The eye in von Hippel–Lindau disease. Long‐term follow‐up of screening and treatment: recommendations

Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11–46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8–38) and SOMs at 29 years (range 22–38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel–Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA). Therefore, [18F]-FDOPA PET/CT, not [68Ga]-(DOTA)-[Tyr3]-octreotate ([68Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.

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Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up

Familial Cancer ◽

10.1007/s10689-012-9525-7 ◽

2012 ◽

Vol 11 (3) ◽

pp. 387-394 ◽

Cited By ~ 9

Author(s):

C. A. Jilg ◽

Hartmut P. H. Neumann ◽

S. Gläsker ◽

O. Schäfer ◽

C. Leiber ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Nephron Sparing Surgery ◽

Von Hippel Lindau ◽

Nephron Sparing ◽

Long Term Follow Up

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STEREOTACTIC RADIOSURGICAL TREATMENT OF CRANIAL AND SPINAL HEMANGIOBLASTOMAS

Neurosurgery ◽

10.1227/01.neu.0000348015.51685.d2 ◽

2009 ◽

Vol 65 (1) ◽

pp. 79-85 ◽

Cited By ~ 54

Author(s):

Jason M. Moss ◽

Clara Y.H. Choi ◽

John R. Adler ◽

Scott G. Soltys ◽

Iris C. Gibbs ◽

...

Keyword(s):

Stereotactic Radiosurgery ◽

Treatment Effectiveness ◽

Attractive Alternative ◽

Von Hippel Lindau ◽

Spinal Lesions ◽

Large Patient ◽

Von Hippel Lindau Disease ◽

The Mean

ABSTRACT OBJECTIVE Stereotactic radiosurgery has been used for nearly 2 decades to treat hemangioblastomas, particularly those that are in surgically inaccessible locations or that are multiple, as is common in von Hippel-Lindau disease. There is a paucity of long-term published radiosurgical treatment outcomes, particularly for spinal lesions, in a large patient population. The purpose of this study was to provide a long-term retrospective evaluation of radiosurgical hemangioblastoma treatment effectiveness, with a special emphasis on the relatively recent use of frameless, image-guided radiosurgery in the treatment of spinal lesions. METHODS From 1991 to 2007, 92 hemangioblastomas in 31 patients, 26 with von Hippel-Lindau disease, were treated with radiosurgery (27 tumors treated with frame-based linear accelerator radiosurgery, and 67 tumors were treated with CyberKnife radiosurgery). The mean patient age was 41 years (range, 18–81 years). The radiation dose to the tumor periphery averaged 23.4 Gy (range, 12–40 Gy). The mean tumor volume was 1.8 cm3 (range, 0.058–65.4 cm3). Tumor response was evaluated in serial, contrast-enhanced, computed tomographic, and magnetic resonance imaging scans. RESULTS Clinical and radiographic follow-up data were available for 82 hemangioblastoma tumors. Only 13 (16%) of the treated hemangioblastomas progressed, whereas 18 tumors (22%) showed radiographic regression, and 51 tumors (62%) remained unchanged in size. With median follow-up of 69 months (range, 5–164 months), the actuarial local control rates at 36 and 60 months were 85% and 82%, respectively. Radiosurgery improved lesion-associated symptoms in 36 of 41 tumors. During the follow-up period, 9 patients died of causes unrelated to the progression of their treated hemangioblastomas, and 5 patients developed radiation necrosis. CONCLUSION Stereotactic radiosurgery is safe and effective in the treatment of hemangioblastomas and is an attractive alternative to surgery for patients, including those with von Hippel-Lindau disease.

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VHL-RELATED NEUROENDOCRINE NEOPLASMS AND BEYOND: AN ISRAELI SPECIALIZED CENTER REAL-LIFE REPORT

Endocrine Practice ◽

10.4158/ep-2020-0220 ◽

2020 ◽

Vol 26 (10) ◽

pp. 1131-1142

Author(s):

Auryan Szalat ◽

Kira Oleinikov ◽

Avital Nahmias ◽

Vardiella Meiner ◽

Simona Ben-Haim ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neuroendocrine Tumor ◽

Neuroendocrine Neoplasms ◽

Pancreatic Neuroendocrine Neoplasms ◽

Von Hippel Lindau ◽

Mutation Carriers ◽

Long Term Follow Up

Objective: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). Methods: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. Results: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. Conclusion: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients. Abbreviations: CNS = central nervous system; HIF = hypoxia inducible factor; PGL = paraganglioma; PHD = prolyl hydroxylase; Pheo = pheochromocytoma; PNEN = pancreatic neuroendocrine neoplasms; PNET = pancreatic neuroendocrine tumor; RCC = clear cell renal cell carcinoma; VHL = Von Hippel-Lindau

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Thermal Ablation of Small Renal Tumors – Present Status

The Scientific World JOURNAL ◽

10.1100/tsw.2007.144 ◽

2007 ◽

Vol 7 ◽

pp. 756-767 ◽

Cited By ~ 6

Author(s):

Jon A. J. Lovisolo ◽

Claudio P. Legramandi ◽

Aldo Fonte

Keyword(s):

Radiofrequency Ablation ◽

Thermal Ablation ◽

Case Series ◽

Renal Tumors ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Prospective Trials

Thermal ablation of renal tumors is achieved by the delivery of extreme heat or extreme cold directly to the lesion in order to obtain in situ destruction of the malignant cells without having to remove the entire organ. Cryotherapy and radiofrequency ablation are becoming more and more attractive for the treatment of small lesions in select cases. Other types of energy such as microwave, laser and high intensity ultrasound have also been used to destroy kidney lesions but must still be considered in the experimental stage. Cryotherapy and radiofrequency ablation are minimally invasive and have been shown to be safe and effective in treating tumors up to 3–4 cm in diameter. However, the number of case series is rather limited and follow-up, especially for radiofrequency ablation, is short. Only now are workers beginning to present outcomes after 5 years for cryoablation. Therefore, the long-term oncological efficacy of these ablation techniques remains to be seen. As longer follow-up and greater patient numbers are reported we will get a clearer picture of the true potential of these modalities. Randomized prospective trials would be auspicable. For now, CA and RFA should be limited to few select patients i.e. patients with comorbidities which render them at high risk for a surgical procedure and possibly patients with genetic conditions such as Von Hippel Lindau disease who will probably develop multiple tumors.

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A Rational Approach to Radiological Screening in Von Hippel-Lindau Disease

Journal of Medical Screening ◽

10.1177/096914139400100205 ◽

1994 ◽

Vol 1 (2) ◽

pp. 88-95 ◽

Cited By ~ 4

Author(s):

R W J Harries

Keyword(s):

Posterior Fossa ◽

Rational Approach ◽

Pedigree Data ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Live Births ◽

Von Hippel Lindau Disease ◽

High Degree

Objectives— To optimise radiological screening in von Hippel-Lindau disease (VHL) while minimising cost and morbidity. Methods— A model of VHL was based on retrospective studies, and Bayes's theorem used to calculate the probability of the gene's presence and the likelihood of further lesions in affected families. A six year follow up was conducted to test the validity of the model. Results— Follow up confirmed the accuracy and validity of the model. Posterior fossa haemangioblastomas occur in 79·2% of VHL cases, supratentorial, retinal and spinal haemangioblastomas in 6·9%, 42·8%, and 22·0%, phaeochromocytomas in 5·2%, and renal carcinomas in 14·5%. Population incidences are 1:15 700 live births (posterior fossa), 1:780 000 (supratentorial), and 1:116 000 (spinal). The birth rate of subjects with VHL is 1:43 000; new mutations occur in 1:178 000 live births. Penetrance is 90%; 40% present with multiple lesions and 6·4% die within two years after diagnosis. Conclusions— For most patients presenting with a VHL-type lesion, with sufficient clinical and pedigree data, the presence or absence of the VHL gene, and the probability of further lesions occurring, can be assessed with a high degree of accuracy using the method described in this paper. Those cases in the non-VHL group do not require long term radiological follow up, nor do their relatives require radiological screening. Subjects in the VHL group should be screened for renal carcinoma indefinitely from the age of 20 years, and all clinically unaffected relatives should be screened genetically for the VHL gene. (Those found negative for the gene do not require further screening, but those found positive should be screened.)

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A long-term survivor of metachronous liver metastases of pancreatic serous cystic neoplasm associated with von Hippel–Lindau disease

Surgical Case Reports ◽

10.1186/s40792-021-01239-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Takashi Kokumai ◽

Masamichi Mizuma ◽

Katsuya Hirose ◽

Hideaki Karasawa ◽

Masaharu Ishida ◽

...

Keyword(s):

Liver Metastases ◽

Surgical Resection ◽

Cystic Neoplasm ◽

Von Hippel Lindau ◽

Initial Surgery ◽

Contrast Enhanced ◽

Serous Cystic Neoplasm ◽

Von Hippel Lindau Disease

Abstract Background Pancreatic serous cystic neoplasm (SCN) is an uncommon exocrine neoplasm, which is believed to be a benign entity. However, some of these neoplasms may occasionally attain metastatic ability. Von Hippel–Lindau disease (VHL) manifests a dominantly inherited systemic syndrome accompanied by several benign or malignant tumors, including cystic tumors, in various organs. We describe here a long-term survival case who underwent surgical resection for metachronous liver metastases of pancreatic SCN associated with VHL disease. Case presentation A 35-year-old woman with VHL underwent total pancreatectomy and right nephrectomy for pancreatic SCN and renal cell carcinoma, respectively. At the 4th year follow-up examination after the resection, contrast-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed arterially hyper-enhanced neoplastic lesions in the segment VI and VIII of the liver. Partial resections of the liver were performed 53 months after the initial surgery. At the 6th month follow-up examination from the second surgery, one and two tumors located in the liver segment III, and VIII, respectively, were detected by contrast-enhanced CT and Gd-EOB-DTPA-enhanced MRI. Anterior segmentectomy and partial resection of the segment III were performed 66 months after the initial surgery and 13 months after the second, respectively. The tumors were pathologically diagnosed as liver metastases of pancreatic SCN synonymous with serous cystadenocarcinoma. She remains disease-free without recurrence 6.5 years after the last operation. Conclusions This is the first report of a case of metastatic SCN associated with VHL. Surgical resection might confer a favorable prognosis in patients of pancreatic SCN with liver metastases.

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Therapy and prevention for mental health: What if mental diseases are mostly not brain disorders?

Behavioral and Brain Sciences ◽

10.1017/s0140525x1800105x ◽

2019 ◽

Vol 42 ◽

Cited By ~ 2

Author(s):

John P. A. Ioannidis

Keyword(s):

Mental Health ◽

Mental Disease ◽

Brain Disorders ◽

Social Stressors ◽

Labor Education ◽

Mental Diseases ◽

Long Term Follow Up ◽

Political Decisions

AbstractNeurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

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