Immunohistochemical Markers to Distinguish Between Hemangioblastoma and Metastatic Clear-cell Renal Cell Carcinoma in the Brain: Utility of Aquaporin1 Combined With Cytokeratin AE1/AE3 Immunostaining

Abstract

Distinguishing hemangioblastomas from metastatic clear-cell renal cell carcinomas (CCRCCs) in the brain is a diagnostic challenge owing to similar clinical and morphologic presentations. Inhibin-alpha and aquaporin1 were shown as positive markers of hemangioblastoma, but are not totally reliable distinguishing hemangioblastoma from metastatic CCRCC. This study shows that the diagnosis can be achieved using a combination of markers. To identify the panel of markers useful for this differential, 67 hemangioblastomas and 34 metastatic CCRCCs were analyzed using a panel of antibodies including aquaporin1, inhibin-alpha, D2-40, cytokeratin AE1/AE3, epithelial membrane antigen, and CD10. The study confirms the usefulness of aquaporin1 (97% sensitivity, 83% specificity) and inhibin-alpha (88% sensitivity, 79% specificity) as positive markers of hemangioblastoma and shows that aquaporin1 is a superior positive marker versus inhibin-alpha for the differential. Positivity of tumor cells with cytokeratin AE1/AE3 is the signature of a metastatic CCRCC (100% specificity, 88% sensitivity) and CD10 expression as well (100% specificity, 79% sensitivity). The combined use of aquaporin1 and AE1/AE3 yields a high degree of sensitivity and specificity to differentiate between hemangioblastoma and metastatic CCRCC. All tumors but one aquaporin1 positive and cytokeratin AE1/AE3 negative (65/66) correspond to hemangioblastomas (97% sensitivity, 97% specificity, 98.5% diagnostic positive predictive value). Tumors with the opposite profile, aquaporin1 negative, and cytokeratin AE1/AE3 positive, (25/25), correspond to metastatic CCRCC (74% sensitivity, 100% specificity, 100% diagnostic positive predictive value). In summary, aquaporin1 is the most sensitive positive marker of hemangioblastoma. Despite its moderate specificity, when used in combination with epithelial marker AE1/AE3, it allowed to reliably distinguish hemangioblastoma from metastatic CCRCC.

Diagnosing and Grading of Brain Tumors: Immunohistochemistry

“…It is suggested that RCC-to-HB metastasis in VHL patients may have been under-recognized. Weinbreck et al (2008) recently confirmed the usefulness of alpha-inhibin and aquaporin-1 as positive markers of HBs, and reported sufficiently high sensitivity and specificity of these markers (88% sensitivity and 79% specificity, 97% sensitivity and 83% specificity, respectively) for the diagnosis of HB versus MCCRCC. In general, RCCs are immunoreactive for epithelial markers, such as EMA and cytokeratins (CAM5.2, AE1/AE3), as well as for CD10 (membranous staining).…”

Role of Pathologist in Driver of Treatment of CNS Tumors

“…Moreover, both tumors may be seen in the von Hippel-Lindau disease. The use of inhibin alfa, aquaporin1 and epithelial markers may differentiate these two tumors [73][74][75]. It has been reported in recent studies that the antibody aquaporin1 is a very reliable marker for hemangioblastoma and that its use with the antibody AE1/AE3 (for RCC) is useful in differentiating the two tumors.…”

Expression of HIF-1 regulated proteins vascular endothelial growth factor, carbonic anhydrase IX and hypoxia inducible gene 2 in hemangioblastomas

“…Pax2 and Pax8 were shown to be negative in hemangioblastomas but positive in the vast majority of CCRCC [2,22]. Aquaporin 1 was found in nearly 100% of hemangioblastomas but only 18% of CCRCC [24,28]. Additionally the stromal cells are also reported to express vimentin (100%), CD56/NCAM (100%), VEGF (100%), S-100 (82%), Ezrin (59%), and CD99 (88%).…”

“…Additionally the stromal cells are also reported to express vimentin (100%), CD56/NCAM (100%), VEGF (100%), S-100 (82%), Ezrin (59%), and CD99 (88%). Up to 36% of hemangioblastomas may be positive for EMA and some are positive for GFAP [11,28]. CD10 has been reported to be expressed in 12% of hemangioblastomas [22].…”

“…A few markers have been suggested as helpful in the diagnosis of hemangioblastoma and in distinguishing hemangioblastoma from CCRCC. Inhibin-A is expressed in 87% to 100% of hemangioblastomas [2,9,22,28]. Pax2 and Pax8 were shown to be negative in hemangioblastomas but positive in the vast majority of CCRCC [2,22].…”