Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene

Lucia Anna Muscarella, Michele Bisceglia, Carlos A. Galliani, Nina Zidar, David Jonathan Ben-Dor, Gianandrea Pasquinelli, Annamaria la Torre, Angelo Sparaneo, Julie Fanburg-Smith, Janez Lamovec, Michal Michal, Carlos E. Bacchi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as “hemangioblastoma-only VHLD” 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas, and LOH in 4 (two as a double hit), all non-renal extraneuraxial hemangioblastomas. Methylation analysis failed to disclose promoter methylation in any case. In conclusion, we report eight new cases from the wide category of extraneuraxial hemangioblastomas (4 paraneuraxial, and 4 renal), one of which was von Hippel-Lindau disease-associated and 7 sporadic. VHL gene alterations were found not only in the von Hippel-Lindau disease-associated tumor, but − for the first time − also in 3 sporadic ones, two of which with novel mutations.

Original languageEnglish (US)
Pages (from-to)1156-1165
Number of pages10
JournalPathology Research and Practice
Volume214
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Hemangioblastoma
von Hippel-Lindau Disease
Genes
Neoplasms
Methylation
Molecular Biology
Paraffin
Mutation
Kidney
Germ-Line Mutation
DNA
Vimentin
Stromal Cells
Electron Microscopy
Cytoplasm
Central Nervous System
Immunohistochemistry
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Cell Biology

Cite this

Muscarella, L. A., Bisceglia, M., Galliani, C. A., Zidar, N., Ben-Dor, D. J., Pasquinelli, G., ... Bacchi, C. E. (2018). Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene. Pathology Research and Practice, 214(8), 1156-1165. https://doi.org/10.1016/j.prp.2018.05.007
Muscarella, Lucia Anna ; Bisceglia, Michele ; Galliani, Carlos A. ; Zidar, Nina ; Ben-Dor, David Jonathan ; Pasquinelli, Gianandrea ; la Torre, Annamaria ; Sparaneo, Angelo ; Fanburg-Smith, Julie ; Lamovec, Janez ; Michal, Michal ; Bacchi, Carlos E. / Extraneuraxial hemangioblastoma : A clinicopathologic study of 10 cases with molecular analysis of the VHL gene. In: Pathology Research and Practice. 2018 ; Vol. 214, No. 8. pp. 1156-1165.
@article{1036697e9127469c9c261ef86e161429,
title = "Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene",
abstract = "Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as “hemangioblastoma-only VHLD” 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas, and LOH in 4 (two as a double hit), all non-renal extraneuraxial hemangioblastomas. Methylation analysis failed to disclose promoter methylation in any case. In conclusion, we report eight new cases from the wide category of extraneuraxial hemangioblastomas (4 paraneuraxial, and 4 renal), one of which was von Hippel-Lindau disease-associated and 7 sporadic. VHL gene alterations were found not only in the von Hippel-Lindau disease-associated tumor, but − for the first time − also in 3 sporadic ones, two of which with novel mutations.",
author = "Muscarella, {Lucia Anna} and Michele Bisceglia and Galliani, {Carlos A.} and Nina Zidar and Ben-Dor, {David Jonathan} and Gianandrea Pasquinelli and {la Torre}, Annamaria and Angelo Sparaneo and Julie Fanburg-Smith and Janez Lamovec and Michal Michal and Bacchi, {Carlos E.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1016/j.prp.2018.05.007",
language = "English (US)",
volume = "214",
pages = "1156--1165",
journal = "Pathology Research and Practice",
issn = "0344-0338",
publisher = "Urban und Fischer Verlag GmbH und Co. KG",
number = "8",

}

Muscarella, LA, Bisceglia, M, Galliani, CA, Zidar, N, Ben-Dor, DJ, Pasquinelli, G, la Torre, A, Sparaneo, A, Fanburg-Smith, J, Lamovec, J, Michal, M & Bacchi, CE 2018, 'Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene', Pathology Research and Practice, vol. 214, no. 8, pp. 1156-1165. https://doi.org/10.1016/j.prp.2018.05.007

Extraneuraxial hemangioblastoma : A clinicopathologic study of 10 cases with molecular analysis of the VHL gene. / Muscarella, Lucia Anna; Bisceglia, Michele; Galliani, Carlos A.; Zidar, Nina; Ben-Dor, David Jonathan; Pasquinelli, Gianandrea; la Torre, Annamaria; Sparaneo, Angelo; Fanburg-Smith, Julie; Lamovec, Janez; Michal, Michal; Bacchi, Carlos E.

In: Pathology Research and Practice, Vol. 214, No. 8, 01.08.2018, p. 1156-1165.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Extraneuraxial hemangioblastoma

T2 - A clinicopathologic study of 10 cases with molecular analysis of the VHL gene

AU - Muscarella, Lucia Anna

AU - Bisceglia, Michele

AU - Galliani, Carlos A.

AU - Zidar, Nina

AU - Ben-Dor, David Jonathan

AU - Pasquinelli, Gianandrea

AU - la Torre, Annamaria

AU - Sparaneo, Angelo

AU - Fanburg-Smith, Julie

AU - Lamovec, Janez

AU - Michal, Michal

AU - Bacchi, Carlos E.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as “hemangioblastoma-only VHLD” 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas, and LOH in 4 (two as a double hit), all non-renal extraneuraxial hemangioblastomas. Methylation analysis failed to disclose promoter methylation in any case. In conclusion, we report eight new cases from the wide category of extraneuraxial hemangioblastomas (4 paraneuraxial, and 4 renal), one of which was von Hippel-Lindau disease-associated and 7 sporadic. VHL gene alterations were found not only in the von Hippel-Lindau disease-associated tumor, but − for the first time − also in 3 sporadic ones, two of which with novel mutations.

AB - Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as “hemangioblastoma-only VHLD” 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas, and LOH in 4 (two as a double hit), all non-renal extraneuraxial hemangioblastomas. Methylation analysis failed to disclose promoter methylation in any case. In conclusion, we report eight new cases from the wide category of extraneuraxial hemangioblastomas (4 paraneuraxial, and 4 renal), one of which was von Hippel-Lindau disease-associated and 7 sporadic. VHL gene alterations were found not only in the von Hippel-Lindau disease-associated tumor, but − for the first time − also in 3 sporadic ones, two of which with novel mutations.

UR - http://www.scopus.com/inward/record.url?scp=85048865996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048865996&partnerID=8YFLogxK

U2 - 10.1016/j.prp.2018.05.007

DO - 10.1016/j.prp.2018.05.007

M3 - Article

C2 - 29941223

AN - SCOPUS:85048865996

VL - 214

SP - 1156

EP - 1165

JO - Pathology Research and Practice

JF - Pathology Research and Practice

SN - 0344-0338

IS - 8

ER -