Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: Histopathological and molecular genetic analysis

Irina A. Lubensky, Svetlana Pack, David Ault, Alexander Vortmeyer, Steven K. Libutti, Peter L. Choyke, McClellan M. Walther, W. Marston Linehan, Zhengping Zhuang

Research output: Contribution to journalArticle

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Abstract

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based singlestrand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear- cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.

Original languageEnglish (US)
Pages (from-to)223-231
Number of pages9
JournalAmerican Journal of Pathology
Volume153
Issue number1
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

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von Hippel-Lindau Disease
Neuroendocrine Tumors
Molecular Biology
Pancreas
Genes
Neoplasms
Collagen
Pancreatic Hormones
Gastrointestinal Hormones
Pancreatic Polypeptide
Chromogranin A
Synaptophysin
Loss of Heterozygosity
Somatostatin
Glucagon
Fluorescence In Situ Hybridization
Germ Cells
Cell Biology
Carcinogenesis
Immunohistochemistry

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients : Histopathological and molecular genetic analysis. / Lubensky, Irina A.; Pack, Svetlana; Ault, David; Vortmeyer, Alexander; Libutti, Steven K.; Choyke, Peter L.; Walther, McClellan M.; Linehan, W. Marston; Zhuang, Zhengping.

In: American Journal of Pathology, Vol. 153, No. 1, 01.01.1998, p. 223-231.

Research output: Contribution to journalArticle

Lubensky, Irina A. ; Pack, Svetlana ; Ault, David ; Vortmeyer, Alexander ; Libutti, Steven K. ; Choyke, Peter L. ; Walther, McClellan M. ; Linehan, W. Marston ; Zhuang, Zhengping. / Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients : Histopathological and molecular genetic analysis. In: American Journal of Pathology. 1998 ; Vol. 153, No. 1. pp. 223-231.
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abstract = "Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based singlestrand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear- cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35{\%} of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65{\%} of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.",
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AU - Vortmeyer, Alexander

AU - Libutti, Steven K.

AU - Choyke, Peter L.

AU - Walther, McClellan M.

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AU - Zhuang, Zhengping

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