossly, the reported average size of the tumor in the pancreas ranges from 1.5 to 12 cm.4 Metastatic tumor deposits often tend to be well circumscribed, being associated with bright yellow-orange to red-brown to white-gray masses. Hemorrhage, necrosis, and/or cystic change may be seen. Although any part of the pancreas may be affected, the more common location includes the head, followed by the tail and then the body.7 If multifocal disease is present, the affected areas are distributed over the entire pancreas. In terms of light microscopy findings, the more common form of renal tumor is that of CCRCC4 (Figures 1 and 2), and the appearance is similar to those described in the primary renal site. Nests, sheets, and cords of polygonal cells are often present, being associated with a rich sinusoidal vascular network (Figure 3). The Fuhrman nuclear grade of the primary renal neoplasm tends to be on the higher grade, although neoplasm with any nuclear grade can be seen to secondarily affect the pancreas.5 Other types of non– clear cell renal cell carcinoma metastases that have been described to affect the pancreas include chromophobe renal cell carcinoma.8 PATHOLOGIC DIFFERENTIAL DIAGNOSES In this review, a more extensive discussion is focused on the more common CCRCC metastasis to the pancreas. For metastatic CCRCC to the pancreas, the differential diagnoses include ductal adenocarcinoma with clear cell appearance (clear cell carcinoma), clear cell endocrine pancreatic tumor, solid serous adenoma of the pancreas, clear cell variant of solid pseudopapillary tumor of the pancreas, and perivascular epithelioid cell tumor (PEComa). Clear cell carcinoma of the pancreas is thought to be a variant of pancreatic ductal carcinoma.9 Although clear cell carcinoma of the pancreas may resemble metastatic clear cell renal cell carcinoma by virtue of tubular/glandular structures lined by clear cells with distinct cell borders and varying degrees of nuclear atypia, recognizable areas of conventional pancreatic ductal adenocarcinoma are usually present at least focally, thereby affording distinction between the 2 entities.9 The presence of intracytoplasmic glycogen reacting positively for periodic acid–Schiff and abolished by diastase on histochemical stain is more in keeping with a diagnosis of metastatic CCRCC, because the tumor cells in clear cell pancreatic carcinoma do not contain mucin or glycogen.9 In troublesome cases, demonstration of CD10 (Figure 4) and PAX8 (Figure 5) expressions on immunohistochemistry stains favors a diagnosis of metastatic CCRCC.10 Although hepatocyte nuclear factor-1b is useful in identifying clear cell carcinoma of the pancreas, this marker is commonly expressed in CCRCC,11 thereby diminishing its discriminatory value. Clear cell endocrine pancreatic tumor, particularly in the setting of von Hippel–Lindau disease, is known to closely mimic metastatic CCRCC, because tumor cells in this group of neoplasm may be arranged in cords, nests, and tubules, all of which can be seen with central hemorrhage, Arch Pathol Lab Med—Vol 140, June 2016

simulating CCRCC.12 Nonetheless, close scrutiny of the neoplasm reveals cords, festoons, and gyriform patterns of tumor cell arrangement, thereby raising the possibility of a neuroendocrine neoplasm. A positive reaction for chromogranin and/or synaptophysin on immunohistochemistry stains will ultimately betray a diagnosis of clear cell endocrine pancreatic tumor, thereby separating it from CCRCC. The solid variant of serous adenoma can imitate CCRCC when it is composed of clear cytoplasm with a well-defined cell border.13 The presence of hemorrhage and cytologic atypia favors a diagnosis of CCRCC. In addition, demonstration of PAX8, CD10, and renal cell carcinoma antigen positivity is in keeping with a diagnosis of CCRCC.10 Recently, there have been reports of metastatic CCRCC to an underlying existing microcystic serous cystadenoma of the pancreas, which may confound recognition of the CCRCC component.14 In such an instance, careful light microscopy observation and the performance of appropriate immunohistochemistry stains (particularly CD10, PAX8, and CK7) are pivotal in arriving at the correct diagnosis, because the cells of serous cystadenoma are CK7 positive with negative expressions for CD10 and PAX8, whereas CCRCC is CK7 negative with positive expressions for CD10 and PAX8. The clear cell variant of solid pseudopapillary tumor of the pancreas may be confused with a metastatic CCRCC superficially by virtue of the clear cells.15 However, the clear cell variant of solid pseudopapillary tumor tends to affect younger individuals (patients are in their early thirties) compared with older individuals in metastatic CCRCC. In addition, a positive staining pattern for synaptophysin and b-catenin on immunohistochemistry supports a diagnosis of pancreatic pseudopapillary tumor rather than CCRCC.15 Another tumor with clear cells that may pose a diagnostic challenge with a metastatic CCRCC is that of PEComa (tumors displaying perivascular epithelioid cell differentiation) of the pancreas.16,17 Although pancreatic PEComa is very rare, PEComa shows overlapping features with CCRCC by being composed of uniform glycogen-rich, polygonal to round epithelioid cells with well-defined cell borders and clear cytoplasm arranged in nests in association with prominent thin-walled vasculature (Figure 6).12,16,17 Consequently, distinction between the 2 entities can be fraught with difficulties based on morphology alone and will often require the performance of a panel of immunohistochemistry stains. Expressions of HMB-45 and smooth muscle actin support a diagnosis of PEComa,16 whereas expressions of cytokeratin, CD10, and PAX8 favor a diagnosis of CCRCC.10 Recently, a clear cell type of intraductal tubulopapillary neoplasm18 has been described where the tumor closely resembles a metastatic CCRCC to the pancreas and exhibits a proliferation of clear cells within the pancreatic duct. The mimicry is further heightened by the neoplasm’s ability to react positively to antibodies against carbonic anhydrase IX and CD10 on immunohistochemistry. Nonetheless, the lack of permeation of the neoplastic cells into the surrounding stroma and the tumor being confined within the pancreatic ducts argue against a diagnosis of CRCC. Besides, the absence of vimentin expression and the presence of mucin expression are not in keeping with CRCC. Obviously, the lack of a discernible mass in the kidney on radiology imaging favors a pancreatic primary. Renal Cell Carcinoma and Pancreas—Cheng & Chuah 599

Figure 1. Low-power view of a metastatic clear cell renal cell carcinoma with areas of hemorrhage affecting the pancreas. Note the apparent circumscription (hematoxylin-eosin, original magnification 320). Figure 2. Medium-power view disclosing the infiltrative nature of neoplastic cells into the surrounding pancreatic tissue (hematoxylin-eosin, original magnification 3100). Figure 3. Clear cells with distinct cytoplasmic border disposed in nests separated by thin fibrovascular stroma. Note the characteristic presence of blood pools (hematoxylin-eosin, original magnification 3400). Figure 4. Cell borders of neoplastic renal cells decorated by antibody against CD10 (immunohistochemistry, original magnification 3400). Figure 5. Diffuse and strong nuclear staining for PAX8, which can be focal in some cases of clear cell renal cell carcinoma (immunohistochemistry, original magnification 3600). 600 Arch Pathol Lab Med—Vol 140, June 2016

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Summary Showing Results of Immunohistochemical Stains That Can Be Used in Discriminating the Various Tumors With Clear Cells Affecting the Pancreas From Clear Cell Renal Cell Carcinoma (CCRCC) CD10 PAX8 RCC Ag Chromogranin Synaptophysin HMB-45 SMA CK8 CK18 CK19 CK20 CA IX CDX2 b-Catenin

CCRCC

CCCP

CCPET

SSA

CCSPT

PEComa

CCITPN

þ þ þ     þ þ 6 19 þ 19 

       þ20 þ20 þ20 620 U 621 22

 þ23  þ þ   þ24 þ24 624 25 U 25 22

       þ26 U U  U U U

þ 625 U  þ   624 624 24 U U U þ22

     þ þ     U U þ28

þ       þ þ U U þ  

Abbreviations: CA IX, carbonic anhydrase IX; CCCP, clear cell carcinoma of pancreas; CCITPN, clear cell type of intraductal tubulopapillary neoplasm of pancreas; CCPET, clear cell pancreatic endocrine tumor; CCSPT, clear cell variant of solid pseudopapillary tumor of pancreas; PEComa, perivascular epithelioid cell tumor; RCC Ag, renal cell carcinoma antigen; SSA, solid variant of serous adenoma; U, insufficient data in the literature at the moment; þ, positive; , negative; 6, may be positive or negative.

Ectopic adrenocortical nodules in the pancreas can replicate the appearance of metastatic CCRCC on histology.12,15 Although adrenocortical nodules are composed exclusively of clear cells, these nodules show arrangement of lipid-rich clear cells in thin cords similar to that of the zona fasciculata of the adrenal cortex, which allows for separation from CCRCC.15 The Table summarizes the immunohistochemical profile of the various clear cell neoplasms affecting the pancreas that may closely resemble CCRCC. References not quoted above are appended within the Table.19–28 Apart from CCRCC, other types of renal cell carcinoma described to metastasize to the pancreas (although uncommon) include chromophobe renal cell carcinoma8 and, very rarely, sarcomatoid renal cell carcinoma.29 In the case of metastatic chromophobe renal cell carcinoma, particularly the eosinophilic variant, the differential diagnoses include acinar cell carcinoma, pancreatic endocrine neoplasm, and solid-pseudopapillary neoplasm.29 Acinar cell carcinoma of the pancreas may look like metastatic chromophobe renal cell carcinoma because both may contain eosinophilic granular cytoplasm. In contrast to the uniform nuclear characteristics of acinar cell carcinoma,30 the nuclei of chromophobe renal cell carcinoma are often irregular and described as ‘‘raisenoid.’’ On immunohistochemistry stains, demonstration of positivity for trypsin and chymotrypsin on immunohistochemistry is more in keeping with an acinar cell carcinoma.30 Metastatic chromophobe renal cell carcinoma may display neoplastic cells with eosinophilic cytoplasm arranged in a somewhat organoid appearance in association with a delicate vascular network,29 and thus it may be mistaken for a pancreatic endocrine neoplasm. Attention to nuclear detail differences between pancreatic endocrine neoplasm and chromophobe renal cell carcinoma is useful in segregating these 2 entities. Stippled, visibly coarse, and evenly distributed chromatin (salt-and-pepper chromatin pattern) is seen in a pancreatic endocrine neoplasm, whereas irregular nuclear membranes with perinuclear

halo are more in keeping with a diagnosis of chromophobe renal cell carcinoma. In a tricky situation, a diagnosis of pancreatic endocrine neoplasm can be confirmed using immunohistochemistry stains for synaptophysin and chromogranin.29 Tumor cells of solid pseudopapillary neoplasm of the pancreas may possess eosinophilic cytoplasm to varying degrees in association with nuclear grooves or indentation,31 thereby resembling a metastatic chromophobe renal cell carcinoma. However, the nuclei of solid pseudopapillary neoplasm show finely dispersed chromatin and are not associated with perinuclear halo. Expressions of b-catenin and synaptophysin on immunohistochemistry favor a diagnosis of solid pseudopapillary neoplasm of the pancreas over a chromophobe renal cell carcinoma. Segregating a poorly differentiated renal cell carcinoma with sarcomatoid morphology from undifferentiated pancreatic carcinoma can be difficult.32 The presence of a significant intraductal component (such as pancreatic intraepithelial neoplasia/PanIN-3) or other preinvasive neoplastic precursors, such as a mucinous cystic neoplasm, would favor a pancreatic primary tumor. However, in the absence of any clues, one may have to rely on relevant clinical history to separate these 2 entities. CONCLUSIONS The incidence and mortality of renal cell carcinoma are apparently on an increasing trend in the industrialized world.7 With advances made in pancreatic surgery as well as the recognition of the rare but unique manner of secondary involvement of the pancreas by renal cell carcinoma, pancreatic resection of metastatic renal cell carcinoma can now be performed safely and is associated with long-term survival in most cases.1–3,7 Therefore, it is necessary that a correct diagnosis of metastatic renal cell carcinoma to the pancreas be made; in such an instance, the consideration of valid differential diagnoses with the performance of adjunct tests, such as immunohistochemistry stains (if deemed

Figure 6. Medium-power view of a perivascular epithelioid cell tumor (PEComa) with clear cells arranged in nests and surrounded by fibrovascular stroma. Note the close mimicry with clear cell renal cell carcinoma (hematoxylin-eosin, original magnification 3200). Arch Pathol Lab Med—Vol 140, June 2016

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appropriate), as well as correlation with clinical and radiologic findings, is vital in arriving at the correct pathologic diagnosis. References 1. Ballarin R, Spaggiari M, Cautero N, et al. Pancreatic metastases from renal cell carcinoma: the state of the art. World J Gastroenterol. 2011;17(43):4747– 4756. 2. Sperti C, Moletta L, Patan`e G. Metastatic tumors to the pancreas: the role of surgery. World J Gastrointest Oncol. 2014;6(10):381–392. 3. Tosoian JJ, Cameron JL, Allaf ME, et al. Resection of isolated renal cell carcinoma metastases of the pancreas: outcomes from the Johns Hopkins Hospital. J Gastrointest Surg. 2014;18(3):542–548. 4. Thompson LD, Heffess CS. Renal cell carcinoma to the pancreas in surgical pathology material. Cancer. 2000;89(5):1076–1088. 5. Maeda H, Okabayashi T, Kobayashi M, et al. Emergency pancreatoduodenectomy for pancreatic metastasis from renal cell carcinoma in a patient with von Hippel-Lindau disease: a case report. Dig Dis Sci. 2006;51(8):1383–1387. 6. Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dub´e syndrome: clinicopathologic findings and genetic alterations. Arch Pathol Lab Med. 2006; 130(12):1865–1870. 7. Benhaim R, Oussoultzoglou E, Saeedi Y, Mouracade P, Bachellier P, Lang H. Pancreatic metastasis from clear cell renal cell carcinoma: outcome of an aggressive approach. Urology. 2015;85(1):135–140. 8. Martignoni G, Pea M, Chilosi M, et al. Parvalbumin is constantly expressed in chromophobe renal carcinoma. Mod Pathol. 2001;14(8):760–767. 9. Kim L, Liao J, Zhang M, et al. Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor1beta. Mod Pathol. 2008;21(9):1075–1083. 10. Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med. 2011;135(1):92–109. 11. Wang CC, Mao TL, Yang WC, Jeng YM. Underexpression of hepatocyte nuclear factor-1b in chromophobe renal cell carcinoma. Histopathology. 2013; 62(4):589–594. 12. Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel-Lindau disease. Am J Surg Pathol. 2001;25(5):602–609. 13. Machado MC, Machado MA. Solid serous adenoma of the pancreas: an uncommon but important entity. Eur J Surg Oncol. 2008;34(7):730–733. 14. Shah L, Tiesi G, Bamboat Z, McCain D, Siegel A, Mannion C. Tumor-totumor metastasis: report of two cases of renal cell carcinoma metastasizing to microcystic serous cystadenoma of the pancreas. Int J Surg Pathol. 2015;23(1): 48–51. 15. Albores-Saavedra J, Simpson KW, Bilello SJ. The clear cell variant of solid pseudopapillary tumor of the pancreas: a previously unrecognized pancreatic neoplasm. Am J Surg Pathol. 2006;30(10):1237–1242.

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16. Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology. 2006;48(1):75–82. 17. Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: the past, the present and the future. Virchows Archiv. 2008;452(2):119–132. 18. Ahls MG, Niedergethmann M, Dinter D, et al. Case report: intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype. Diagn Pathol. 2014;9:11. 19. Kim MY, Go H, Koh J, et al. Napsin A is a useful marker for metastatic adenocarcinomas of pulmonary origin. Histopathology. 2014;65(2):195–206. 20. Hruban RH, Klimstra DS. Adenocarcinoma of the pancreas. Semin Diagn Pathol. 2014;31(6):443–451. 21. Xiao W, Hong H, Awadallah A, Zhou L, Xin W. Utilization of CDX2 expression in diagnosing pancreatic ductal adenocarcinoma and predicting prognosis. PLoS One. 2014;9(1):e86853. 22. Kim MJ, Jang SJ, Yu E. Loss of E-cadherin and cytoplasmic-nuclear expression of beta-catenin are the most useful immunoprofiles in the diagnosis of solid-pseudopapillary neoplasm of the pancreas. Hum Pathol. 2008;39(2):251– 258. 23. Chan JK. Newly available antibodies with practical applications in surgical pathology. Int J Surg Pathol. 2013;21(6):553–572. 24. Notohara K, Hamazaki S, Tsukayama C, et al. Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10. Am J Surg Pathol. 2000;24(10):1361–1371. 25. Chan ES, Alexander J, Swanson PE, Jain D, Yeh MM. PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. Am J Surg Pathol. 2012;36(5):737–743. 26. Reese SA, Traverso LW, Jacobs TW, Longnecker DS. Solid serous adenoma of the pancreas: a rare variant within the family of pancreatic serous cystic neoplasms. Pancreas. 2006;33(1):96–99. 27. Sangoi AR, Ohgami RS, Pai RK, Beck AH, McKenney JK, Pai RK. PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma. Mod Pathol. 2011;24(3):412–424. 28. Flavin RJ, Cook J, Fiorentino M, Bailey D, Brown M, Loda MF. b-Catenin is a useful adjunct immunohistochemical marker for the diagnosis of pulmonary lymphangioleiomyomatosis. Am J Clin Pathol. 2011;135(5):776–782. 29. Campbell F, Verbeke CS. Secondary neoplasia. In: Campbell F, Verbeke CS, eds. Pathology of the Pancreas: A Practical Approach. London, England: Springer Verlag; 2013:171–175. 30. Wood LD, Klimstra DS. Pathology and genetics of pancreatic neoplasms with acinar differentiation. Semin Diagn Pathol. 2014;31(6):491–497. 31. Terris B, Cavard C. Diagnosis and molecular aspects of solid-pseudopapillary neoplasms of the pancreas. Semin Diagn Pathol. 2014;31(6):484–490. 32. Hruban RH, Pitman MB, Klimstra DS. Adenocarcinoma variants. In: Hruban RH, Pitman MB, Klimstra DS, eds. Tumors of the Pancreas. Washington, DC: American Registry of Pathology; 2007:177–181. AFIP Atlas of Tumor Pathology; 4th series.

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