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von Hippel–Lindau disease (VHL)

Familial neoplastic condition characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys, adrenals, pancreas, and reproductive organs caused by genetic aberrations of the tumor suppressor gene VHL.

Familial neoplastic condition characterized by the presence of benign and malignant tumors affecting the CNS, kidneys, adrenals, pancreas, and reproductive organs caused by genetic aberrations of the tumor suppressor gene VHL.

  • Autosomal dominant inheritance
  • Occurs in 1 in 36000 people
  • 20% are de-novo mutations
Major tumors and cysts in VHL disease
Major tumors and cysts in von Hippel–Lindau disease. | Shuin, T., Yamasaki, I., Tamura, K., Okuda, H., Furihata, M., & Ashida, S. (2006). Von Hippel–Lindau Disease: Molecular Pathological Basis, Clinical Criteria, Genetic Testing, Clinical Features of Tumors and Treatment. Japanese Journal of Clinical Oncology, 36(6), 337–343. https://doi.org/10.1093/jjco/hyl052

History:

The VHL disease was described in von Hippel’s literature in 1911 and Lindau’s literature in 1926. Melmon and Rosen established the notion of the VHL disease in 1964 . The positional cloning for the disease was started by Latif et al. with the accumulation of DNA in VHL families. Identification of the VHL disease gene was published in 1993. The responsible gene was named as ‘VHL tumor suppressor gene’, which is located on the chromosome 3p25–26 . Further studies showed that the VHL gene is also inactivated in sporadic RCC, HB and Pheo.


Classification

  • Type 1 (without pheochromocytoma)
  • Type 2 (with pheochromocytoma):
    • Type 2A: Pheochromocytoma + CNS hemangioblastomas – RCC.
    • Type 2B: Pheochromocytoma + CNS hemangioblastomas + RCC
    • Type 2C: Pheochromocytoma – hemangioblastomas – RCC

Pathophysiology

Germline mutations of VHL tumor suppressor gene (chromosome 3)

Von Hippel-Lindau is caused by autosomal dominant mutation of the von Hippel–Lindau tumor suppressor gene on chromosome 3 that result in an abnormal pVHL. pVHL regulates a protein known as HIF-1-alpha, which is responsible for cellular response to hypoxia. VHL genetic mutations result in alterations to pVHL at the HIF-1-alpha binding site. As a result, pVHL does not bind effectively to HIF-1-alpha which, in turn, leads to the transcription of several genes and subsequent upregulation of growth factors including erythropoietin, vascular endothelial growth factor, platelet-derived growth factor B, and other genes involved in glucose uptake and metabolism.
VCB-CUL2 complex
VCB-CUL2 complex is formed with binding of VHL protein to elongin C, elongin B and CUL2. The complex then binds HIF and leads to degradation in normoxic conditions. | Lonser RR, Glenn GM, Walther M, et al. von Hippel–Lindau disease. Lancet. 2003a;361:2059–2067
  • pVHL ubiquitinates hypoxia-inducible factor 1a

Presentation

Common manifestations:

Hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors.
  1. CNS hemangioblastoma (including retinal hemangioblastoma) (M/C, 60% cases)
  2. Endolymphatic sac tumours (ELST) (25% cases)
  3. Renal cell carcinoma (RCC) (~60% cases)
  4. Pheochromocytoma (paraganglioma elsewhere), and/or glomus tumor (20% cases)
  5. Neuroendocrine neoplasm and/or multiple cysts of the pancreas (15% cases)

CNS hemangioma (M/C, 60% cases):

Benign blood vessel tumour (high vascularity with hyperchromatic nuclei) which can cause headaches, vomiting, sensory or motor deficits, and ataxia.
  • Brain stem, spine → Mass, focal lesions, CSF flow → ↑ ICP
  • Cerebellum → Ataxia (loss of balance), CSF flow block → ↑ ICP
VHL CNS presentation
(A) Axial T1-weighted postcontrast magnetic resonance image (MRI) of a cerebellar hemangioblastoma (arrowheads) with an associated cyst (asterisk) in a 40-year-old woman. (B) Sagittal T1-weighted postcontrast MRI of medullary hemangio-blastoma (arrowheads) with associated brainstem edema (asterisk) in a 12-year-old girl. (C) Sagittal T1-weighted postcontrast MRI of the cervical spinal cord of a 50-year-old man. Hemangioblastoma (black arrowheads) is located in the dorsal spinal cord at C5 and C6, and is associated with a large syrinx (asterix). (D) Hematoxylin and eosin staining of a hemangioblastoma showing the lipid-laden stromal cells (arrows) distributed within a capillary network (arrowheads). | Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH Lancet. 2003 Jun 14; 361(9374):2059-67.

Retinal hemangioblastomas (up to 60%):

Although not the most common tumor in VHL, they are often the first manifestation.
  • Retinal angioma → Retinal detachment, blindness (5–8%)
VHL Renal hemangioblastoma
(A) Peripheral retinal hemangioblastoma (black arrowhead) with enlarged vessels (white arrowheads) in a 22-year-old woman. (B) Peripheral retinal hemangioblastoma (arrowhead) with fibrous changes, and hard exudates and retinal edema (asterisk) in a 24-year-old man. (C) Retinal hemangioblastoma (arrowhead) on the optic nerve head with yellow retinal hard exudates (asterisk) in a 32-year-old man. | Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH Lancet. 2003 Jun 14; 361(9374):2059-67.

Endolymphatic sac tumors (ELST):

Develop from endolymphatic epithelium within the vestibular aqueduct which play a role in the production and resorption of endolymph which is found within the cochlea and semicircular canals.
  • Ear fullness, disequilibrium, and hearing loss
  • Larger lesions (>3 cm): Facial paresis
Endolymphatic sac tumors (ELSTs)
Endolymphatic sac tumors (ELSTs): (A) Axial T1-weighted postcontrast magnetic resonance image shows large heterogeneously enhancing tumor in the right mastoid region (arrowheads). (B) Axial computed tomography through the same region showing the bony erosion of posterior petrous region that often occurs in these tumors (arrowheads). (C) Hematoxylin and eosin stained section showing the typical histologic features of neoplasm, including cuboidal epithelium (arrowheads) in a papillary pattern. | Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH Lancet. 2003 Jun 14; 361(9374):2059-67.

Renal manifestations:

Renal manifestations of VHL include benign renal cysts (50–70%) and clear cell carcinoma (30%)
  • RCC: Renal mass with flank pain or hematuria
  • Simple renal cysts: Asymptomatic; complex cysts: Solid renal masses
VHL Renal manifestations
(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. | Varshney, N., Kebede, A. A., Owusu-Dapaah, H., Lather, J., Kaushik, M., & Bhullar, J. S. (2017). A Review of Von Hippel-Lindau Syndrome. Journal of kidney cancer and VHL, 4(3), 20–29. https://doi.org/10.15586/jkcvhl.2017.88

Pheochromocytomas/paragangliomas:

They can be bilateral and occasionally multifocal. Pheochromocytomas usually present in the second decade of life in VHL patients and rarely transform into malignant tumors. These tumors produce catecholamines, such as excessive norepinephrine, causing hypertension, tachycardia, palpitations, headaches, sweating, pallor, and nausea
  • Pheochromocytomas → ↑ Norepinephrine & epinephrine → Sympathetic overactivity (headaches, sweating, palpitations, HTN)
    • Pheo crisis (fatal): ↑↑↑ Catecholamines (noerpinephrine & epinephrine)
VHL: Pheochromocytoma
(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. | Varshney, N., Kebede, A. A., Owusu-Dapaah, H., Lather, J., Kaushik, M., & Bhullar, J. S. (2017). A Review of Von Hippel-Lindau Syndrome. Journal of kidney cancer and VHL, 4(3), 20–29. https://doi.org/10.15586/jkcvhl.2017.88

Pancreatic neuroendocrine tumors and cysts (35–70%):

There are usually multiple cysts that present without symptoms. Serous cystadenomas and neuroendocrine tumors are other manifestations of pancreatic lesions in VHL syndrome
VHL: PNeTs
(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. | Varshney, N., Kebede, A. A., Owusu-Dapaah, H., Lather, J., Kaushik, M., & Bhullar, J. S. (2017). A Review of Von Hippel-Lindau Syndrome. Journal of kidney cancer and VHL, 4(3), 20–29. https://doi.org/10.15586/jkcvhl.2017.88

Epididymal cystadenomas

Males with VHL can develop cystadenomas in the epididymis. They may arise unilaterally or bilaterally in 25–60% of VHL males (Table 3). They are benign in nature and do not require surgery

Broad ligament cystadenomas

Papillary cystadenomas are rare but found in the mesosalpinx and the broad ligament (5, 14, 16). They may be present unilaterally or bilaterally in women with VHL syndrome. The incidence is unknown (Table 3). The tumor may present as an abdominopelvic mass with symptoms of abdominal discomfort or a painful adnexal mass (5, 14, 16).

Diagnosis

Diagnositic criteria:

  1. At least 2 CNS hemangioblastomas, or
  2. At least 1 CNS hemangioblastoma + 1 other manifestation, or
  3. At least 1 of the manifestations described above, and a pathogenic mutation in VHL gene or a first-degree relative with VHL.

Lab studies:

  • Plasma free metanephrines
  • 24-h urinary measurement of catecholamines

Contrast-enhanced MRI:

gold standard for detecting and monitoring CNS hemangioblastomas. It is between 90% and 100% sensitive in the detection of these tumors and is the preferred modality compared to CT. Identification of extra-adrenal tumors may benefit from meta-iodobenzylguanidine (MIBG) scintigraphy

Tissue biopsy:

  • Classic pattern: Small nests (zellballen) of neuroendocrine cells (chief cells) with interspersed small blood vessels
  • Variant and combined patterns: Diffuse growth, large zellballen, spindle cells, cell cords, etc

Management

Craniospinal lesions:

  • Surgically resected safely and are often curative.
  • Asymptomatic lesions monitored with annual imaging
  • Stereotactic radiosurgery (SRS)

Capillary retinal hemangioblastoma

Management depending on the location and size of the lesions
  • Laser photocoagulation
  • Cryotherapy
  • Vitreoretinal surgery
  • External beam radiotherapy (refractory cases)

ELSTs:

  • Surgical resection is the mainstay therapy
  • Radiation therapy (unresectable tumors)

RCCs:

  • No intervention necessary for tumors < 3 cm
  • Partial nephrectomy: Tumors ≥ 3 cm (to reduce the risk of metastasis while maintaining kidney function)
  • Percutaneous and laparoscopic radiofrequency ablation therapy: Smaller tumors (<3 cm) with low complication rates

Pancreatic cysts:

Do not require surgical intervention
  • PNETs with a potential for metastatic disease: Resected with enucleation by Whipple’s procedure or partial pancreatectomy depending on the size and location of the tumor

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