Original ArticleSpecific immunohistochemical pattern of carbonic anhydrase IX is helpful for the diagnosis of CNS hemangioblastoma
Introduction
Hemangioblastomas are vascular neoplasms of the CNS with a characteristic lipid-rich stromal cell component. These tumors are mainly located in the posterior fossa. However, they also occur in the spinal cord and very rarely in the cerebral hemispheres. Hemangioblastomas arise not only as solitary and sporadic tumors, but also in the setting of von Hippel–Lindau (VHL) syndrome [2], [17]. Among other lesions, VHL syndrome includes hemangioblastomas, cystic lesions of liver, kidney and pancreas, renal cell carcinomas and pheochromocytomas [13]. Syndromal cases show a mutational inactivation of the VHL gene located in chromosome 3p25–26. The VHL protein (pVHL) interacts with hypoxia-inducible factor (HIF), inducing its rapid degradation. Under hypoxic conditions or when pVHL is functionally inhibited, the HIF is stabilized with expression of hypoxia-induced genes such as vascular endothelial growth factor (VEGF), which is thought to be responsible for the vascular component of hemangioblastomas. Moreover, inactivated pVHL causes overexpression of transmembrane carbonic anhydrases including CA IX. The VHL gene is also affected in sporadic hemangioblastomas [10].
VHL is also associated with the oncogenesis of renal clear cell carcinoma [27]. Although most renal clear cell carcinomas are sporadic and not related to von Hippel–Lindau disease, deletion of 3p, the locus for VHL, is found in the vast majority of cases. Moreover, renal clear cell carcinomas show remarkable histological similarities with hemangioblastoma. The expression of the hypoxia-associated antigen carbonic anhydrase IX in renal clear cell carcinoma is well known and is used to separate it from other renal cancer subtypes in the differential diagnosis [11]. Because of its usefulness in subtyping renal cancers [4], [25], the diagnostic antibody belongs to the routine panel in many pathology laboratories. The morphological and genetic similarities between renal clear cell cancers and hemangioblastomas suggest that carbonic anhydrase IX is expressed in hemangioblastomas as well. This could help establish the diagnosis and distinguish it from other histological and/or radiological mimickers of hemangioblastoma. Besides metastatic clear cell carcinomas of different origins, other mimickers include clear cell and microcystic meningiomas and pilocytic astrocytomas. The latter, in particular, often shows both radiological and histomorphological similarities.
The aim of this retrospective immunohistochemical analysis was to evaluate the expression of carbonic anhydrase IX and its value in the diagnosis and differential diagnosis of hemangioblastomas.
Section snippets
Case collection
The records of the Augsburg Institute of Pathology were screened for hemangioblastomas in the years between 1999 and 2014. In cases with available paraffin blocks, immunohistochemical staining for carbonic anhydrase IX was performed, except in cases for the years 2013–2014 in which this marker already was part of our routine panel in suspicious cases. Keratin staining was performed if not done during the primary evaluation.
The same procedure took place for clear cell and microcystic
Case collection
The clinicopathological data are summarized in Table 1. A total of 20 hemangioblastomas in 19 patients were identified in our files. One case was supratentorial in location, 16 cases were cerebellar lesions and three tumors were found in the spinal cord. The von Hippel–Lindau disease was confirmed in three cases (Table 2).
A collection of 46 cases served as the control. This collection consists of 12 pilocytic astrocytomas, seven gliomas (grades II–IV), 11 meningiomas, one pleomorphic
Discussion
Hemangioblastomas are uncommon WHO grade I tumors of the central nervous system [2]. Most of these are located in the posterior fossa. Only a very small proportion occurs outside the CNS [30]. The tumors consist of a prominent vascular and stromal component. The latter is considered to be the true neoplastic part, while the often impressive vascular proliferation is very likely caused by the overexpression of vascular endothelial growth factor of the stromal cells and therefore is only an
Disclosure/conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors are grateful to Anneliese Stöckl and Kerstin Bauer for their archival work. Furthermore, a special thanks to Kathrin Ferstl-Blahetek and Elfriede Schwarz for their excellent technical assistance and Hallie Kretsinger for reading and editing of the manuscript as a scientific native speaker. The authors received no funding from any source.
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2018, Seminars in Diagnostic PathologyCitation Excerpt :The stromal cells of HBL are immunoreactive for α-inhibin and brachyury (Fig. 1), but they lack keratin and epithelial membrane antigen, both of which are typically seen in RCC. On the other hand, both tumor types may potentially express vimentin, PAX8, and carbonic anhydrase-IX (CA9).4–9 Rare examples of both glioblastoma (GBM; grade IV astrocytoma) and meningioma are capable of showing divergent epithelial differentiation, manifested by the histologic presence of gland-like structures, squamous foci, clear-cell or rhabdoid features, or signet ring-cell change10–13 (Figs. 2 and 3).