VHL patients develop tumors in brain, spinal cord, nerve roots, kidney, adrenal gland and extra-adrenal ganglia, pancreas, epididymis and broad ligament. VHL disease produces highly characteristic neuropathologic changes which are presented in this review. Highly vascularized tumors, hemangioblastomas, involve cerebellum and spinal cord of the majority of patients. A smaller number of patients may develop endolymphatic sac tumors that originate in the petrous bone, but may extend into the brain. Lastly, neuropathology may be produced by metastasis of renal clear cell carcinoma or other VHL disease-associated neoplasms.

Sommaruga S, Vortmeyer AO (2014) Neuropathology of von Hippel-Lindau Disease. J Transl Med Epidemiol 2(1): 1011.

•    von Hippel-Lindau Disease
•    Developmental arrest
•    Hemangioblastoma
•    Endolymphatic sac tumor
•    Metastasis

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome, characterized by the frequent development of specific tumors in selective topographic sites. Affected patients develop central nervous system (CNS) hemangioblastomas, renal clear cell carcinomas, pheochromocytomas and extra-adrenal paragangliomas, endolymphatic sac tumors, pancreatic microcystic adenomas and pancreatic neuroendocrine tumors [1]. Male patients frequently develop epididymal cystadenoma, while female patients occasionally develop clear cell tumors of the broad ligament. The incidence of VHL disease is about one in 36,000 live births [2,3] and the disease has over 90 % of penetrance by age 65 [4].

Patients with VHL disease carry a germline mutation of the VHL tumor suppressor gene (VHL) [5]. The “second hit”, inactivation of the wild-type VHL copy, appears to be a prerequisite for tumorigenesis [6]. VHL inactivation causes activation of hypoxia-inducible factors HIF1 and HIF2 as well as HIF target proteins including VEGF, erythropoiesis factor Epo, nitric oxide synthase (NOS), and glucose transporter 1 (GLUT1) which are abundantly expressed in VHL disease-associated tumors. This article reviews VHL disease-associated tumors that involve or potentially affect the central nervous system: hemangioblastoma, endolymphatic sac tumor, and tumor metastasis.

Hemangioblastoma

Hemangioblastomas are the most vascular of nervous system tumors. While sporadic hemangioblastomas constitute 1 to 2 % of intracranial neoplasms, they are observed in 80% of von Hippel-Lindau (VHL) patients and are a defining feature of VHL disease [4,7-9]. Hemangioblastomas occur equally in women and men and show a consistent pattern of topographic distribution.

Retina, cerebellum, brainstem and the dorsal spinal cord are the most frequent localizations. Multiple hemangioblastomas occur frequently in patients with VHL disease.

Although hemangioblastomas are benign tumors, they may cause significant neurological deficits [10,11]. Hemangioblastomas in the cerebellum and brainstem are associated with a high mortality rate if they are not treated before producing acute hydrocephalus, tonsillar herniation, and brainstem compression [4,12,13]. Symptoms are usually not caused by the tumor itself but rather by an associated pseudocyst or syrinx, which is caused by the tumor [14] and which is usually much larger than the tumor itself [15].

Usually the diagnosis can be established by MRI because of the typical appearance of a densely contrast-enhancing tumor with smooth margins, often as a “cystic lesion” with a contrast enhancing solid tumor at the margins of a pseudocyst in the cerebellum or a syrinx in the spinal cord [16,17].

Pathology: Grossly, the tumor nodule appears soft with bright or dark red color. Recorded tumor sizes vary between less than 2mm3 and 36cm3 [18]. Histologically, surrounding brain or pseudocyst wall tissue reveals chronic astrocytosis with abundant Rosenthal fibers; pseudocystic spaces are a result of secretory tumoral activity, as they disappear weeks or months after successful surgical removal of the hemangioblastoma nodule [19].

The histology of hemangioblastomas varies remarkably (Figure 1). Cytologically, hemangioblastomas are composed of two main constituents. The first cytologic component is characterized by conspicuous neoplastic clear cells carrying VHL gene deletion [20] – a near-consistent feature of any tumor arising in the context of VHL disease. Conventionally, neoplastic clear cells in hemangioblastomas are called “stromal” cells. “Stromal” cells do not exist in normal nervous system tissue, and their origin has been controversial. They appear as lipid- and glycogen-rich cells with abundant clear cytoplasm and small to intermediate-sized nuclei the outline of which is frequently scalloped by lipidized bubbles. Nuclei may be round, enlarged, or bizarre-shaped, mitotic figures are rare. The other, second cytologic component of hemangioblastomas is represented by abundant mature vascular structures. Most, if not all of these vascular structures represent reactive angiogenesis [20,21].

Hemangioblastomas show not only marked cytological, but also marked architectural variation (Figure 1). Tumor cells may be rather inconspicuous and nearly obscured by abundant reactive angiogenesis which gives the appearance of an “angiomatotic” process that was originally described by von Hippel. This pattern is frequently referred to as “reticular” [22] or “mesenchymal” [18]. Other tumors may reveal prominent epitheloid clusters of tumor cells and are referred to as “cellular” [22] or “epitheloid” [18]. A recent study on 156 tumors concluded that the architectural pattern correlates with tumor size [18]; small tumors of less than 8 mm³ in size consistently showed mesenchymal architecture, while larger tumors additionally revealed epitheloid patterns [18]. The clustering of “stromal” cells has been interpreted as differentiation of hemangioblast precursor cells into blood islands, and a subset of these tumors reveals downstream differentiation into red blood cell precursors [23,24]. In remarkable contrast to small, intensely vascularized tumors, larger hemangioblastomas with prominent epitheloid cell (“cellular”) clusters may resemble cancerous growth and need to be differentiated from metastatic renal clear cell carcinoma.

Selective genetic analysis of the “stromal” cells in CNS and retinal tumors revealed them to be VHL-deficient [20, 21,25] and thus to represent neoplastic cells. Secondary to VHL deficiency, hypoxia inducible factors (HIF) activation and vascular endothelial growth factor (VEGF) expression, hemangioblastomas show intense reactive vascularization.

“Stromal” cell differentiation into red blood cells has been noted [23,26] and demonstrated [24,27] confirming Cushing’s original concept of a hemangioblastic origin of hemangioblastomas [28]. The hemangioblastic nature of hemangioblastomas has been further confirmed by their positive immunoreactivity with antibodies against Scl, brachyury, Csf-1R, Gata-1, Flk-1 and Tie-2 [29]. While hemangioblastic differentiation occurs during embryonic and early fetal CNS development, hemangioblasts are not constituents of mature nervous system. The possible persistence of hemangioblastic activity in the nervous system of VHL patients has revived Lindau’s original concept that VHL tumorigenesis is initiated by disturbed embryonal development [30]. Anatomic studies on spinal cord and cerebellum of VHL patients revealed numerous developmentally arrested structural elements [31] that serve as potential precursor material for hemangioblastic tumors [32].

Endolymphatic sac tumors (ELSTs)

The endolymphatic sac and duct are part of the nonsensory membranous labyrinth of the inner ear. Putative functions include maintenance of homeostasis [33,34] and pressure [35] of the inner ear, phagocytosis of debris [36] and immunologic functions [37,38]. In 1989, Heffner reported papillary-cystic tumors of the temporal bone and identified the endolymphatic sac as most likely site of origin [39]. In 1997, ELSTs were identified as component tumors of VHL disease by clinical observation [40], subsequently confirmed by genetic and molecular studies [20, 41-43]. As further confirmation of VHL deficiency, neoplastic cells were found to show activation of both HIF1 and HIF2 [42]. In addition, ELSTs express CAIX and GLUT-1, downstream targets of HIF [42]. ELSTs also co-express erythropoietin (EPO) and his receptor (EPOR), which has been implicated in promotion of their growth [44].

Early diagnosis and early management are important prognostic factors [45-47]. Numerous studies report that surgical resection is the best treatment [39,45-59]. When hearing loss has occurred, it is irreversible. However, in most cases further hearing loss is prevent by surgery [46-49,53,55,58,60,61] and symptoms like vertigo and tinnitus disappear [47-49,53,60]. Complications and recurrence are more prone to happen in patients with large tumors and after subtotal resection [39,46,50,53,57,59]. Stereotactic radiosurgery may be considered when surgery is not possible and in cases of focal recurrence [49,58,62].

Pathology: Grossly, ELSTs present as bright or dark red soft tissue masses [49]. Reported sizes vary between 3mm3 [42] and 54cm3 [59]. Histologically, three types of architecture have been identified - papillary, cystic and epitheloid clear cell patterns [39,42] (Figure 2). Extensively vascularized papillary structures are consistently observed. Papillary proliferations are lined by a single row of cuboidal epithelial cells. Mitotic figures are rare. Areas of cystic growth can be observed in a subset of tumors. The cysts have a single epithelial lining and frequently contain proteinaceous material. Epitheloid clear cell clusters, reminiscent of renal clear cell carcinoma, can be occasionally observed. Extensive hemosiderin deposits are common and associated with degenerative features including fibrosis, inflammation and cholesterol cleft formation. A feature of all tumors is extensive vascularization. Immunoreactivity with anti-AE1/AE3 [39,42,59,60,63], anti-MAK-6 [42,60] and anti-NSE [42,64] appear consistently positive in the tumoral cells. A subset of cases reveals positive reactivity for EMA [42,59,60,63,64], S100 [39,42,59,64] vimentin [60] and synaptophysin [64].

Structural and molecular analysis of surgical and autopsy material derived from VHL patients identified endolymphatic sac/duct epithelium as primary site of origin [42]. In the extraosseous portion of the endolymphatic sac as well as along the entire intraosseous endolymphatic sac/duct multifocal microscopic papillary projections were identified as potential precursor structures as molecular analysis of these structures revealed loss of heterozygosity of VHL, positive nuclear signal for HIF1 and HIF2 as well as expression of target proteins CAIX and GLUT-1 [42]. Although precursor structures were also identified in extraosseous endolymphatic sac, tumorigenesis appears to occur exclusively from intraosseous portions of the endolymphatic sac/duct system as temporal bone location and bony erosion appears to be a frequent, if not consistent feature of these tumors [39,42]. It remains therefore unclear, whether bone erosion occurs due to aggressive biology or due to intraosseous location.

Metastasis

Metastasis into the nervous system can occur from three different types of VHL disease-associated tumors. Most frequently, metastasis is caused by renal carcinoma the clear cell morphology of which may strikingly resemble primary hemangioblastoma or ELST. Far less frequently observed is metastatic pheochromocytoma/ paraganglioma or metastatic neuroendocrine tumors.

Renal clear cell carcinoma (RCCC) is the most frequent malignant neoplasm occurring in the context of VHL disease and occurs in 24 to 45% of VHL patients [1,4,8]. Mean age at presentation is 39 years [1]. Prognosis of VHL disease mainly depends on the occurrence of RCCC and postoperative complications after neurosurgery. Before introduction of modern imaging methods like CT and MRI, 13 to 42% of VHL patients died of metastatic renal cell carcinoma [65]. As RCCCs often remain asymptomatic for long intervals, monitoring of VHL patients with contrast-enhanced abdominal CT is essential for early diagnosis [1]. Early detection of RCCCs in VHL patients has significantly reduced morbidity and mortality of VHL disease [1].

Pathology: Metastasis of RCCC can occur anywhere within the nervous system. If metastasis occurs into cerebellum, brainstem, or spinal cord, differentiation from primary hemangioblastoma may be difficult because of significant overlap of morphologic features. Both hemangioblastoma and metastatic RCCC are composed of tumor cells with clear or vacuolated cytoplasm, are extensively vascularized and may reveal similar clustering of epitheloid cells. Both types of tumors share VHL gene deficiency as well as expression of VEGF, HIF, CAIX and other VHL target proteins.

Helpful histologic features are more distinct cytoplasmic membranes of renal carcinoma cells. Also, mitotic figures are frequently found in RCCC, but are rare in hemangioblastoma. Also, necrosis is virtually never seen in hemangioblastoma, unless tumors had been pretreated with radiation or embolization. Immunohistochemistry is a valuable tool to distinguish hemangioblastoma from metastatic renal clear cell carcinoma. Initially, EMA has been identified as a marker for metastatic RCCC [66-73], while hemangioblastomas are near consistently positive for NSE [67,70,74,75]. Additional useful markers have been subsequently described including brachyury [76], NCAM [77], aquaporin 1 [73,78,79], AE1/AE3 [70,73], GLUT 1, vimentine [70,80-84], D2-40 [73,85] and RCC marker (antibody) [86] (Table 1). Combined immunohistochemistry for PAX2, PAX8 and inhibin A [87] has been suggested to be most useful to resolve the differential diagnosis. In a particularly challenging tumor with focal expression of EMA the diagnosis of hemangioblastoma was ascertained after proteome comparison of microdissected tumor areas on 2D gels [88].

Immunohistochemistry is particularly useful for identifying tumor heterogeneity that is caused by tumor metastasis into hemangioblastoma as a recent study found 8% of hemangioblastomas to be involved by metastatic tumor [89].

Table 1: Immunohistochemical differentiation between Hemangioblastoma and Metastatic RCCC.

1. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet. 2003; 361: 2059-2067.

2. Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991; 28: 443- 447.

3. Neumann HP, Wiestler OD. Clustering of features and genetics of von Hippel-Lindau syndrome. Lancet. 1991; 338: 258.

4. Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990; 77: 1151-1163.

5. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260: 1317-1320.

6. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996; 122: 135-140.

7. Melmon kl, rosen sw. Lindau’s disease. Review of the literature and study of a large kindred. Am J Med. 1964; 36: 595-617.

8. Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology. 1995; 194: 629-642.

9. Vortmeyer AO, Falke EA, Gläsker S, Li J, Oldfield EH. Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms. Acta Neuropathol. 2013; 125: 333-350.

10. Neumann HP, Eggert HR, Weigel K, Friedburg H, Wiestler OD, Schollmeyer P. Hemangioblastomas of the central nervous system. A 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg. 1989; 70: 24-30.

11. de la Monte SM, Horowitz SA. Hemangioblastomas: clinical and histopathological factors correlated with recurrence. Neurosurgery. 1989; 25: 695-698.

12. Neumann HP. Prognosis of von Hippel-Lindau syndrome. Vasa. 1987; 16: 309-311.

13. Lamiell JM, Salazar FG, Hsia YE. von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore). 1989; 68: 1-29.

14. Lonser RR, Vortmeyer AO, Butman JA, Glasker S, Finn MA, Ammerman JM, et al. Edema is a precursor to central nervous system peritumoral cyst formation. Ann Neurol. 2005; 58: 392-399.

15. Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003; 98: 82-94.

16. Resche F, Moisan JP, Mantoura J, de Kersaint-Gilly A, Andre MJ, Perrin-Resche I, et al. Haemangioblastoma, haemangioblastomatosis, and von Hippel-Lindau disease. Adv Tech Stand Neurosurg. 1993; 20: 197-304.

17. Filling-Katz MR, Choyke PL, Oldfield E, Charnas L, Patronas NJ, Glenn GM, et al. Central nervous system involvement in Von Hippel-Lindau disease. Neurology. 1991; 41: 41-46.

18. Shively SB, Beltaifa S, Gehrs B, Duong H, Smith J, Edwards NA, et al. Protracted haemangioblastic proliferation and differentiation in von Hippel-Lindau disease. J Pathol. 2008; 216: 514-520.

19. Lonser RR, Vortmeyer AO, Butman JA, Glasker S, Finn MA, Ammerman JM, et al. Edema is a precursor to central nervous system peritumoral cyst formation. Ann Neurol. 2005; 58: 392-399.

20. Vortmeyer AO, Gnarra JR, Emmert-Buck MR, Katz D, Linehan WM, Oldfield EH, et al. von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease. Hum Pathol. 1997; 28: 540-543.

21. Lee JY, Dong SM, Park WS, Yoo NJ, Kim CS, Jang JJ, et al. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res. 1998; 58: 504-508.

22. Hasselblatt M, Jeibmann A, Gerss J, Behrens C, Rama B, Wassmann H, et al. Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases. Neuropathol Appl Neurobiol. 2005; 31: 618-622.

23. Stein aa, schilp ao, whitfield rd. The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg. 1960; 17: 751- 761.

24. Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, et al. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res. 2003; 63: 7051-7055.

25. Chan CC, Vortmeyer AO, Chew EY, Green WR, Matteson DM, Shen DF, et al. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch Ophthalmol. 1999; 117: 625-630.

26. Zec N, Cera P, Towfighi J. Extramedullary hematopoiesis in cerebellar hemangioblastoma. Neurosurgery. 1991; 29: 34-37.

27. Park DM, Zhuang Z, Chen L, Szerlip N, Maric I, Li J, et al. von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med. 2007; 4: e60.

28. Cushing H, Bailey P. Hemangiomas of Cerebellum and Retina (Lindau’s Disease): With the Report of a Case. Trans Am Ophthalmol Soc. 1928; 26: 182-202.

29. Gläsker S, Li J, Xia JB, Okamoto H, Zeng W, Lonser RR, et al. Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res. 2006; 66: 4167-4172.

30. Lindau A: Studien uber Kleinhirnzysten. Bau, Pathogenese und Beziehung zur Angiomatosis retinae. Acta Path et Microbiol Scand. 1926; 1: 1-126.

31. Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH. Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol. 2004; 55: 721-728.

32. Vortmeyer AO, Tran MG, Zeng W, Gläsker S, Riley C, Tsokos M, et al. Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006; 210: 374-382.

33. Ninoyu O, Meyer zum Gottesberge AM. Ca++ activity in the endolymphatic space. Arch Otorhinolaryngol. 1986; 243: 141-142.

34. Wackym PA, Glasscock ME 3rd, Linthicum FH Jr, Friberg U, RaskAndersen H. Immunohistochemical localization of Na+, K+-ATPase in the human endolymphatic sac. Arch Otorhinolaryngol. 1988; 245: 221-223.

35. Morgenstern C, Amano H, Orsulakova A. Ion transport in the endolymphatic space. Am J Otolaryngol. 1982; 3: 323-327.

36. Erwall C, Friberg U, Bagger-Sjöbäck D, Rask-Andersen H. Degradation of the homogeneous substance in the endolymphatic sac. Acta Otolaryngol. 1988; 105: 209-217.

37. Rask-Andersen H, Stahle J. Immunodefence of the inner ear? Lymphocyte-macrophage interaction in the endolymphatic sac. Acta Otolaryngol. 1980; 89: 283-294.

38. Harris JP. Autoimmunity of the inner ear. Am J Otol. 1989; 10: 193- 195.

39. Heffner DK. Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases. Cancer. 1989; 64: 2292-2302.

40. Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, et al. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997; 277: 1461-1466.

41. Kawahara N, Kume H, Ueki K, Mishima K, Sasaki T, Kirino T. VHL gene inactivation in an endolymphatic sac tumor associated with von Hippel-Lindau disease. Neurology. 1999; 53: 208-210.

42. Gläsker S, Lonser RR, Tran MG, Ikejiri B, Butman JA, Zeng W, et al. Effects of VHL deficiency on endolymphatic duct and sac. Cancer Res. 2005; 65: 10847-10853.

43. Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von Hippel-Lindau disease gene alterations associated with endolymphatic sac tumor. J Natl Cancer Inst. 1997; 89: 970-972.

44. Vogel TW, Vortmeyer AO, Lubensky IA, Lee YS, Furuta M, Ikejiri B, et al. Coexpression of erythropoietin and its receptor in endolymphatic sac tumors. J Neurosurg. 2005; 103: 284-288.

45. Hansen MR, Luxford WM. Surgical outcomes in patients with endolymphatic sac tumors. Laryngoscope. 2004; 114: 1470-1474.

46. Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ, Glasscock ME 3rd. Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol. 2002; 23: 378-387.

47. Lonser RR, Baggenstos M, Kim HJ, Butman JA, Vortmeyer AO. The vestibular aqueduct: site of origin of endolymphatic sac tumors. J Neurosurg. 2008; 108: 751-756.

48. Butman JA, Kim HJ, Baggenstos M, Ammerman JM, Dambrosia J, Patsalides A, et al. Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease. JAMA. 2007; 298: 41-48.

49. Butman JA, Linehan WM, Lonser RR. Neurologic manifestations of von Hippel-Lindau disease. JAMA. 2008; 300: 1334-1342.

50. Carlson ML, Thom JJ, Driscoll CL, Haynes DS, Neff BA, Link MJ, et al. Management of primary and recurrent endolymphatic sac tumors. Otol Neurotol. 2013; 34: 939-943.

51. Hou ZH, Huang DL, Han DY, Dai P, Young WY, Yang SM. Surgical treatment of endolymphatic sac tumor. Acta Otolaryngol. 2012; 132: 329-336.

52. Husseini ST, Piccirillo E, Taibah A, Paties CT, Almutair T, Sanna M. The Gruppo Otologico experience of endolymphatic sac tumor. Auris Nasus Larynx. 2013; 40: 25-31.

53. Kim HJ, Butman JA, Brewer C, Zalewski C, Vortmeyer AO, Glenn G, et al. Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg. 2005; 102: 503-512.

54. Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diagnosis of endolymphatic sac tumors. Laryngoscope. 2006; 116: 40-46.

55. Roche PH, Dufour H, Figarella-Branger D, Pellet W. Endolymphatic sac tumors: report of three cases. Neurosurgery. 1998; 42: 927-932.

56. Rodrigues S, Fagan P, Turner J. Endolymphatic sac tumors: a review of the St. Vincent’s hospital experience. Otol Neurotol. 2004; 25: 599- 603.

57. Timmer FC, Neeskens LJ, van den Hoogen FJ, Slootweg PJ, Dunnebier EA, Pauw BK, et al. Endolymphatic sac tumors: clinical outcome and management in a series of 9 cases. Otol Neurotol. 2011; 32: 680-685.

58. Bambakidis NC, Megerian CA, Ratcheson RA. Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status. Otol Neurotol. 2004; 25: 773-781.

59. Bae CW, Cho YH, Chung JW, Kim CJ. Endolymphatic sac tumors : report of four cases. J Korean Neurosurg Soc. 2008; 44: 268-272.

60. Lonser RR, Kim HJ, Butman JA, Vortmeyer AO, Choo DI, Oldfield EH. Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med. 2004; 350: 2481-2486. 

61. Codreanu CM, Duet M, Hautefort C, Wassef M, Guichard JP, Giraud S, et al. Endolymphatic sac tumors in von Hippel-Lindau disease: report of three cases. Otol Neurotol. 2010; 31: 660-664.

62. Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons SW, Preul MC. Endolymphatic sac tumor: unique features of two cases and review of the literature. Acta Neurochir (Wien). 2002; 144: 1047- 1053.

63. Butman JA, Nduom E, Kim HJ, Lonser RR. Imaging detection of endolymphatic sac tumor-associated hydrops. J Neurosurg. 2013; 119: 406-411.

64. Kempermann G, Neumann HP, Volk B. Endolymphatic sac tumours. Histopathology. 1998; 33: 2-10.

65. Walther MM, Choyke PL, Glenn G, Lyne JC, Rayford W, Venzon D, et al. Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol. 1999; 161: 1475-1479.

66. Andrew SM, Gradwell E. Immunoperoxidase labelled antibody staining in differential diagnosis of central nervous system haemangioblastomas and central nervous system metastases of renal carcinomas. J Clin Pathol. 1986; 39: 917-919.

67. Gouldesbrough DR, Bell JE, Gordon A. Use of immunohistochemical methods in the differential diagnosis between primary cerebellar haemangioblastoma and metastatic renal carcinoma. J Clin Pathol. 1988; 41: 861-865.

68. Hufnagel TJ, Kim JH, True LD, Manuelidis EE. Immunohistochemistry of capillary hemangioblastoma. Immunoperoxidase-labeled antibody staining resolves the differential diagnosis with metastatic renal cell carcinoma, but does not explain the histogenesis of the capillary hemangioblastoma. Am J Surg Pathol. 1989; 13: 201216.

69. Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma. Mod Pathol. 2005; 18: 788- 794.

70. Lach B, Gregor A, Rippstein P, Omulecka A. Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol. 1999; 23: 299-310.

71. Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol. 2003; 27: 1152-1156.

72. Ishizawa K, Komori T, Hirose T. Stromal cells in hemangioblastoma: neuroectodermal differentiation and morphological similarities to ependymoma. Pathol Int. 2005; 55: 377-385.

73. Weinbreck N, Marie B, Bressenot A, Montagne K, Joud A, Baumann C, et al. 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. Am J Surg Pathol. 2008; 32: 1051-1059.

74. Becker I, Paulus W, Roggendorf W. Histogenesis of stromal cells in cerebellar hemangioblastomas. An immunohistochemical study. Am J Pathol. 1989; 134: 271-275.

75. Grant JW, Gallagher PJ, Hedinger C. Haemangioblastoma. An immunohistochemical study of ten cases. Acta Neuropathol. 1988; 76: 82-86.

76. Barresi V, Vitarelli E, Branca G, Antonelli M, Giangaspero F, Barresi G. Expression of brachyury in hemangioblastoma: potential use in differential diagnosis. Am J Surg Pathol. 2012; 36: 1052-1057.

77. Böhling T, Mäenpää A, Timonen T, Vantunen L, Paetau A, Haltia M. Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma. Acta Neuropathol. 1996; 92: 461-466.

78. Chen Y, Tachibana O, Oda M, Xu R, Hamada J, Yamashita J, et al. Increased expression of aquaporin 1 in human hemangioblastomas and its correlation with cyst formation. J Neurooncol. 2006; 80: 219- 225.

79. Longatti P, Basaldella L, Orvieto E, Dei Tos AP, Martinuzzi A. Aquaporin 1 expression in cystic hemangioblastomas. Neurosci Lett. 2006; 392: 178-180.

80. Frank TS, Trojanowski JQ, Roberts SA, Brooks JJ. A detailed immunohistochemical analysis of cerebellar hemangioblastoma: an undifferentiated mesenchymal tumor. Mod Pathol. 1989; 2: 638-651.

81. Mizuno J, Iwata K, Takei Y. Immunohistochemical study of hemangioblastoma with special reference to its cytogenesis. Neurol Med Chir (Tokyo). 1993; 33: 420-424.

82. Ding XH, Zhou LF, Tan YZ, Zhao Y, Zhu JJ. Histologic and histogenetic investigations of intracranial hemangioblastomas. Surg Neurol. 2007; 67: 239-245.

83. Lee C, Park JW, Suh JH, Nam KH, Moon KC. Histologic variations and immunohistochemical features of metastatic clear cell renal cell carcinoma. Korean J Pathol. 2013; 47: 426-432.

84. Dierick AM, Praet M, Roels H, Verbeeck P, Robyns C, Oosterlinck W. Vimentin expression of renal cell carcinoma in relation to DNA content and histological grading: a combined light microscopic, immunocytochemical and cytophotometrical analysis. Histopathology. 1991; 18: 315-322.

85. Roy S, Chu A, Trojanowski JQ, Zhang PJ. D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas. Acta Neuropathol. 2005; 109: 497-502.

86. Ingold B, Wild PJ, Nocito A, Amin MB, Storz M, Heppner FL, et al. Renal cell carcinoma marker reliably discriminates central nervous system haemangioblastoma from brain metastases of renal cell carcinoma. Histopathology. 2008; 52: 674-681.

87. Carney EM, Banerjee P, Ellis CL, Albadine R, Sharma R, Chaux AM, et al. PAX2(-)/PAX8(-)/inhibin A(+) immunoprofile in hemangioblastoma: A helpful combination in the differential diagnosis with metastatic clear cell renal cell carcinoma to the central nervous system. Am J Surg Pathol. 2011; 35: 262-267.

88. Vortmeyer AO, Weil RJ, Zhuang Z. Proteomic applications for differential diagnosis of histologically identical tumors. Neurology. 2003; 61: 1626-1627.

89. Jarrell ST, Vortmeyer AO, Linehan WM, Oldfield EH, Lonser RR. Metastases to hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2006; 105: 256-263.