A Review of Von Hippel-Lindau Syndrome

Abstract

Von Hippel-Lindau syndrome (VHL) is a familial neoplastic condition seen in approximately 1 in 36,000 live births. It is caused by germline mutations of the tumor suppressor gene VHL, located on the short arm of chromosome 3. While the majority of the affected individuals have a positive family history, up to 20% of cases arise from de novo mutations. VHL syndrome is characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Common manifestations include hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors. Diagnosis of VHL is prompted by clinical suspicion and confirmed by molecular testing. Management of VHL patients is complex and multidisciplinary. Routine genetic testing and surveillance using various diagnostic techniques are used to help monitor disease progression and implement treatment options. Despite recent advances in clinical diagnosis and management, life expectancy for VHL patients remains low at 40-52 years. This article provides an overview of the major clinical, histological, and radiological findings, as well as treatment modalities.

Keywords: endolymphatic sac tumors; hemangioblastomas; pancreatic neuroendocrine tumors; pheochromocytoma; von Hippel-Lindau syndrome.

Figure 1

(A) Axial T1 postcontrast images demonstrate an enhancing mural nodule (white arrow) with accompanying cyst (*) in the right cerebellar hemisphere exerting a mass effect upon the midline and fourth ventricle (double white arrow). (B) Hematoxylin-eosin staining showing scattered large hyperchromatic nuclei, vacuolated cells, and multiple capillaries which are classic features of the cellular type of hemangioblastoma.

Figure 2

(A) Axial T2 weighted images show a T2 hypointense lesion in the posteromedial aspect of the midportion of the right kidney (white arrow). (B) Axial T1 postcontrast images show enhancement of the lesion (dashed white arrow) indicating a solid renal mass such as renal cell carcinoma. (C) Low-power- and (D) high-power-hematoxylin-eosin staining showing a typical picture of clear cell renal cell carcinoma with nests of clear cells surrounded by intricately branching vascular septa.

Figure 3

(A) Coronal Single-shot fast spin echo (SSFSE) image of the abdomen shows a high signal lesion (white arrow) within the medial limb of the left adrenal gland. (B) Coronal T1 postcontrast image shows a homogeneously enhancing mass (dashed white arrow) consistent with pheochromocytoma. (C) and (D) Hematoxylin-eosin staining showing nests of tumor cells (zellballen growth pattern) surrounded by a discontinuous layer of sustentacular cells and fibrovascular stroma intermixed with blood.

Figure 4

(A) Axial CT images of the abdomen with contrast show a mass in the head of the pancreas (white arrow) in a patient with abnormal gastrin levels clinically. (B) SPECT-CT images of a patient after administration of In-111-octreoscan show abnormal uptake in the pancreatic head mass (dashed white arrow). (C) Low-power- and (D) high-power-hematoxylin-eosin staining showing uniform neuroendocrine cells.