CNS tumor

Other tumors

Hemangioblastoma

Authors: Rebecca Yoda, M.D., P.J. Cimino, M.D., Ph.D.

Resident / Fellow Advisory Board: Meaghan Morris, M.D., Ph.D.

Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.

Topic Completed: 6 July 2021

Minor changes: 6 July 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Hemangioblastoma [title] CNS

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Table of Contents

Cite this page: Yoda R, Cimino PJ. Hemangioblastoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumorhemangioblastoma.html. Accessed December 3rd, 2021.

Definition / general

Benign, slowly growing, highly vascular neoplasm containing neoplastic stromal cells which usually involves the cerebellum, brainstem or spinal cord
Generally associated with loss or inactivation of the VHL gene, with frequent occurrence in von Hippel-Lindau (VHL) disease (Am J Clin Pathol 1997;107:459)

Essential features

Circumscribed, enhancing solid cystic mass, most frequently located in the cerebellum and observed as a cyst with enhancing mural nodule (AJNR Am J Neuroradiol 1992;13:1343)
Composed of neoplastic stromal cells with foamy cytoplasm within a background network of numerous small vessels
Associated with loss of function of VHL, with frequent occurrence in von Hippel-Lindau (VHL) disease (Am J Clin Pathol 1997;107:459)
Other neoplasms associated with VHL may be histologic mimics (e.g. clear cell renal cell carcinoma, paraganglioma, pheochromocytoma)
WHO grade 1

Terminology

Hemangioblastoma
Capillary hemangioblastoma (not recommended)
Lindau tumor (not recommended)
Angioblastoma (not recommended)

ICD coding

ICD-O: 9161/1 - hemangioblastoma
ICD-10:
- D33.0 - benign neoplasm of brain, supratentorial
- D33.1 - benign neoplasm of brain, infratentorial
- D33.2 - benign neoplasm of brain, unspecified
- D33.3 - benign neoplasm of cranial nerves
- D33.4 - benign neoplasm of spinal cord
- D33.7 - benign neoplasm of other specified parts of central nervous system
- D33.9 - benign neoplasm of central nervous system, unspecified
ICD-11:
- XH6810 - hemangioblastoma
- 2F7Y - neoplasms of uncertain behavior of other specified site

Epidemiology

0.141 per 100,000 person years (Front Oncol 2020;10:570103)
Cerebellar
- ~1 - 2% of primary CNS tumors (Surg Neurol 1977;7:79)
- ~7 - 12% of primary posterior fossa tumors (Surg Neurol 1977;7:79)
Spinal
- ~2% of spinal tumors (Neuroepidemiology 2016;46:14)
Genetics
- ~70% sporadic (J Neurosurg 1989;70:24, Neurosurgery 2001;48:55)
- ~30% familial with VHL syndrome (J Neurosurg 1989;70:24, Neurosurgery 2001;48:55)
Mean age at presentation (J Neurosurg 1989;70:24)
- Sporadic ~47 yrs
- VHL ~29 yrs
Sex: M:F = 1 - 1.25:1 (Neuroepidemiology 2016;46:14, Front Oncol 2020;10:570103)

Sites

Occur throughout the central nervous system
- Common: cerebellum > brainstem > spinal cord (Front Oncol 2020;10:570103)
- Rare: cerebrum, peripheral nervous system (J Neurosurg 2014;120:1055)
VHL syndrome - multiple hemangioblastomas (Neurosurgery 2001;48:55, J Neurosurg 2014;120:1055)

Pathophysiology

VHL loss of function implicated in most cases
- Normal VHL protein (pVHL)
  - Regulates cell cycle (Proc Natl Acad Sci U S A 1998;95:993)
  - Regulates cellular hypoxia signaling via the HIF (hypoxia inducible factor) complex, which under hypoxic conditions leads to enhanced levels of growth factors (e.g. vascular endothelial factor, platelet derived growth factor, transforming growth factor alpha) (Nat Rev Cancer 2015;15:55)
- Pseudohypoxia hypothesis
  - Loss of function of VHL → loss of regulation of HIF complex → increased expression of growth factors in absence of hypoxia → increased angiogenesis and tumor growth (Best Pract Res Clin Endocrinol Metab 2010;24:957)
- VHL syndrome (Eur J Hum Genet 2011;19:617)
  - Autosomal dominant tumor predisposition syndrome resulting from inactivating germline mutation in the VHL tumor suppressor gene
  - Biallelic VHL inactivation

Etiology

Sporadic: up to 78% of sporadic cases with VHL loss of function (J Neurol Neurosurg Psychiatry 2001;70:644, Cancer Res 1998;58:504, Acta Neuropathol Commun 2014;2:167)
Familial (VHL syndrome): ~60% of VHL disease patients develop hemangioblastoma (J Neurol Neurosurg Psychiatry 1999;67:758)

Diagrams / tables

Images hosted on other servers:

VHL regulation of the HIF pathway

Clinical features

Symptoms
- General
  - Increased intracranial pressure / hydrocephalus (J Neurosurg 2008;108:210)
  - Secondary polycythemia due to erythropoietin production (Neurosurgery 2013;72:930, Blood 1998;92:3388, AJNR Am J Neuroradiol 1992;13:1343)
  - Hemorrhage (World Neurosurg 2015;83:1180.e13, Neurosurgery 2005;57:71, Neurosurg Rev 2010;33:11)
- Cerebellar
  - Dysmetria, ataxia (J Neurosurg 2008;108:210)
- Spinal
  - Pain, hypesthesia, incontinence (Neurosurgery 2001;49:321, AJNR Am J Neuroradiol 2001;22:206)
- VHL syndrome sites of involvement (Eur J Hum Genet 2011;19:617)
  - CNS: hemangioblastoma
  - Retina: hemangioblastoma
  - Head / neck: paraganglioma
  - Kidney: clear cell renal cell carcinoma, cysts
  - Adrenal: pheochromocytoma
  - Pancreas: neuroendocrine islet cell tumor, cysts
  - Inner ear: endolymphatic sac tumor
  - Epididymis: papillary cystadenoma
  - Broad ligament: cystadenoma

Diagnosis

Based on histologic and immunophenotypic features (Acta Neuropathol 2013;125:333)
Clinical history of VHL syndrome or evidence of genetic alterations leading to VHL inactivation is supportive

Laboratory

Secondary polycythemia (~5 - 40% of cases) (Neurosurgery 2013;72:930, Blood 1998;92:3388, AJNR Am J Neuroradiol 1992;13:1343)

Radiology description

General
- Well demarcated enhancing mass ranging from solid to cystic, frequently presenting as a cyst with an enhancing mural nodule (AJNR Am J Neuroradiol 1992;13:1343)
- Spinal cord tumors often associated with syrinx (AJR Am J Roentgenol 1989;152:1087)
Magnetic resonance imaging (MRI)
- Nodule: T1 hypointense to isointense, T2 hyperintense (AJNR Am J Neuroradiol 1992;13:1343)
- Serpentine flow voids in the nodular portion (AJNR Am J Neuroradiol 1992;13:1343)
- Often abuts the pia (Cancer Imaging 2012;12:237)
- Cyst wall rarely enhances (Cancer Imaging 2012;12:237)
Computed tomography
- Mural nodule is isodense to the brain on noncontrast scans (J Comput Assist Tomogr 1982;6:912)
- Calcification usually absent (J Comput Assist Tomogr 1982;6:912)

Radiology images

Images hosted on other servers:

T1+C MRI posterior fossa

Prognostic factors

Excellent prognosis with complete surgical resection (Childs Nerv Syst 2020;36:2537, JAMA Neurol 2018;75:620, J Neurosurg 2008;108:210)
Outcome better in sporadic cases than in VHL syndrome cases (Brain Tumor Pathol 2000;17:111)

Case reports

41 year old man with a family history of VHL syndrome and a synonymous VHL mutation (BMC Med Genet 2020;21:42)
42 year old man with cerebellopontine angle tumor (Surg Neurol Int 2017;8:264)
54 year old woman with a past medical history of VHL syndrome and bilateral clear cell renal cell carcinoma found to have an enhancing intramedullary mass at C6 / C7 (J Clin Neurosci 2015;22:215)
63 year old man with suspected posterior inferior cerebellar artery aneurysm (World Neurosurg 2019;122:165)

Treatment

Surgical resection - standard of care (JAMA Neurol 2018;75:620)
Stereotactic radiosurgery may provide some control for unresectable tumors but data on safety and long term efficacy is limited (J Neurosurg 2015;122:1469, Neuro Oncol 2010;12:80)

Clinical images

Images hosted on other servers:

Cystic mass in medulla

Multiple spinal masses

Gross description

Solid or cystic with mural nodule (J Neurosurg 2003;98:82)
Well circumscribed and pseudoencapsulated
Highly vascular
Red with yellow / orange cut surface regions attributed to lipid content

Gross images

Contributed by Rebecca Yoda, M.D.

Hemangioblastoma cut surfaces

Images hosted on other servers:

Variegated red-yellow tumor

Hemangioblastoma in situ

Frozen section images

Contributed by P.J. Cimino, M.D., Ph.D.

Moderate hypercellularity

Microscopic (histologic) description

Architecture (Acta Neuropathol 2013;125:333)
- Composed of neoplastic stromal cells arranged between numerous small vessels
- Compact, generally noninfiltrative growth with variable lobularity
Stromal component
- Mild nuclear pleomorphism with degenerative atypia
- Clear, foamy cytoplasm with lipid containing vacuoles
- Rare hyaline globules
Vascular component
- Numerous thin walled vessels
- Well demarcated border with neoplasm
Other findings
- Mitotic figures rare to absent
- Intratumoral hemorrhage
- Mast cells
- Cyst-like spaces
- Adjacent parenchyma may have piloid gliosis with Rosenthal fibers
- Extramedullary hematopoiesis (~15%) (Neurosurgery 1991;29:34)
Histologic variants
- Reticular (Neuropathol Appl Neurobiol 2005;31:618)
  - Capillaries > stromal cells
  - More common
- Cellular (Neuropathol Appl Neurobiol 2005;31:618)
  - Stroma cells > capillaries
  - Less common

Microscopic (histologic) images

Contributed by P.J. Cimino, M.D., Ph.D.

Circumscribed border

Vascular and stromal cells

Foamy cytoplasm

Large branching vessels

Hyalinized stroma

Extensive hemorrhage

Nuclear atypia

Inhibin

CAIX

CD31

PAX8

Virtual slides

Images hosted on other servers:

Hemorrhagic tumor

Highly vascular tumor

Cytology description

Generally resistant to smear (squash preparation), resulting in larger tissue clumps
Successful cytologic smear preparations include the following (Acta Cytol 1998;42:1104):
- Cytoplasm
  - Foamy
  - Indistinct cytoplasmic borders
- Nuclei
  - Mildly pleomorphic
  - Hyperchromatic, speckled chromatin
  - Nuclear grooves
- Hemosiderin
- Clumping of cohesive cells often obscures cytologic features

Cytology images

Contributed by P.J. Cimino, M.D., Ph.D.

Smear preparation

Positive stains

Stromal cells
- Inhibin alpha (Am J Surg Pathol 2011;35:262, Am J Surg Pathol 2003;27:1152, Neuropathology 2010;30:580, Am J Surg Pathol 2008;32:1051)
- N-CAM1 (CD56) (Arch Pathol Lab Med 2007;131:641)
- S100 (100%; scattered positive cells) (Am J Surg Pathol 1989;13:207)
- Carbonic anhydrase IX & XII (Neuro Oncol 2005;7:465)
- Brachyury (91% cytoplasmic) (Am J Surg Pathol 2012;36:1052)
- Vimentin (86 - 100%) (Mod Pathol 1989;2:638)
- Aquaporin 1 (Am J Surg Pathol 2008;32:1051)
- TFE3 (Am J Transl Res 2020;12:4498)
- Oil red O (Arch Pathol Lab Med 2007;131:641)
Vascular cells
- Endothelial cell markers (e.g. CD31, CD34) (Arch Pathol Lab Med 2007;131:641)
- Reticulin (highlights vessel walls)

Negative stains

AE1 / AE3 (Am J Surg Pathol 2008;32:1051)
CAM5.2 (Arch Pathol Lab Med 2007;131:641)
RCC marker (Neuropathology 2010;30:580)
PAX8 (Am J Surg Pathol 2011;35:262)
PAX2 (5%) (Am J Surg Pathol 2011;35:262)
CD10 (0 - 12%) (Am J Surg Pathol 2008;32:1051, Neuropathology 2010;30:580)
EMA (0 - 36%; membranous or diffuse cytoplasmic) (Am J Surg Pathol 1989;13:207, Am J Surg Pathol 2008;32:1051)
NSE (33%) (Am J Surg Pathol 1989;13:207)
GFAP (18%; scattered individual cells) (Histol Histopathol 1996;11:1049)

Electron microscopy description

Lipid droplet containing stromal cells seen between capillaries (J Neuropathol Exp Neurol 2002;61:1027)

Electron microscopy images

Images hosted on other servers:

EM lipid droplets

Molecular / cytogenetics description

VHL syndrome
- Biallelic inactivation of VHL (J Neurol Neurosurg Psychiatry 2001;70:644)
Sporadic
- Up to 78% of cases show loss / inactivation of VHL (J Neurol Neurosurg Psychiatry 2001;70:644, Cancer Res 1998;58:504, Acta Neuropathol Commun 2014;2:167, Neuro Oncol 2017;19:1228)
Distinctive epigenetic classifying signature can be determined by genome wide DNA methylation array profiling (Acta Neuropathol 2018;136:181)
MicroRNA (miRNA) patterns include elevated miRNA-9 and decreased miRNA-200a (Brain Pathol 2012;22:522)

Molecular / cytogenetics images

Images hosted on other servers:

VHL next generation sequencing

Recurrent loss of chromosome 3

DNA methylation based classification

Idiogram of VHL mutation

Videos

Hemangioblastoma MRI

Hemangioblastoma histopathology

Sample pathology report

Brain, cerebellum, excision:
- Hemangioblastoma, WHO grade 1

Differential diagnosis

Metastatic clear cell renal cell carcinoma:
- Anaplasia, prominent nucleoli
- Mitotic activity
- Necrosis
- Usually lacks foamy / vacuolated cytoplasm
- Positive for AE1 / AE3, CAM5.2, EMA, CD10, PAX2, PAX8, RCC marker (Am J Surg Pathol 2008;32:1051, Arch Pathol Lab Med 2007;131:641, Mod Pathol 2005;18:788, Neuropathology 2010;30:580, Adv Anat Pathol 2010;17:377)
- Negative for inhibin alpha, brachyury, N-CAM1 (J Neuropathol Exp Neurol 2017;76:289, Mod Pathol 2005;18:788, Am J Surg Pathol 2003;27:1152, Arch Pathol Lab Med 2007;131:641, Am J Surg Pathol 2012;36:1052)
Meningioma (clear cell, microcystic, angiomatous subtypes):
- Usually positive for EMA (weak, patchy cytoplasmic), PR, SSTR2A (J Neuropathol Exp Neurol 2017;76:289)
- Negative for inhibin alpha, brachyury (J Neuropathol Exp Neurol 2017;76:289, Am J Surg Pathol 2012;36:1052)
Solitary fibrous tumor:
- Positive for nuclear STAT6 (J Neuropathol Exp Neurol 2017;76:289)
- Negative for inhibin alpha (J Neuropathol Exp Neurol 2017;76:289)
Glioma:
- Smear shows fibrillary processes, less cohesion
- Ependymoma:
  - Perivascular pseudorosettes, ependymal rosettes and canals
  - Positive for GFAP (Appl Immunohistochem Mol Morphol 2000;8:25)
  - EMA may show paranuclear dot-like or ring-like staining (Appl Immunohistochem Mol Morphol 2000;8:25)
- Pilocytic astrocytoma:
  - Biphasic appearance
    - Compact fibrillar portions with Rosenthal fibers
    - Loose microcystic portions with eosinophilic granular bodies
  - Generally positive for GFAP, Olig2 (Am J Surg Pathol 2012;36:43, J Neuropathol Exp Neurol 2004;63:499)
  - MAPK pathway activating genetic alterations (e.g. KIAA1549-BRAF fusion) (Nat Genet 2013;45:602)
- Diffuse glioma:
  - Neoplastic glioma cells infiltrate background brain parenchyma (single cell infiltration, entrapped axons and neurons)
  - Generally positive for GFAP, Olig2 (Acta Neuropathol 1986;72:15, J Neuropathol Exp Neurol 2004;63:499)
Paraganglioma:
- Smear demonstrates individual cells
- Neuroendocrine cytologic features with uniform, round nuclei
- Zellballen architecture
- Diffusely positive for synaptophysin, chromogranin (J Clin Med 2018;7:280)
- Sustentacular cells positive for S100 (J Clin Med 2018;7:280)
Capillary angioma / hemangioma:
- Lobular architecture
- Absence of extravascular stromal cells

Additional references

Louis: WHO Classification of Tumours of the Central Nervous System, 4th Edition, 2016, Perry: Practical Surgical Neuropathology - A Diagnostic Approach, 2nd Edition, 2017, Burger: Smears and Frozen Sections in Surgical Neuropathology, 1st Edition, 2009

Board review style question #1

A 47 year old man presents with ataxia. MRI reveals a solitary cerebellar cyst with an enhancing mural nodule. A representative histologic photo of the surgical specimen is shown. On immunohistochemical stains, stromal cells are negative for AE1 / AE3 and PAX8. Which of the following IHC stains is most likely to be positive in stromal cells?

CAM5.2
CD31
Inhibin alpha
PAX2
RCC marker

Board review style answer #1

C. Inhibin alpha is positive in hemangioblastoma stromal cells. CAM5.2 (answer A) is negative in hemangioblastoma and positive in epithelial neoplasms. CD31 (answer B) is negative in hemangioblastoma stromal cells and positive in vascular endothelial cells. PAX2 (answer D) is negative in hemangioblastoma and positive in renal cell carcinoma. RCC marker (answer E) is negative in hemangioblastoma and positive in renal cell carcinoma.

Comment Here

Reference: Hemangioblastoma

Board review style question #2

A 32 year old woman is found to have multiple enhancing intra-axial mixed solid cystic masses in the cerebellum and spinal cord as well as numerous bilateral renal cysts and a renal mass. A biopsy of a cerebellar mass is shown. A germline mutation is most likely to be present in which gene?

FLCN
NF2
PKD1
TSC1
VHL

Board review style answer #2

E. VHL. Von Hippel-Lindau syndrome manifestations may include multiple hemangioblastomas, renal cysts and renal cell carcinoma.

FLCN - Birt-Hogg-Dubé syndrome (increased risk of renal cysts and tumors; no CNS involvement)
NF2 - neurofibromatosis type 2 (increased risk of various lesions primarily affecting the nervous system, including schwannoma, meningioma, ependymoma; no renal involvement)
PKD1 - autosomal dominant polycystic kidney disease (associated with bilateral renal cysts and berry aneurysms; no other CNS involvement)
TSC1 - tuberous sclerosis (renal manifestations may include angiomyolipoma and cysts; CNS manifestations may include cortical tubers and subependymal giant cell astrocytoma; no known association with hemangioblastoma)

Comment Here

Reference: Hemangioblastoma