CNS tumor
Other tumors
Hemangioblastoma

Resident / Fellow Advisory Board: Meaghan Morris, M.D., Ph.D.
Deputy Editor-in-Chief: Chunyu "Hunter" Cai, M.D., Ph.D.
Rebecca Yoda, M.D.
P.J. Cimino, 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

Rebecca Yoda, M.D.
P.J. Cimino, M.D., Ph.D.
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Cite this page: Yoda R, Cimino PJ. Hemangioblastoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumorhemangioblastoma.html. Accessed July 24th, 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
Sites
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
    • 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
Diagrams / tables

Images hosted on other servers:

VHL regulation of the HIF pathway

Clinical features
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
Radiology description
Radiology images

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T1+C MRI posterior fossa

Prognostic factors
Case reports
Treatment
Clinical images

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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



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Variegated red-yellow tumor

Hemangioblastoma in situ

Frozen section images

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

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
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

Electron microscopy description
Electron microscopy images

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EM lipid droplets

Molecular / cytogenetics description
Molecular / cytogenetics images

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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
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?

  1. CAM5.2
  2. CD31
  3. Inhibin alpha
  4. PAX2
  5. 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.

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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?

  1. FLCN
  2. NF2
  3. PKD1
  4. TSC1
  5. VHL
Board review style answer #2
E. VHL. Von Hippel-Lindau syndrome manifestations may include multiple hemangioblastomas, renal cysts and renal cell carcinoma.

  1. FLCN - Birt-Hogg-Dubé syndrome (increased risk of renal cysts and tumors; no CNS involvement)
  2. NF2 - neurofibromatosis type 2 (increased risk of various lesions primarily affecting the nervous system, including schwannoma, meningioma, ependymoma; no renal involvement)
  3. PKD1 - autosomal dominant polycystic kidney disease (associated with bilateral renal cysts and berry aneurysms; no other CNS involvement)
  4. 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)

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Reference: Hemangioblastoma
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