How To Distinguish Between A Metastatic Renal Cell Carcinoma And A Diffuse Malignant Mesothelioma

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1 Expression of Renal Cell Carcinoma Associated Markers Erythropoietin, CD10, and Renal Cell Carcinoma Marker in Diffuse Malignant Mesothelioma and Metastatic Renal Cell Carcinoma Kelly J. Butnor, MD; Andrew G. Nicholson, DM; D. Craig Allred, MD; Dani S. Zander, MD; Douglas W. Henderson, MBBS; Roberto Barrios, MD; Abida K. Haque, MD; Timothy C. Allen, MD; Deanna E. Killen, HTMLT; Philip T. Cagle, MD Context. Metastatic renal cell carcinoma (MRCC) involving the thorax can be difficult to distinguish from diffuse malignant mesothelioma (DMM) using traditional morphologic approaches. Standard panels of immunohistochemical markers are of limited benefit. Objective. To investigate several antibodies to renal cell carcinoma associated proteins for differentiating MRCC from DMM. Design. One hundred DMMs and 20 MRCCs were evaluated for immunoexpression of erythropoietin. The same cases and an additional 45 DMMs were evaluated for CD10 and renal cell carcinoma marker (RCCMa) immunoreactivity. Results. Erythropoietin was expressed in 100% of DMMs and MRCCs. Staining for CD10 was observed in 54% of DMMs and 100% of MRCCs. RCCMa stained 26% of DMMs and 55% of MRCCs. Although erythropoietin staining was similarly strong and diffuse in both DMM and MRC, patterns of staining for RCCMa and CD10 differed between MRCC and DMM. Immunoreactivity was strong and diffuse for both RCCMa and CD10 in most MRCCs. Of CD10-positive DMMs, nearly half showed staining in less than 50% of tumor cells and about one fourth of positive cases exhibited only weak to moderately intense staining. Only half of RCCMa-positive DMMs showed staining in more than 49% of tumor cells and staining was only weak to moderately intense in most cases. Conclusions. Given the overlap in the expression of renal cell carcinoma markers in MRCC and DMM, results with these markers must be interpreted cautiously and should be used in conjunction with mesothelium-associated markers. Differences in expression may potentially help distinguish MRCC from DMM inasmuch as strong and diffuse expression of RCCMa and CD10 supports a diagnosis of MRCC over DMM. (Arch Pathol Lab Med. 2006;130: ) Like diffuse malignant mesothelioma (DMM), metastatic renal cell carcinoma (MRCC) can cause pleural effusions, pleural thickening, and chest wall masses. MRCC can also exhibit a broad spectrum of histologic appearances, and overlap exists between the histologic features of MRCC and DMM. 1 4 Although glycoprotein-associated immunohistochemical markers have proven utility for distinguishing most types of adenocarcinomas from DMM, Accepted for publication January 12, From the Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington (Dr Butnor); Department of Histopathology, Royal Brompton Hospital, London, United Kingdom (Dr Nicholson); Department of Pathology, Baylor College of Medicine, Houston, Tex (Dr Allred); Department of Pathology, University of Texas Health Science Center at Houston (Dr Zander); Anatomical Pathology Department, Flinders Medical Centre, Adelaide, Australia (Dr Henderson); Department of Pathology, The Methodist Hospital, Houston, Tex (Drs Barrios, Haque, and Cagle and Ms Killen); and Department of Pathology, University of Texas Health Science Center at Tyler (Dr Allen). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Kelly J. Butnor, MD, Department of Pathology, Fletcher Allen Health Care/University of Vermont, 111 Colchester Ave, Burlington, VT ( kelly.butnor@vtmednet.org). these antibodies have shown a limited ability to distinguish MRCC from DMM. A small number of studies have explored the value of so-called mesothelium-associated antibodies, such as cytokeratin (CK) 5/6 and calretinin, in evaluating DMM from MRCC and found them to be relatively reliable in distinguishing these entities. 5 7 However, mesothelium-associated markers are not entirely specific for DMM and have been reported to stain occasional renal cell carcinomas. Recently, several antisera have been found to be highly sensitive for renal cell carcinoma. We evaluated 3 of these antibodies, erythropoietin (EPO), CD10, and renal cell carcinoma marker (RCCMa), for their utility in distinguishing between DMM and MRCC. The results suggest a limited role for CD10 and RCCMa in the evaluation of neoplasms with extensive intrathoracic spread. MATERIALS AND METHODS One-hundred forty-five cases of DMM and 20 cases of MRCC were retrieved from the archives of Baylor College of Medicine, Houston, Tex; University of Texas Medical Branch at Galveston; University of Texas Health Science Center at Houston; Flinders Medical Centre, Adelaide, Australia; and Royal Brompton Hospital, London, United Kingdom. The study was approved by the Arch Pathol Lab Med Vol 130, June 2006 RCC Markers in Mesothelioma and Metastatic RCC Butnor et al 823

2 Antibody n Diffuse Malignant Mesothelioma No. (%) of Positive Cases Immunohistochemical Staining Results* Expression Negative Low High n EPO (100) 0 1 M 80 S 16 M 3W CD (54) S 8M 2W RCCMa (26) S 5M 12 W 32 S 11 M 3S 11 M 5W Metastatic Renal Cell Carcinoma No. (%) of Positive Cases Expression Negative Low High (100) S (100) 0 1 S 1M (55) 9 2 S 1M * EPO indicates erythropoietin; S, strong intensity; M, moderate intensity; W, weak intensity; and RCCMa, renal cell carcinoma marker. 18 S 7S 1W Baylor College of Medicine institutional review board. The diagnosis of DMM was based on typical histologic features, in conjunction with appropriate clinical and radiographic findings. One hundred three DMMs were epithelial, 36 were biphasic, and 6 exhibited a purely sarcomatoid growth pattern. Immunohistochemical staining with a panel of antibodies that included a cytokeratin cocktail and at least 2 glycoprotein-associated markers (eg, epithelial membrane antigen, carcinoembryonic antigen, B72.3, Leu-M1, Ber-Ep4, and/or TTF-1) and 2 mesothelium-associated markers (eg, calretinin, HBME-1, thrombomodulin, or CK 5/6) was performed as part of the original diagnostic evaluation at the contributing institutions. All patients diagnosed with MRCC to the pleura had a previous or concurrent histologically confirmed renal cell carcinoma. Most MRCCs exhibited clear cell morphology, with some showing variably eosinophilic cytoplasm and/or focally sarcomatoid morphology. Immunohistochemical studies were performed on formalinfixed, paraffin-embedded sections using an avidin-biotin-peroxidase complex method. Sections from the paraffin blocks were cut at 4 m, placed on positively charged slides, deparaffinized in organic solvents, treated with methanolic H 2 O 2 to quench endogenous peroxidase activity, and rehydrated. Following rehydration, heat-induced epitope retrieval was performed by placing sections in 10mM citrate buffer (ph 6.0) and heating for 20 minutes in a vegetable steamer (Black & Decker, Shelton, Conn). After cooling for 20 minutes, sections were reacted with antibody against EPO receptor (rabbit IgG polyclonal; Research Diagnostic, Inc, Flanders, NJ; 1:100), CD10 (clone 56C6, murine IgG monoclonal; NeoMarkers, Inc, Fremont, Calif; 1:50), and renal cell carcinoma marker (gp200, clone PN-15, murine IgG monoclonal; NeoMarkers; 1:50). The antibodies were detected with En- Vision -labeled polymer kits for rabbit or mouse antibodies (DakoCytomation, Carpinteria, Calif) using a Dako Autostainer. Appropriate positive and negative controls were used for every case with each staining run. Immunohistochemical staining was semiquantitatively graded by one of us (K.J.B.) without prior knowledge of the results of previously performed immunohistochemical stains for glycoprotein-associated and mesothelium-associated markers. Immunoexpression was graded as low (10% 49% of cells) or high (50% 100% of cells). Tumors with less than 10% of cells staining were considered negative. The intensity of staining was recorded as weak, moderate, or strong. Statistical significance was evaluated with the Fisher s exact test. RESULTS The immunohistochemical findings are summarized in Table 1. One hundred of the 145 DMM were tested for EPO, all of which showed positive staining. In most cases, staining was strong and diffuse (Figure 1). The distribution of staining was cytoplasmic with perinuclear accentuation in some cases. EPO stained sarcomatoid DMMs and the sarcomatoid component of biphasic DMMs as effectively as epithelioid mesothelioma cells. In MRCC, EPO staining was uniformly strong and diffuse and cytoplasmic in distribution (Figure 2). CD10 staining was observed in 78 (54%) of 145 DMMs, slightly more than half of which (55%) showed high immunoexpression (Figure 3). Seventy-three percent of CD10-positive DMMs showed strong intensity staining, 24% exhibited moderately intense staining, and 3% stained weakly. The distribution of staining was predominantly cytoplasmic with membranous accentuation. Staining was observed in both sarcomatoid and epithelioid mesothelioma cells. Cytoplasmic and membranous staining for CD10 was seen in 20 (100%) of 20 MRCCs (Figure 4). Ninety percent of cases showed strong intensity high immunoexpression. Of the 2 cases that exhibited low immunoexpression, strong intensity staining was observed in 1 and the other showed moderately intense staining. Thirty-eight (26%) of 145 DMMs exhibited cytoplasmic and membranous RCCMa staining, divided equally into cases showing high or low immunoexpression (Figure 5). Only 13% of RCCMa-positive DMMs demonstrated strong intensity staining. Staining was predominantly seen in epithelioid DMM and was rare in purely sarcomatoid DMMs and largely restricted to the epithelioid component of biphasic DMMs. RCCMa stained the cytoplasm and cytoplasmic membrane in 11 (55%) of 20 MRCCs, the majority of which (72%) showed high immunoexpression (Figure 6). Of MRCCs positive for RCCMa, 81% exhibited strong intensity staining. The differences in negative ( 10% of tumor cells staining) versus positive staining of DMM and MRCC for both CD10 (P.001) and RCCMa (P.02) were statistically significant. COMMENT Renal cell carcinoma has a propensity to metastasize to distant sites and can mimic a wide variety of other neoplasms. Pleural metastases of MRCC can be extensive and like DMM can take the form of pleural masses, nodular pleural thickening, or diffuse pleurotrophic growth with rindlike encasement of the lung. 1 4 MRCC can also mimic malignant mesothelioma (MM) histologically, with patterns ranging from epithelioid to biphasic to purely sarcomatoid. 6,7 Adding to the diagnostic challenge, foamy and clear cell variants of MM histologically reminiscent of conventional (clear cell) renal cell carcinoma have been described A single uniformly sensitive and specific marker for DMM remains elusive. The current immunohistochemical approach to the diagnosis of DMM uses a panel of anti- 824 Arch Pathol Lab Med Vol 130, June 2006 RCC Markers in Mesothelioma and Metastatic RCC Butnor et al

3 Figure 1. Diffuse malignant mesothelioma exhibits strong and diffuse cytoplasmic immunoreactivity for erythropoietin (immunoperoxidase, original magnification 40). Figure 2. Metastatic renal cell carcinoma with diffuse cytoplasmic erythropoietin staining (immunoperoxidase, original magnification 40). Figure 3. Diffuse malignant mesothelioma with patchy moderate intensity cytoplasmic CD10 staining (immunoperoxidase, original magnification 40). Figure 4. Intense cytoplasmic and membranous CD10 positivity in metastatic renal cell carcinoma (immunoperoxidase, original magnification 40). Figure 5. Diffuse malignant mesothelioma with weak cytoplasmic and membranous renal cell carcinoma marker staining (immunoperoxidase, original magnification 40). Figure 6. Diffuse cytoplasmic and membranous immunoreactivity of metastatic renal cell carcinoma for renal cell carcinoma marker (immunoperoxidase, original magnification 40). Arch Pathol Lab Med Vol 130, June 2006 RCC Markers in Mesothelioma and Metastatic RCC Butnor et al 825

4 bodies selected not only to detect DMM but also to evaluate for other neoplasms with similar clinical, radiographic, and morphologic characteristics. Antibody panels routinely include mesothelium-associated antibodies, as well as antibodies against glycoproteins. Although the latter are effective tools for supporting diagnoses of most types of adenocarcinoma, glycoprotein-associated markers are relatively insensitive for detecting MRCC. For this reason, previous immunohistochemical studies aimed at distinguishing DMM from MRCC have focused predominantly on so-called mesothelium-associated antibodies. Although sensitive for DMM, mesothelium-associated antibodies are not entirely specific. Cytokeratins 5 and 6, which are expressed by most DMMs, were immunohistochemically detectable in 3 (2.7%) of 110 renal cell carcinomas. 5,7,12 16 Immunostaining for the Wilms tumor protein, WT1 protein, occurs in most DMMs. Positive staining has also been reported in 2 cases of renal cell carcinoma tested for this antibody. 5,17 Although HBME-1 is a sensitive marker for MM, 1 of 10 renal cell carcinomas metastatic to the pleura stained for this marker. 18 Thrombomodulin, although recognized as a sensitive marker for MM, is not as specific as other mesothelium-associated antibodies. Nineteen (14%) of 134 renal cell carcinomas have shown thrombomodulin immunoreactivity. 5 7,13,14,16,18 Calretinin appears to be a useful marker in separating MM from renal cell carcinoma. Typically positive in MM, calretinin was negative in 113 (98%) of 115 renal cell carcinomas examined for this marker. 5,7,13 16,19,20 Mesothelin, which is strongly expressed in a high proportion of MM, was absent in all 65 MRCCs examined. 5,21 Established glycoprotein-associated antibodies are of limited diagnostic value in distinguishing DMM from MRCC. Carcinoembryonic antigen is widely used in immunohistochemical panels for separating DMM from metastatic carcinoma. This marker, which is typically negative in DMM and positive in pulmonary adenocarcinoma, has been uniformly negative in all 89 cases of renal cell carcinoma reported. 5,7,14 Staining for MOC-31, a rarity in MM, has been observed in 50% of renal cell carcinomas tested for this marker. 5 Ber-Ep4, which is usually negative in MM, stains most carcinomas metastatic to the pleura. 22 However, this marker has demonstrated low sensitivity for renal cell carcinoma, staining only 48 (44%) of 109 cases. 5 7,14 Leu-M1 (CD15), a marker that is negative in the vast majority of DMMs, has a sensitivity for renal cell carcinoma identical to Ber-Ep4 of 44% (positive in 30/68 cases). 5,6,22 In recent years, several antibodies have been recognized as sensitive markers of renal cell carcinoma. In the present study, we assessed the diagnostic utility of 3 such markers, EPO, CD10, and RCCMa, for discriminating between DMM and MRCC. Erythropoietin is a glycoprotein hormone that induces erythropoiesis. Tumor cell induction of EPO is responsible for polycythemia in a number of malignancies, including renal cell carcinoma. 23 Erythropoietin staining has been reported in a high proportion of primary renal cell carcinomas (84%), as well as in metastatic renal cell carcinoma. 24,25 Immunoexpression of EPO in MM has not been well studied. A study examining EPO staining in lung carcinomas included 1 case of MM that was positive for EPO. 26 Interestingly, a substantial proportion of lung cancers in the same study showed positive EPO staining. In the present study, EPO staining was uniformly present in a strong and diffuse fashion in both DMM and MRCC. Sarcomatoid DMMs stained as robustly for this marker as did biphasic and epithelioid DMMs. Based on these findings, EPO does not appear to have a role in immunohistochemical panels designed to separate DMM from MRCC. CD10, as evidenced by its alternate name, CALLA, which stands for common acute lymphoblastic leukemia antigen, was originally developed as a specific marker for non B-, non T-cell acute lymphoblastic leukemia. 27 Subsequently, CD10 immunoexpression was reported in other hematopoietic malignancies, such as follicular lymphoma, as well as in several nonhematopoietic neoplasms, including malignant melanoma, endometrial stromal sarcoma, and renal cell carcinoma Diffuse cytoplasmic CD10 staining has been reported in 89% to 94% of primary clear cell and papillary renal cell carcinomas. 30 In contrast, chromophobe renal cell carcinomas have shown absent staining. 30 In a series of 3 renal cell carcinomas metastatic to the gynecologic tract, all cases were CD10 positive. 32 Data on CD10 staining in MM are sparse, with an overall staining rate of 48% in 2 prior reports. 5,30 In the present study, MRCCs uniformly stained for CD10. Slightly greater than half of DMMs in our study were also immunoreactive for CD10. CD10 staining was not restricted to epithelioid DMMs. About half of sarcomatoid and biphasic DMMs also showed staining. We did note some differences in CD10 staining between MRCC and DMM. Whereas CD10 staining was strong and diffuse in most MRCCs, in those DMMs that were positive for CD10, immunoexpression was low in nearly 45% and only weak to moderately intense in 27% of cases. RCCMa is a monoclonal antibody against the proximal renal tubule antigen gp200 glycoprotein. In prior studies, immunoreactivity for RCCMa has been detected in 75% to 96% of primary clear cell and papillary renal cell carcinomas and 67% to 84% of MRCCs. 5,33 35 Considerably lower rates of staining were observed in chromophobe (0% 45%) and sarcomatoid (25%) renal cell carcinomas. 5,34,35 Renal cell carcinoma marker has shown high specificity for renal cell carcinoma. Expression of RCCMa by other neoplasms has been limited to parathyroid adenomas, a small proportion of breast and embryonal carcinomas, and rare (8%) epithelial DMMs. 5,33,35 In the present study, we identified DMM staining for RCCMa in approximately one fourth of cases, half of which showed staining in less than 50% of cells and in most positive cases was only of weak to moderate intensity. Staining was observed predominantly in epithelioid DMMs and in the epithelioid component of biphasic DMMs. In conclusion, we have found that several antibodies reported to be highly sensitive for renal cell carcinoma, EPO, CD10, and RCCMa, are expressed not only in MRCC but also in a substantial number of DMMs. Erythropoietin does not appear to be useful in discriminating MRCC from DMM because this antibody is uniformly expressed in both tumors. For the other 2 antibodies, CD10 was 100% sensitive for MRCC but only 46% specific, whereas RCCMa was only 55% sensitive for MRCC and 74% specific. However, both the extent and intensity of CD10 and RCCMa immunoreactivity in DMM is less than is observed in MRCC. CD10 and RCCMa staining, in conjunction with a panel of sensitive and specific mesotheliumassociated markers and detailed clinical and radiographic information, may play a limited role in the distinction between MRCC and DMM. A diagnosis of MRCC should be 826 Arch Pathol Lab Med Vol 130, June 2006 RCC Markers in Mesothelioma and Metastatic RCC Butnor et al

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