1. Pancreatic surgery evolution
from major towards parenchyma sparing resection in von Hippel-Lindau (VHL) patients
4 cases and literature review
1Egoroff V.I, 1Petrov R.V., 2Beltsevich D.G .
Bakhrushins Hospital
Endocrinology Scientific Center

3. Коротко о важном:1. несмотря на серьезный диагноз самочувствие и жизненная активность большинства пациентов ничем не отличается от нормы 2. средний возраст манифестации 23г. Но посмотрите сколько времени уходит на постановку правильного диагноза это обусловлено тем что лишь малая толика пациентов участвуют в исследованиях и находятся под пристальным наблюдением специалистов. Для подавляющего большинства пациентов это «айсберг» с которым им предстоит столкнуться в молодом работоспособном возрасте.

4. Von Hippel-Lindau (VHL) disease ICD 10 Q85.8
Definition
Von Hippel-Lindau (VHL) disease ICD 10 Q85.8
is an inherited autosomal dominant syndrome
with high (100%) penetrance
manifested by a variety
of benign
and malignant tumors
* Clinical features, diagnosis, and management of von Hippel-Lindau disease (Literature review current through: Sep / This topic last updated: Sep 21, 2016)

5. History
1904г. Eugen von Hippel, german ophthalmologist - retinal vascular abnormality
1926г. Arvid Lindau, swedish pathologist, first described the hemangioblastomas of the brain and spine in His description included a systematic compilation of all other published patients, including those of von Hippel, and described changes in different abdominal organs.
1965г. Melmon K.L, Rosen S.W. – coined the term «von Hippel-Lindau» to describe
1993г. Latif et al. identification and study the tumor suppressor gene gave rise to new milestone of disease history
Случаи ретинальных ангиом впервые выявленные Хиппелем в 26-м году были систематически обобщены и подытожены шведским патологом Линдау а спустя полвека Мелман и Rolsen свели эти две фамилии в названии единого наследственного синдрома. Открытие Гена супрессора роста опухоли в 93-м году международный группой учёных стало новым этапом в истории изучения этого забоолевания
Identification of the von Hippel-Lindau disease tumor suppressor gene. Latif F1, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al6Science May 28;260(5112):

6. 200 000 people in the world have VHL Incidence 1 : 36 000
Epidemiology
people in the world have VHL
Incidence 1 :
Prevalence 1- 9 / =
20 % patients have «de novo» VHL mutations
VHL occurs in every ethnic group, everywhere in the world.
Sabine Schmid Management of von Hippel-Lindau Disease: An Interdisciplinary Review Oncol Res Treat 2014;37:761–771

7. VHL gene location and structure OMIM (Online Mendelian Inheritance in Man): 193300 ; 608537
is located on the short arm of chromosome 3 at a site called 3p25-p26
VHL - 3 exons
- Germinal mutations > 370
- Somatic(sporadic) > 1500+
Somatic mozaicism
рVHL
Germline mutations cause von Hippel-Lindau disease. VHL mutations are heterogeneous and distributed widely throughout the coding sequence except 5' for the translation initiation site for pVHL19. There is a few recurrent mutations and only one founder effect is known, originating from Germany (T292C resulting in a Tyr98His substitution).
Point mutations occur in about 60% of cases (Figure 2) and large deletions in about 40%. VHL 1 (without pheochromocytoma) is mainly produced by mutations responsible for truncated protein (deletions, frameshift mutations and nonsense mutations). VHL type 2 (with high risk of pheochromocytoma) is mainly produced by missense mutations. Type 2B is the potentially "full" form of the disease (frequent mutations: Arg167Gln, Arg167Trp). Type 2A is associated with a very low risk of clear cell renal cell cancer (RCC) (common mutation: Tyr98His). Type 2C is characterized by the occurrence of pheochromocytoma only (example: Leu188Val).
Between 10 and 15% of cryptic VHL cases could be explained by de novo mutations and there are some cases of germline mosaicism.
There is some evidence that genetic modifiers may influence the phenotypic expression of the disease.
Somatic Mutations are encountered in 60 % of sporadic clear cell RCC. In addition, 15% of tumours show evidence of inactivation by methylation. VHL alterations have been associated with occupational exposure to trichlorethylene.
Somatic mutations are also frequent in CNS sporadic hemangioblastoma but rarer in sporadic endolymphatic sac tumours, pancreatic serous cystadenomas and endocrine tumours, epididymal cystadenomas and pheochromocytomas
It is also estimated that no DNA mutation or deletion can be foundin approximately 10% of people clinically diagnosed with VHL. These people haveVHL, but current DNA testing has not been able to find the alteration in their DNA. Insome cases, the VHL mutation is present only in certain cells, but not in all cells, makingthe person “mosaic” for VHL.
Latif F1, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Identification of the von Hippel-Lindau disease tumor suppressor gene. Science May 28;260(5112):

8. Е3 ubiquitin ligase complex
The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.
One of the targets of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α). HIF-2α is one part (subunit) of a larger protein complex called HIF, which plays a critical role in the body's ability to adapt to changing oxygen levels. HIF controls several genes involved in cell division, the formation of new blood vessels, and the production of red blood cells. It is the major regulator of a hormone called erythropoietin, which controls red blood cell production. HIF's function is particularly important when oxygen levels are lower than normal (hypoxia). However, when adequate oxygen is available, the VCB-CUL2 complex keeps HIF from building up inappropriately in cells.
VHL ген служит матрицей для РНК которая в свою очередь приводит к синтезу белка являющегося частью комплекса называемого VCB-CUL2. Этот комплекс нацелен на разрушение других белков когда в них больше нет потребности. Распад белков – нормальный процесс который удаляет поврежденные или ненужные белки и помогает поддерживать естественные функции клетки.

9. Inheritance Knudson «Two-hit» model
A reference handbook for people with von Hippel-Lindau,their families, and their medical team Written by the VHL Alliance Edition 5 Revised 2015

10. Phenotypic manifestations
70%
Retinal hemangioblastoma
Hemangobastomas up to %
breinstem %
cerebellum %
spine %
15%
Endolymphatic sac tumor
Pheochromocytomas Norepinephrine secretion
& paraganglyomas %
panCyst & cystadenomas % pNETs %
ccRCC %
Papillary cystadenomas of broad uterine ligament %
Rare:
Hemangioblastoma of brain
Liver splen lung hemangiomas & cyst
INTRODUCTION — Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. A VHL gene abnormality is present in approximately 1 in 36,000 individuals [1-3].
The initial manifestations of disease can occur in childhood, adolescence, or adulthood, with a mean age at initial presentation of approximately 26 years [1]. The spectrum of VHL-associated tumors includes:
●Hemangioblastomas of the brain (cerebellum) and spine
●Retinal capillary hemangioblastomas (retinal angiomas)
●Clear cell renal cell carcinomas (RCCs)
●Pheochromocytomas
●Endolymphatic sac tumors of the middle ear
●Serous cystadenomas and neuroendocrine tumors of the pancreas
●Papillary cystadenomas of the epididymis and broad ligament
The different types of VHL disease, their clinical manifestations and management, the genetic diagnosis of VHL, and appropriate surveillance protocols will be reviewed here. The molecular biology and pathogenesis of VHL disease are discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
TYPES OF VHL DISEASE — Families with VHL disease have been divided into types 1 and 2, based upon the likelihood of developing pheochromocytoma [4]. Type 2 families are more likely to carry a missense mutation in the VHL gene.
●Type 1 – Patients in kindreds with type 1 disease have a substantially lower risk of developing pheochromocytomas, although they are at high risk for the other VHL-associated lesions.
●Type 2 – Kindreds with type 2 disease are at high risk for developing pheochromocytoma. Type 2 disease is subdivided based upon the risk of developing renal cell carcinoma (RCC). Type 2A and 2B families have a low and high incidence of RCC, respectively, while type 2C kindreds are characterized by the development of pheochromocytomas only, without RCC or hemangioblastoma. These subclassifications should be used as a guide and are not absolute. Continued surveillance for other VHL-related lesions should continue, for example, in individuals who present with type 2C characteristics.
The goal of improving survival and quality of life in patients with VHL disease has been aided by a better understanding of the natural history of VHL-associated tumors [5]. As a result, surveillance strategies have been developed for affected individuals, which have led to the detection of small, asymptomatic tumors prior to the development of metastases or other complications. In addition, therapeutic advances (eg, renal-sparing surgery in RCC) have improved outcomes by decreasing the incidence of renal failure when therapy is required. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
The molecular pathogenesis of VHL disease is discussed elsewhere. A "two-hit" model appears to apply to this disorder. Affected patients have a germline mutation that inactivates one copy of the VHL gene in all cells. For disease to occur there must be loss of expression of the second, normal allele through somatic mutation or deletion of the second allele, or through hypermethylation of its promoter. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
OCCURRENCE AND AGE OF ONSET OF VHL-RELATED LESIONS — VHL-related lesions occur over a wide range of ages, as outlined in the table (table 1) [6]. Age of onset of screening varies by lesion, with screening for retinal lesions commencing at a very young age, and screening for other lesions starting slightly later. (See 'Surveillance protocols' below.)
HEMANGIOBLASTOMAS
Clinical manifestations — Hemangioblastomas are well-circumscribed, capillary vessel-rich benign neoplasms, which do not invade locally or metastasize. However, they can cause symptoms through pressure on adjacent structures and through hemorrhage, due to either the hemangioblastoma itself or cyst formation around the lesion. The clinical presentation and management of sporadic hemangioblastomas are discussed elsewhere. (See "Hemangioblastoma".)
Hemangioblastomas are the most common lesions associated with VHL disease, affecting 60 to 84 percent of patients, and typically occur in the cerebellum, spinal cord, or retina [1,2,7]. Patients with VHL-associated hemangioblastomas tend to be younger than those with sporadic hemangioblastomas with a mean age at diagnosis in one series of 29 years, and a range of 9 to 78 years of age [1]. While sporadic hemangioblastomas usually are solitary and generally do not recur after surgery, lesions in patients with VHL disease tend to be infratentorial and multiple [8]. In a detailed analysis of 160 patients with VHL disease and hemangioblastoma, 655 discrete tumors were identified, of which 51 percent were in the spinal cord, 38 percent in the cerebellum, 10 percent in the brainstem, and 2 percent supratentorial [7].
We recommend that all patients with either a retinal or central nervous system (CNS) hemangioblastoma be tested for VHL germline mutations, even in the case of a single lesion. Where access to genetic investigations is limited, it would be reasonable to focus testing on patients with lesions presenting under the age of 50 years since the likelihood of identifying a germline VHL mutation is inversely correlated with the age of the patient.
In a cohort of 188 consecutive patients presenting with a seemingly sporadic hemangioblastoma, no family history of VHL, and no other evidence of the disease, VHL germline mutations were present in 5 percent of cases [9]. Of those who tested negative, 5 percent developed a VHL-related lesion in the ensuing years, which may result from being mosaic for a VHL mutation. (See 'Somatic mosaicism' below.)
Because CNS hemangioblastomas often initially develop in the second decade, routine screening with magnetic resonance imaging (MRI) of the brain and spinal cord is recommended in patients with VHL disease starting after the age of 10. (See 'Surveillance protocols' below.).
Management — CNS hemangioblastomas can remain dormant for unpredictable periods of time or can present with accelerated growth [7,10]. Currently there are no definitive clinical (eg, age, gender, location), radiographic, or specific molecular markers (ie, underlying mutations) that can predict the natural history of a given lesion, and regular follow-up with imaging and observation of clinical signs and symptoms is necessary.
A review of 225 patients with 1921 CNS hemangioblastomas demonstrated that 51 percent of lesions did not grow. In the remaining 49 percent of hemangioblastomas, 72 percent grew in a saltatory (stepwise), 6 percent in a linear, and 22 percent in an exponential fashion [11]. Partial germline deletions and male sex were associated with increased tumor burden. The unpredictable nature of hemangioblastoma growth emphasizes the need for ongoing surveillance in these patients.
Therapeutic efforts should focus on avoiding treatment-related morbidity by minimizing the frequency of surgical interventions because of the frequent development of multiple lesions. Small asymptomatic lesions can be followed with careful surveillance. Although surgery usually can successfully remove lesions in the spinal cord, brainstem, and cerebellum, intervention is reserved until lesions become symptomatic or they display accelerated growth [7,8,12,13]. Patients who demonstrate progression by neural imaging should be followed at more frequent intervals for evidence of clinical symptoms.
Stereotactic radiosurgery (SRS) and conventional fractionated radiation therapy (RT) may play a role in treating lesions that are not readily accessible by surgery [14,15]. There are no randomized prospective studies that compare the long-term efficacy and safety of SRS with conventional RT for hemangioblastomas. In a prospective observational study performed at the National Institutes of Health, diminishing tumor control over time was observed in lesions treated with SRS [14]. On the basis of these findings, prophylactic treatment of asymptomatic hemangioblastomas with SRS is not recommended, and surgery is still considered the standard of care when feasible [16].
At this time, no effective systemic therapy has been validated for hemangioblastomas. A prospective clinical trial with sunitinib, an antiangiogenic agent, failed to demonstrate response in hemangioblastomas [17]. Preclinical data suggested that inhibitors of fibroblast growth factor receptors (FGFRs) may provide some value in the management of hemangioblastomas. Based on these findings, a case report of response to the antiangiogenic agent pazopanib, which possesses modest FGFR blocking activity, was reported [18]. Further work needs to be done to define the value of specific antiangiogenic agents for hemangioblastomas.
Outcomes with different therapeutic approaches for the management of hemangioblastoma are discussed elsewhere. (See "Hemangioblastoma", section on 'Treatment'.)
RETINAL CAPILLARY HEMANGIOBLASTOMAS — Retinal capillary hemangioblastomas are typically found either in the peripheral retina and/or the juxtapapillary region. Visual loss from retinal capillary hemangioblastomas is generally caused by exudation from the tumor, causing retinal edema or by tractional effects, in which glial proliferation on the surface of the tumor induces retinal striae and distortion [19]. In addition, retinal capillary hemangioblastomas can hemorrhage, leading to retinal detachment, glaucoma, and loss of vision.
Retinal capillary hemangioblastomas are found in up to 70 percent of VHL patients by age 60 years; they are often multifocal and bilateral. Compared with patients with sporadic retinal hemangioblastomas, patients with VHL are much younger and more likely to have multiple lesions. In one series of 31 patients with VHL and 37 patients without VHL disease, the VHL patients were younger (18 versus 36 years of age, respectively), had an average of four tumors, and were more likely to develop new tumors than those without the disease [20].
In a study of 890 patients with VHL, 335 patients had a retinal capillary hemangioblastoma in at least one eye. Lesions were detected unilaterally in 42 percent and bilaterally in 58 percent of affected patients. No correlation was detected between the age, gender, or laterality of involvement. Of involved eyes, 87 percent had tumors that could be individually visualized; of these, tumors were commonly found in the peripheral retina (85 percent) only, and less commonly in the juxtapapillary area (15 percent). The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25 percent of eyes having more than one quadrant of retinal involvement [21]. An assessment of the genotype-phenotype relationship in retinal capillary hemangioblastoma suggested that 15 percent of individuals with complete deletions of VHL protein had hemangioblastoma development versus an overall prevalence in the patient population of 37 percent. The risk of vision loss was found to increase with age although tumor number did not increase significantly as a function of age.
As is the case with seemingly sporadic central nervous system (CNS) hemangioblastomas, any patient presenting with a retinal capillary hemangioblastoma (particularly if prior to age 40) should have a complete evaluation for the presence of VHL. (See 'Clinical manifestations' above.)
Routine surveillance for retinal capillary hemangioblastoma is recommended for patients with VHL disease because of its high frequency. The frequent onset of such lesions during childhood makes it important to initiate ophthalmologic surveillance in the pediatric population and is one of the reasons that genetic testing for VHL mutations in young children is recommended. (See 'Surveillance protocols' below.)
The treatment of retinal capillary hemangioblastoma requires that the benefits of treatment be balanced against potential treatment-related complications. Whether the smallest lesions can be carefully observed without specific treatment until there is any evidence of growth or symptoms is controversial [22]. Some groups recommend that retinal capillary hemangioblastoma be treated immediately upon detection in order to prevent growth and complications, whereas others wait for some change in size before initiating treatment.
Laser photocoagulation and cryotherapy are effective in over 70 percent of cases, generally with a single treatment, and are the preferred methods of treatment [22]. An exception is that hemangioblastomas of the optic nerve should not be treated with these methods because of the deleterious side effects on the normal retina. Photodynamic therapy can also be considered as an option in the treatment of retinal capillary hemangioblastoma, although limited data exist on its efficacy. External beam RT may have a role for salvage therapy if other modalities have failed [23].
Investigational approaches have focused on interfering with angiogenesis. The experimental vascular endothelial growth factor (VEGF) receptor inhibitor semaxinib (SU5416) was reported to successfully reduce peritumoral edema and improve vision in six patients with VHL, although the drug did not reduce the actual tumor size itself [24-27]. This agent is not commercially available.
In a study assessing impact of sunitinib on VHL-related lesions, the very small number of individuals with retinal lesions did not show signs of improvement [17]. In a small study, the VEGF-binding monoclonal antibody ranibizumab produced only a minimal effect in one of five patients [28]. These types of investigational approaches may be useful to reduce the symptoms generated from hemangioblastomas of the optic nerve that are difficult to treat. Further studies need to be performed to better understand the biology of the hemangioblastoma cell of origin and its endothelium, and to develop more effective systemic therapies.
RENAL CELL CARCINOMAS
Clinical presentation — Patients with VHL disease are at risk for developing multiple renal cysts and renal cell carcinomas (RCC), which occur in approximately two-thirds of patients [1]. Virtually all VHL-associated RCCs are clear cell tumors [2]. RCCs of predominant papillary, chromophobe, or oncocytic histology are not associated with VHL disease, but can be associated with other cancer susceptibility syndromes [29,30]. (See "Hereditary kidney cancer syndromes".)
Although the diagnosis of RCC is rare in VHL disease prior to age 20, there are teenage cases of RCC, and screening is initiated in adolescence. RCC occurs with increasing frequency thereafter [1,2,31]. The mean age at onset in one large series was 44 years and it was estimated that 69 percent of patients surviving to age 60 would develop RCC [1]. The incidence of RCC is lower in patients who carry missense mutations in the VHL gene in which pheochromocytoma is prominent, although the same surveillance recommendations apply independently of the mutation type [4]. (See 'Types of VHL disease' above.)
RCCs are often multicentric and bilateral, and can arise either in conjunction with cysts or de novo from noncystic renal parenchyma. Although renal cysts may be benign, they are thought to represent a premalignant lesion; solid components within otherwise benign-appearing renal cysts almost always contain RCC [32]. (See "Simple and complex renal cysts in adults".)
Histopathologic changes in the renal parenchyma are widespread and are not limited to renal cysts [33]. Systematic microscopic analysis identified numerous clear cell abnormalities, which are thought to be precursors for clear cell RCC. Similar clear cell precursors were not seen in the renal parenchyma from patients with sporadic RCC or from patients without RCC.
Growth kinetics of RCC in VHL patients were described in a series of 96 renal tumors in 64 VHL patients with analyzed germline mutations (54 out of 64 treated, 10 out of 64 active surveillance) over a mean follow-up of 55 months [34]. In this series, the mean growth rate of 96 tumors was 4.4 mm/year (standard deviation [SD] 3.2, median 4.1 mm/year), and mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). Obviously, patients with larger lesions or faster growth rates need to have a tailored approach to their follow-up.
The recommended surveillance strategy for early detection of suspicious renal cystic lesions in patients with VHL disease is discussed below. (See 'Surveillance protocols' below.)
Treatment — The therapeutic approach to RCC in patients with VHL disease has shifted from radical nephrectomy to nephron-sparing approaches (observation for small lesions, partial nephrectomy, cryotherapy, and radiofrequency ablation), with the goal of preserving as much renal parenchyma as possible [31,35-37]. Patients diagnosed with VHL disease should be aware of these recommendations and should seek care from a urologist familiar with VHL guidelines if a renal mass is discovered. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
Several factors have contributed to this change:
●Improved imaging modalities (eg, computed tomography [CT], magnetic resonance imaging [MRI], and ultrasound), combined with regular surveillance programs, have led to the identification of more RCCs at an early stage.
●Solid renal tumors <3 cm in diameter generally have a low metastatic potential and can be safely monitored as long as they remain stable. In one study, for example, serial imaging studies were performed in 96 patients with VHL disease and small renal tumors [36]. Surgery was performed in 52 when a tumor reached a threshold size of 3 cm in diameter. Only two patients required nephrectomy, and none developed metastatic disease at a median follow-up of 60 months. In the other 44 patients, this size threshold was not used as an indication for immediate surgery. In this group, 12 patients required nephrectomy, and 11 developed metastatic disease with a median follow-up of 66 months. (See "Diagnostic approach, differential diagnosis, and treatment of a small renal mass".)
●Partial nephrectomy appears to be as effective as total nephrectomy for early stage RCC. Repeated partial nephrectomies may be feasible in carefully selected patients to preserve renal parenchyma and avoid dialysis [37]. The rationale and results with partial nephrectomy for patients with RCC are discussed separately. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
●Other nephron-sparing approaches, particularly cryoablation and radiofrequency ablation, may permit the eradication of multiple small tumors while minimizing damage to the normal kidney. (See "Radiofrequency ablation and cryoablation for renal cell carcinoma".)
Continued close surveillance is required after treatment of RCC in VHL patients. New renal tumors are detected in approximately 30 percent of patients by five years and 85 percent by 10 years. The risk of metastatic disease appears to be low as long as the patient is carefully monitored. However, in one report of 21 such patients, two developed metastatic disease at a median follow-up of 29 months [31].
Renal transplantation has been used in VHL patients who required bilateral nephrectomy for RCC or developed end-stage renal disease. Experience is limited, because of concerns that immunosuppressive therapy might enhance the risk of tumor recurrence. However, this concern was not borne out in at least one study of 32 patients with VHL disease who received renal transplants and 32 matched transplant recipients without VHL disease [38]. At an average follow-up of four years, no differences were observed between the two groups in graft and patient survival or renal function.
Several antiangiogenic agents have been developed for patients with metastatic RCC, with or without a VHL syndrome diagnosis, and sunitinib and pazopanib have been approved as frontline treatment for patients with metastatic disease [39]. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma".)
Systemic therapy options are being studied in patients with VHL disease and RCC. With the advent of vascular endothelial growth factor (VEGF)-targeted therapy that can decrease the size of RCC lesions, it may be possible to decrease frequency of surgical intervention through chronic or intermittent use of currently available agents. A clinical trial assessing sunitinib in 15 VHL patients showed a 33 percent partial response rate [17]. An ongoing clinical trial is testing pazopanib in the same patient population (NCT ).
PHEOCHROMOCYTOMAS
Clinical features — Pheochromocytomas are seen both sporadically and in association with a number of genetic syndromes, including VHL disease, multiple endocrine neoplasia type 2, mutations of the succinate dehydrogenase (SDH) subunits A, B, D, and C, and rarely, neurofibromatosis type 1. The different familial syndromes manifesting pheochromocytomas are discussed in detail elsewhere. (See "Pheochromocytoma in genetic disorders".)
All patients with pheochromocytoma should have a genetic evaluation to identify the underlying syndrome so that proper surveillance can be initiated for other tumors for which the patient is at risk. Given the increasing number of genes associated with these tumors, genetic testing generally relies on a multi-gene next-generation sequencing panel for making the appropriate genetic diagnosis. The presence of pheochromocytoma is used to define types 2A-C VHL disease.
In one evaluation of 271 patients with apparently sporadic pheochromocytoma (no other tumors or family history of the disease) from population-based registries in Germany and Poland, all were tested for germline mutations in VHL and only three of the other genes (RET, SDHB, SDHD) that have been implicated in familial pheochromocytoma [40]. A germline VHL mutation was identified in 30 patients overall (11 percent) and in 42 percent of those who presented at age 18 or younger. A positive family history had been established at last follow-up in 12 of the 30 patients and at least four others had a de novo germline VHL mutation since both parents tested negative. (See "Clinical presentation and diagnosis of pheochromocytoma".)
Pheochromocytomas in VHL disease tend to be seen in younger patients, are often multiple, may be extra-adrenal, and are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL [41-44]. Pediatric cases of pheochromocytomas are not infrequent [45,46].
Two large series illustrate the clinical characteristics of pheochromocytomas in patients with VHL disease:
●In a report from the National Institutes of Health of 64 patients with VHL disease and pheochromocytomas, a total of 106 tumors were identified [43]. Of these, 12 percent originated outside the adrenal gland and 35 percent of patients were asymptomatic, without hypertension or evidence of increased catecholamine production.
●In the Mayo Clinic experience, 20 of 109 patients with VHL disease (18 percent) had a pheochromocytoma at a median age of 30 years, including three originating outside the adrenal gland [42]. Detailed analysis of these patients failed to reveal evidence of catecholamine production in one-third.
Tumors that produce catecholamines may be associated with the typical clinical signs and symptoms of pheochromocytomas, including hypertension, diaphoresis, tachycardia, and apparent mood changes.
The possibility of an occult pheochromocytoma needs to be considered whenever a patient with VHL disease requires surgery because of the potential risk of anesthetic complications, including sympathetic overactivity and severe hypertension.
Diagnosis — In addition to the surveillance described below, pheochromocytomas can be detected with radiographic imaging via plasma metanephrine/normetanephrine testing and, less commonly, urine metanephrine/normetanephrine testing. (See 'Surveillance protocols' below.)
Conventional imaging may not be sufficient because of the potential for extra-adrenal lesions, referred to as paragangliomas. Studies with 18F-DOPA PET provide some context and suggest that metaiodobenzylguanidine (MIBG) scanning is not effective at detecting pheochromocytomas in patients with VHL:
●A pilot study of 18F-DOPA PET in seven patients with VHL indicated a high detection rate (7 out of 7), as did computed tomography (CT) scan. On the other hand [(123/131)I]-MIBG scintigraphy failed to detect 4 of the 7 lesions [47].
●These data were confirmed in an independent study of 48 patients with hereditary and nonhereditary cases [48].
●In a prospective study assessing adrenal imaging of 52 patients with VHL disease, 390 lesions were identified by CT (n = 139), magnetic resonance imaging (MRI; n = 117), 18F-FDG PET (n = 94), and 18F-DOPA PET (n = 40). 18F-DOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6 percent of patients and 4.4 percent of lesions [49].
●In a prospective study of 197 patients with VHL-associated pancreatic lesions, clinical and imaging characteristics were analyzed to study the associations between 18F-FDG PET uptake, tumor growth, and the development of metastatic disease. Metastatic disease was detected by 18F-FDG PET in three patients in whom it was not detected by CT scan and suggested non-neoplastic disease in an additional three patients.
Measurement of plasma metanephrines and normetanephrines provides important diagnostic information. In a study of patients with VHL disease and multiple endocrine neoplasia type 2 (MEN-2), measurements of plasma normetanephrines and metanephrines provided a sensitivity of 97 percent and a specificity of 96 percent [50]. VHL patients almost exclusively produced normetanephrines (indicating norepinephrine production), so a high normetanephrine to metanephrine ratio is expected in patients with VHL disease.
Management — The treatment of choice for symptomatic pheochromocytomas is surgical removal after appropriate alpha-adrenergic blockade and other supportive measures, if needed [51].
It is critical to follow established protocols to suppress catecholamine production in the preoperative period, and follow patients carefully perioperatively and postoperatively for several weeks to ensure that endocrine and cardiovascular function has not been compromised by prolonged overproduction of catecholamines. Additional information on the pharmacologic management of patients with pheochromocytoma prior to surgery is discussed elsewhere. (See "Treatment of pheochromocytoma in adults" and "Pheochromocytoma in children".)
ENDOLYMPHATIC SAC TUMORS OF THE MIDDLE EAR
Manifestations — Papillary cystadenomas of the endolymphatic sac are highly vascular lesions arising within the posterior portion of the temporal bone [52]. Common clinical manifestations include hearing loss, tinnitus, vertigo, and less often, facial muscle weakness [52-55].
Three mechanisms have been described to account for the hearing loss and other symptoms associated with endolymphatic sac tumors (ELSTs) [55].
●Tumors can invade the otic capsule, resulting in destruction of the membranous labyrinth and disruption of endolymphatic flow.
●Sudden, irreversible hearing loss may be due to intralabyrinthine hemorrhage.
●Gradual onset of hearing loss, tinnitus, and vertigo can be caused by blockage of endolymphatic sac resorption of fluid (hydrops).
Although these tumors also occur sporadically, they arise at a younger age in VHL patients, in whom they are often bilateral. In one series, for example, bilateral tumors were present in 28 percent of the patients with VHL versus 1 percent in the patients without VHL disease [54]. In two other reports in VHL patients, 5 of 34 tumors (15 percent) were bilateral [52,53].
ELSTs are common in patients with VHL disease, within an incidence of approximately 15 percent on detailed evaluation [52-54,56-58].
Diagnosis — ELSTs may be difficult to detect with a single modality. Patients with VHL disease should be questioned annually about any auditory or vestibular symptoms with routine audiology performed for surveillance. Any patient with abnormalities in auditory tests should be screened for the presence of these tumors by computed tomography (CT) of the skull base or magnetic resonance imaging (MRI) with fine cuts of the temporal bones [52]. These lesions can be very difficult to see radiographically. Whether surgery is indicated for patients with an asymptomatic tumor is controversial [55], and additional studies are required to assess the risk of acute hearing loss in such patients.
Radiologic findings include retrolabyrinthine location, intratumoral calcification on CT scan, hyperintense focal signals on T1-weighted (noncontrast-enhanced) MRI, and a heterogeneous signal on T2-weighted MRI scan [59,60]. Visualization of these lesions requires dedicated images, and ELSTs will often be missed on brain MRI scans ordered for surveillance of cerebellar hemangioblastoma.
In a prospective 40-patient study, ELSTs were suspected based on audiovestibular symptoms, audiometry, and MRI in 34, 30, and 12.5 percent of subjects, respectively. More than 90 percent of radiologically diagnosed ELSTs were associated with abnormal audiometric findings [61].
Management — Management of ELSTs needs to consider the presence and severity of symptoms, their generally slow growth rate, and the potential complications associated with surgery. Treatment of ELSTs is primarily surgical; if the lesions can be completely excised, surgery is curative [62-64]. Stereotactic radiosurgery may have a role for recurrent disease [65].
Cochlear implants may be an option for patients with hearing loss due to bilateral ELSTs [66]. (See "Hearing amplification in adults", section on 'Cochlear implants'.)
PANCREATIC TUMORS — Pancreatic abnormalities are common in patients with VHL disease. In a multi-institutional study of 158 consecutive patients from 94 affected families, 77 percent had lesions in the pancreas, including cysts (70 percent), serous cystadenomas (9 percent), and neuroendocrine tumors (9 percent) [67]. In another series of 633 patients with VHL disease, neuroendocrine tumors were identified in 108 (17 percent) [68].
Simple pancreatic cysts and serous cystadenomas may be asymptomatic even when the radiologic presentation is dramatic. However, such lesions can cause epigastric pain and discomfort [69,70]. Pancreatitis and pancreatic failure are exceedingly rare complications, although some degree of exocrine pancreatic dysfunction has been reported. Asking about change in stool characteristics and digestive patterns should be part of a comprehensive review of systems with VHL patients who have pancreatic cysts. Mucinous cysts of the pancreas are not seen in association with VHL disease, and VHL patients do not have an increased risk of pancreatic adenocarcinoma. (See "Classification of pancreatic cysts".)
Neuroendocrine tumors of the pancreas can metastasize to the liver and may produce symptoms due to secreted peptides (eg, diarrhea from vasoactive intestinal peptide and hypoglycemic episodes from insulin) [67]. In one series of 108 patients with neuroendocrine tumors, nine (8 percent) had metastatic disease [68].
However, most of these tumors are asymptomatic and grow slowly for prolonged periods without producing symptoms of peptide overproduction. In two combined series, none of 25 patients had symptoms related to peptide hormone secretion [67,71]. As a result, many of these lesions are diagnosed incidentally during routine VHL surveillance for renal lesions [68]. (See 'Surveillance protocols' below.)
Management of pancreatic neuroendocrine tumors is surgical. Resection is generally reserved for lesions greater than 3 cm in diameter in the body or tail of the pancreas, or 2 cm in diameter in the head of the pancreas [68,72]. Smaller asymptomatic lesions may be monitored with imaging at yearly intervals. In a study of 108 VHL patients with pancreatic neuroendocrine tumors, tumors <3 cm, with a doubling time >500 days, and mutations in VHL gene exons 1 or 2 had a minimal risk for metastasis, suggesting that such patients could be managed with observation [68].
PAPILLARY CYSTADENOMAS OF THE EPIDIDYMIS AND BROAD LIGAMENT — Papillary cystadenomas occur in both the epididymis in men and the broad ligament in women (also known as adnexal papillary tumors of probable mesonephric origin) [73]. Single epididymal cysts are common in the general population and should not raise suspicion for VHL disease in the absence of other VHL-related findings. On the other hand, bilateral papillary cystadenomas are almost pathognomonic of VHL disease [2,74]. In one series of 56 patients with VHL who were screened with both ultrasound and physical examination, 30 had epididymal abnormalities, two-thirds of which were bilateral. Papillary cystadenomas are benign and generally asymptomatic, and no treatment is required [74]. (See "Evaluation of nonacute scrotal pathology in adult men".)
Papillary cystadenomas in the broad ligament in women are also asymptomatic in most patients, and thus the true incidence of these lesions is unknown [75,76]. Symptoms that have been reported include pain, dyspareunia, and menorrhagia; treatment is symptomatic.
VHL MUTATIONS IN SPORADIC TUMORS — Sporadic renal cell carcinomas (RCCs), pheochromocytomas, endolymphatic sac tumors (ELSTs), and hemangioblastomas frequently have acquired somatic (as opposed to germline) abnormalities involving the VHL gene, supporting a role for the VHL gene in tumorigenesis in sporadic cases [29,58,77-81]. As noted above, two hits appear to be required in VHL disease in both the hereditary and sporadic tumors. The hits can result from inherited mutations, somatic mutations followed by loss of heterozygosity, or loss of gene expression caused by promoter hypermethylation. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
The following observations illustrate the frequency with which this occurs:
●Somatic mutations of the VHL gene and/or allelic deletion may be present in as many as 50 percent of sporadic hemangioblastomas. (See "Hemangioblastoma", section on 'Molecular biology'.)
●Abnormalities of the VHL gene are also found in 50 to 60 percent of patients with sporadic RCC, suggesting that the VHL gene has a role in pathogenesis in this setting as well. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Von Hippel Lindau gene'.)
●VHL gene abnormalities in apparently sporadic pheochromocytoma are observed less commonly (in 4 percent of benign lesions and in 17 percent of malignant tumors in a series of 72 patients) [79]. However, some of these patients actually have germline mutations and, therefore, VHL disease [40]. (See 'Pheochromocytomas' above.).
DIAGNOSIS
Genetic testing — Although clinical criteria were originally developed for the diagnosis of VHL disease primarily based upon the finding of more than one VHL-associated tumor, detection of a germline mutation in the VHL gene now is typically used to establish the diagnosis, particularly in patients who undergo genetic testing after being diagnosed with a single manifestation of the condition or are tested as the result of having a close relative diagnosed with VHL disease [2,39].
Genetic testing, which is typically performed on peripheral blood lymphocytes, involves DNA sequencing, using either primer-based exonic sequencing or next-generation sequencing (NGS) techniques. Gene copy number loss is assessed using read-depth from NGS data [82] or confirmed directly using a targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA) [83]. Many patients now undergo genetic testing using larger multi-gene panels by NGS analysis that include the VHL gene as one of the cancer susceptibility genes under study, including those cancer patients undergoing paired tumor/normal sequencing [84].
Germline mutations in the VHL gene can be inherited or arise de novo. The latter frequency has been reported to be as high as 20 percent of VHL patients in older studies, although this has not explored in detail in more recent studies [85]. Rare patients may have the clinical features of VHL without a detectable mutation due to mosaicism for the VHL mutation. (See 'Somatic mosaicism' below.).
Patients suspected of having VHL disease should be referred to specialized centers for evaluation, genetic counseling, and definitive diagnosis, even if there is no family history of VHL disease. Approved VHL Clinical Care Centers are listed at the VHL Alliance website. These centers have been approved for standards of care that were developed by the VHL Alliance’s Medical Advisory Board.
Comprehensive genetic testing of the VHL gene should be based on the presence of one or more characteristic lesions. Proposed criteria for testing are summarized in the table (table 2). Testing for a specific familial VHL mutation should then be performed for at-risk relatives based upon having a blood relative with an established diagnosis of VHL disease.
Over the last five years, there has been an increasing use of whole-exome sequencing for diagnosis of Mendelian disorders [86]. Given this change in practice, there are now recommendations by the American College of Medical Genetics and Genomics for the reporting of the incidental (or secondary) findings of pathogenic or likely pathogenic variants in a list of 56 genes (including the VHL gene), even if the original indication for testing was unrelated to a cancer diagnosis [87]. Thus, there is the likelihood that individuals, particularly young children, will be molecularly diagnosed with presymptomatic VHL disease prior to any features of the disorders.
Somatic mosaicism — In a patient with somatic mosaicism, a mutation occurs during embryonic development after fertilization; in these circumstances, some cells will be normal while others carry the mutation. In contrast to detecting germline mutations, diagnostic difficulties are more likely as the clinical presentation depends on the proportion of cells that carry the VHL mutation [88,89]. Although an individual with somatic mosaicism may present with classic VHL disease, the mutation may not be detectable in the peripheral blood because the hematologic stem cells do not carry the mutation.
Thus, the possibility of mosaicism should be considered in patients presenting with VHL-associated tumors and a negative VHL genetic test using peripheral blood cells. The disease manifestations in such patients are dependent upon when the de novo mutation event occurred in embryogenesis. The earlier the new mutation occurred, the more tissue types are likely to be affected. Testing for mosaicism can include genetic testing on skin fibroblasts or on buccal mucosal cells. The use of NGS technologies also provides increased opportunities to detect VHL variants that exist at very low levels in the circulation [90]. Testing of multiple tumors from the same patient with mosaicism can sometimes provide information on the causative mutation but should be interpreted by an experienced geneticist or genetic counselor.
Genetic counseling — Patients should be referred for appropriate genetic advice in conjunction with testing for VHL mutations [39]. VHL disease is inherited in an autosomal dominant fashion, and affected individuals have a 50 percent probability of transmitting the VHL mutation to each offspring.
Among patients with somatic mosaicism, the risk to offspring depends upon whether or not the germ tissue carries the mutation, although that cannot be determined clinically. Thus, patients with documented mosaicism should be counseled that their risk of having an affected child may be as high as 50 percent and the affected child will inherit the mutation in 100 percent of their cells and potentially have more severe manifestations of the disease.
The diagnosis of VHL in a child of unaffected parents can be very alarming, and the concept of de novo mutations should be carefully explained. In particular, parents should be reassured and potential guilt alleviated by explaining that the mutation is unlikely to be the result of any action that occurred immediately prior to or during the pregnancy.
There is increasing awareness of the concern of parents as to when to provide information about the diagnosis to children with a positive VHL genetic test. In general, it is best for this information to be conveyed in multiple settings as the child's maturity increases, and parents may benefit from the support of a medical professional in initiating these discussions [39].
PREGNANCY AND VHL — Prospective parents planning or carrying a pregnancy at risk for VHL disease have multiple options for learning the VHL mutation status of the fetus. The couple may choose not to know until after the child is born. If prenatal genetic testing is not performed, then all at-risk children should be tested for the VHL mutation found in the affected parent in order to determine whether or not the VHL disease surveillance regimen is required.
A couple may choose prenatal diagnosis after pregnancy is initiated, utilizing a sample obtained by amniocentesis or chorionic villus sampling. Some couples that choose prenatal diagnosis wish to know the carrier status prior to birth in order to prepare, while others may elect to terminate a pregnancy if the fetus is affected. Prospective parents should also be provided with information about reproductive technologies that greatly lower their risk of having a child with VHL disease, such as sperm or oocyte donation (depending on which parent is affected), and preimplantation genetic diagnosis. The latter involves testing embryos fertilized in vitro for the familial VHL mutation, usually on a single cell of a blastocyst, and selecting unaffected embryos for implantation [91]. The various reproductive options available to prospective parents require thoughtful discussion and genetic counseling. (See "Preimplantation genetic diagnosis".)
Whether VHL-related lesions demonstrate new or accelerated growth during pregnancy is controversial [92-94]. Nevertheless, it is prudent to take particular care during follow-up of these individuals, especially if they have a prior history of pheochromocytomas, CNS lesions, or retinal lesions [92,93].
All women with pheochromocytomas need to have these surgically removed before attempting to become pregnant. Growth or development of pheochromocytomas can have catastrophic consequences during pregnancy and delivery, so plasma metanephrine and normetanephrine testing during early and late pregnancy is warranted.
Women with existing retinal, brain, and spinal cord lesions may be at increased risk for tumor growth during pregnancy [93,95]. Eyes should be checked regularly throughout the pregnancy, and noncontrast magnetic resonance imaging (MRI) may be considered in the fourth month to follow up on CNS lesions. Delivery via cesarean section should be considered to lower the probability of developing increased intracranial pressure.
SURVEILLANCE PROTOCOLS — Morbidity and mortality in patients with VHL disease have decreased substantially due to an improved understanding of the natural history of the serious clinical manifestations of the disorder, better imaging techniques, and improvements in therapy. Surveillance is important not only to detect new lesions at an early stage, but also to monitor small asymptomatic lesions for evidence of progression.
Surveillance has focused primarily on hemangioblastomas (including retinal capillary hemangioblastomas), renal cell carcinomas (RCCs), and pheochromocytomas, the three manifestations most often resulting in severe disability or death. Surveillance recommendations need to be adapted to the individual patient, taking into account the presence of previously diagnosed asymptomatic disease and disease manifestations in other members of the family. However, there is variability within families, and patients should understand that they may develop manifestations of VHL disease that were not seen in their affected relatives.
There is some controversy concerning the optimal frequency for various imaging and screening procedures, which attempts to balance the risks and costs versus the potential for a delayed diagnosis. The following summarizes recommendations made by the VHL Alliance in conjunction with their Medical Advisory Board.
Ages 1 to 4
Annually
●Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist skilled in diagnosis and management of retinal disease, especially for children known to carry the VHL mutation.
●Pediatrician to look for signs of neurological disturbance, nystagmus, strabismus, white pupil, and abnormalities in blood pressure, vision, or hearing.
Ages 5 to 15
●Physical examination and neurological assessment by a pediatrician informed about VHL disease, with particular attention to blood pressure (lying and standing), hearing issues, neurological disturbance, nystagmus, strabismus, white pupil, and other signs which might indicate the need for a referral to a retinal specialist.
●Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL, using a dilated exam.
●Test for plasma metanephrines or urinary metanephrines using 24-hour urine test.
●Abdominal ultrasonography annually from eight years or earlier if indicated. Abdominal magnetic resonance imaging (MRI) or functional imaging scan only if biochemical abnormalities are found.
Every 2 to 3 years
●Complete audiology assessment by an audiologist annually if any hearing loss, tinnitus, or vertigo is found.
●In the case of repeated ear infections, MRI with contrast of the internal auditory canal using thin slices, to check for a possible endolymphatic sac tumor (ELST).
Ages 16 and beyond
●Eye/retinal examination with indirect ophthalmoscopy using a dilated examination by an ophthalmologist informed about VHL disease.
●Quality ultrasound and MRI scan of the abdomen with and without contrast to assess kidneys, pancreas, and adrenals at least every other year, but not during pregnancy.
●Physical examination by a clinician informed about VHL disease.
Every 2 years
●MRI with contrast of brain, cervical, thoracic, and lumbar spine with thin cuts through the posterior fossa, and attention to inner ear/petrous temporal bone to rule out both ELST and hemangioblastomas.
●Audiology assessment by an audiologist.
During pregnancy — A review of VHL progression during pregnancy at one VHL center in the Netherlands demonstrated that there appeared to be accelerated growth of cerebellar hemangioblastoma in the two years around pregnancy [93], although this was not observed in a second series [95]. In addition, there were a number of VHL-related pregnancy complications which suggest that women with VHL who are pregnant should have close follow-up.
●Regular retinal checkup to anticipate potentially more rapid progression of lesions.
●Test for pheochromcytoma in early, mid, and again late pregnancy to ensure that there is no active pheochromcytoma during pregnancy or, especially, labor and delivery.
●During the fourth month of pregnancy, MRI – without contrast – to check on any known lesions of the brain and spine. If known retinal, brain, or spinal lesions, consider caesarean section [96].
ADDITIONAL RESOURCES — Summary information concerning VHL disease may be useful for counseling patients and affected families. The following organization can provide such information:
VHL Alliance
2001 Beacon Street, Suite 208
Boston, MA 02135
Telephone:
Toll free number in the United States and Canada: VHL
FAX:
The VHL Handbook is available in eight languages as a download on the web or through the VHL Alliance office. The handbook is a reference guide for patients and their health care teams.
SUMMARY AND RECOMMENDATIONS — Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. The spectrum of VHL-associated tumors includes hemangioblastomas (including retinal hemangioblastomas), clear cell renal cell carcinomas (RCCs), pheochromocytomas, endolymphatic sac tumors (ELSTs) of the middle ear, serous cystadenomas and neuroendocrine tumors of the pancreas, and papillary cystadenomas of the epididymis and broad ligament.
The primary goal of management for patients with VHL disease is the early diagnosis and treatment of tumors that otherwise might cause severe disability or death:
●The diagnosis of VHL disease is based upon the detection of a germline mutation in the VHL gene and rarely by multiple VHL-associated tumors in the absence of a germline mutation. (See 'Diagnosis' above.)
●With the increasing use of next-generation sequencing test methods in the care of cancer patients, there is likely to be an increase in the diagnosis of VHL disease in patients with the apparently sporadic forms of VHL-associated tumors, as well as, more rarely, from incidental findings in patients undergoing whole exome or genome sequencing for other indications. Changes in ascertainment, for example by secondary finding analysis in patients undergoing whole genome or whole exome sequencing, may result in an apparent amelioration of the disease burden since current knowledge is primarily based on individuals presenting with symptomatic disease and their close relatives. (See 'Diagnosis' above.)
●Central nervous system hemangioblastomas are the most common lesions in patients with VHL disease, and tend to be multiple and infratentorial. Annual retinal examinations should be initiated beginning in infancy or early childhood to diagnose and treat retinal hemangioblastomas at an early enough stage to preserve vision. Every other year, imaging of the brain and spinal cord with magnetic resonance imaging (MRI) starting after the age of 15 years is indicated to establish the diagnosis and minimize disease-related complications. (See 'Hemangioblastomas' above and 'Surveillance protocols' above.)
●Clear cell RCCs occur in approximately 70 percent of VHL patients who survive to 60 years of age. Annual imaging of the kidneys with MRI or computed tomography (CT) is indicated to establish the diagnosis. For patients in whom an RCC is diagnosed, we recommend a nephron-sparing approach to remove lesions that are 3 cm or larger whenever possible (Grade 1B). (See 'Renal cell carcinomas' above and "Radiofrequency ablation and cryoablation for renal cell carcinoma" and "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
●Pheochromocytomas tend to be seen in younger patients, are often multiple or extra-adrenal, and although symptoms can be present, are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL disease who are primarily diagnosed based on the presence of symptoms. Annual assessment of plasma metanephrines should begin with young children. Annual imaging of the abdomen for pheochromocytomas and pancreatic tumors should be initiated during adolescence. (See 'Pheochromocytomas' above.)
●ELSTs are slowly-growing lesions that can cause significant hearing loss and may be bilateral. Baseline audiometry and brain MRI should be carried out in adolescents. Retesting and appropriate imaging are indicated if there are symptoms of ringing, tinnitus, pain, or change of auditory acuity. (See 'Endolymphatic sac tumors of the middle ear' above.)
●Prospective parents planning or carrying a pregnancy at risk for VHL disease should be offered genetic counseling and should also be provided with information about reproductive technologies that lower their risk of having a child with VHL (see 'Genetic counseling' above). Additionally, women who plan to or become pregnant may need a much higher level of surveillance than usual. (See 'Pregnancy and VHL' above and 'During pregnancy' above.)
Epididimis cystadenomas %
Binderup et al. Von Hippel-Lindau disease (vHL) National clinical guideline for diagnosis and surveillance in Denmark 3rd Edition Danish Medical Journal · December 2013

11. Classification
based upon the likelihood of developing pheochromocytoma
Important for prognosis and surveillance
TYPES OF VHL DISEASE — Families with VHL disease have been divided into types 1 and 2, based upon the likelihood of developing pheochromocytoma [4]. Type 2 families are more likely to carry a missense mutation in the VHL gene.
●Type 1 – Patients in kindreds with type 1 disease have a substantially lower risk of developing pheochromocytomas, although they are at high risk for the other VHL-associated lesions.
●Type 2 – Kindreds with type 2 disease are at high risk for developing pheochromocytoma. Type 2 disease is subdivided based upon the risk of developing renal cell carcinoma (RCC). Type 2A and 2B families have a low and high incidence of RCC, respectively, while type 2C kindreds are characterized by the development of pheochromocytomas only, without RCC or hemangioblastoma. These subclassifications should be used as a guide and are not absolute. Continued surveillance for other VHL-related lesions should continue, for example, in individuals who present with type 2C characteristics.
The goal of improving survival and quality of life in patients with VHL disease has been aided by a better understanding of the natural history of VHL-associated tumors [5]. As a result, surveillance strategies have been developed for affected individuals, which have led to the detection of small, asymptomatic tumors prior to the development of metastases or other complications. In addition, therapeutic advances (eg, renal-sparing surgery in RCC) have improved outcomes by decreasing the incidence of renal failure when therapy is required. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
The molecular pathogenesis of VHL disease is discussed elsewhere. A "two-hit" model appears to apply to this disorder. Affected patients have a germline mutation that inactivates one copy of the VHL gene in all cells. For disease to occur there must be loss of expression of the second, normal allele through somatic mutation or deletion of the second allele, or through hypermethylation of its promoter. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
Neumann and Wiestler (1991) classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). Brauch et al. (1995) further subdivided VHL type 2 into type 2A (with pheochromocytoma) and type 2B (with pheochromocytoma and renal cell carcinoma). Hoffman et al. (2001) noted that VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma.
Binderup et al. Von Hippel-Lindau disease (vHL) National clinical guideline for diagnosis and surveillance in Denmark 3rd Edition Danish Medical Journal · December 2013

12. 2 clinical features Diagnostic criteria The retina: Hemangioblastoma
The cerebellum, the medulla oblongata, or the spinal cord: Hemangioblastoma
The inner ear: Endolymphatic sac tumour (ELST)2
The kidneys: Renal cell carcinoma
Pheochromocytoma, paraganglioma, and/or glomus tumour
The pancreas: Neuroendocrine neoplasms and/or multiple cysts
manifestation And pathogenic VHL mutation OR at least one first-degree relative with VHL
Binderup et al. Von Hippel-Lindau disease (vHL) National clinical guideline for diagnosis and surveillance in Denmark 3rd Edition Danish Medical Journal · December 2013

13. Criteria for referral to a von Hippel-Lindau (VHL) clinic: MGH (Massachusetts General Hospital)
Exactly normetanephrine type secretion
Management of von Hippel-Lindau Disease: An Interdisciplinary Review 2014

14. Surveillance 1-4 YO Annual
indirect ophthalmoscopy by an ophthalmologist skilled in retinal disease, esp. for children with VHL
Pediatrician:neurological, Blood pressure, vision/hearing disturbances, nystagmus, strabismus, white pupil,
5 -15 YO Annual item 1 +
plasma metanephrines and/or urinary metanephrines using 24-hour urine test
Abdomen US high quality since 8YO/ or earlier if indicated. Abdominal MRI or functional imaging (MIBG) scan only if biochemical abnormalities are found
Every 2-3 year
audiology assessment annually if any hearing loss, tinnitus, or vertigo is found
In the case of repeated ear infections, MRI with contrast of the internal auditory canal using thin slices, to check for a possible endolymphatic sac tumor (ELST).
16 & > Annual item 1,2 +
MRI -/+ iv contrast : kidney, pancreas, adrenal glands, but not during pregnancy
Every 2 year
MRI + iv contrast brain, whole spine
audiology assessment
SURVEILLANCE PROTOCOLS — Morbidity and mortality in patients with VHL disease have decreased substantially due to an improved understanding of the natural history of the serious clinical manifestations of the disorder, better imaging techniques, and improvements in therapy. Surveillance is important not only to detect new lesions at an early stage, but also to monitor small asymptomatic lesions for evidence of progression.
Surveillance has focused primarily on hemangioblastomas (including retinal capillary hemangioblastomas), renal cell carcinomas (RCCs), and pheochromocytomas, the three manifestations most often resulting in severe disability or death. Surveillance recommendations need to be adapted to the individual patient, taking into account the presence of previously diagnosed asymptomatic disease and disease manifestations in other members of the family. However, there is variability within families, and patients should understand that they may develop manifestations of VHL disease that were not seen in their affected relatives.
There is some controversy concerning the optimal frequency for various imaging and screening procedures, which attempts to balance the risks and costs versus the potential for a delayed diagnosis. The following summarizes recommendations made by the VHL Alliance in conjunction with their Medical Advisory Board
A reference handbook for people with von Hippel-Lindau,their families, and their medical team Written by the VHL Alliance Edition 5 Revised 2015

15. «The Dandelion effect»
Treatment strategy
«The Dandelion effect»
Dandelions demonstrate that cells need to mature to a certain
point before they know how to send out seeds and plant more tumors in other places. There is
no need to pull up every green one, but it is important to pick them while they are yellow
A reference handbook for people with von Hippel-Lindau,their families, and their medical team Written by the VHL Alliance Edition 5 Revised 2015

16. Papers in Russia
1.Treatment options for renal cell carcinoma in patients with von Hippel-Lindau disease. Tsimafeyeu I, Demidov L.J Cancer Res Ther Oct-Dec;6(4): doi: / PMID:
2.Von Hippel—Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipomaТипа Архив патологии O.V. Dolzhansky1, M.M. Morozova1, S.A. Korostelev2, I.V. Kanivets2, N.K. Chardarov1, G.A. Shatveryan1, E.M. Paltseva1, D.N. Fedorov1 1Acad. B.V. Petrovsky Russian Surgery Research Center, Moscow; 2Research Center for Medical Genetics, Moscow, Russia
3. М.И. Комаров, И.В. Поддубная ДВУХСТОРОННИЙ РАК ПОЧЕК, ЭТИОЛОГИЯ И ПАТОГЕНЕЗ ФГБУ «РОНЦ им. Н.Н. Блохина» РАМН, Москва№ 3/том 12/2013 РОССИЙСКИЙ БИОТЕРАПЕВТИЧЕСКИЙ ЖУРНАЛ
4. М.Ю. ЮКИНА , проф. А.Н. ТЮЛЬПАКОВ, проф. Е.А. ТРОШИНА, д.м.н. Д.Г. БЕЛЬЦЕВИЧ Болезнь фон Гиппеля—Линдау (VHL-синдром) ПРОБЛЕМЫ ЭНДОКРИНОЛОГИИ, 2, доклад клинического наблюдения в журнале Ожирение и метаболизм
5. Г.Ю. Евзиков, ЛЕЧЕНИЕ МНОЖЕСТВЕННЫХ ГЕМАНГИОБЛАСТОМ СПИННОГО МОЗГА И ПРОДОЛГОВАТОГО МОЗГА У ПАЦИЕНТА С БОЛЕЗНЬЮ ГИППЕЛЯ — ЛИНДАУ. КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ И ОБЗОР ЛИТЕРАТУРЫ НЕВРОЛОГИЧЕСКИЙ ЖУРНАЛ, № 3, 2013
6. Ф. Е. Шадричев а Болезнь Гиппеля–Линдау ОФТАЛЬМОЛОГИЧЕСКИЕ ВЕДОМОСТИ Том I №
7. Б.Я. Алексеев, Органосохраняющее лечение больных с VHL-синдромом Oнкология. Журнал им. П.А. Герцена, 5, 2014
8. УМАНЕЦ Н.Н., ЛАКИЗА А.ВПРИМЕНЕНИЕ ВЫСОКОЧАСТОТНОЙ ЭЛЕКТРОСВАРКИ БИОЛОГИЧЕСКИХ ТКАНЕЙ ДЛЯ ГЕМОСТАЗА ПРИ ЭНДОРЕЗЕКЦИИ ГЕМАНГИОМЫ В ХОДЕ ВИТРЭКТОМИИ У ПАЦИЕНТОВ С СИНДРОМОМ ГИППЕЛЬ - ЛИНДАУ. Институт глазных болезней и тканевой терапии им В.П. Филатова НАМН Украины Офтальмологический журнал 2013
9. Яковлева Екатерина Сергеевна; Эффективность антиангиогенной терапии и прогностическое значение гена VHL у больных метастатическим раком почки : диссертация кандидата медицинских наук : ГУ "Российский онкологический научный центр РАМН"

17. Endocrinology Scientific Center experience (greatest in RF)
Yukina, Lysenko. Moscow 2013 «Diagnosis and perioperative management in patients suffered from pheochromocytoma».
61 VHL patients

19. Epidemiology of pancreatic involvement on VHL
Pancreatic lesions: may be НВ & ccRCC mets
Simple Cysts %
SCA %
pNETs %
Pancreatic lesions are the sole abdominal manifestation in up to 12% of patients with VHL at initial diagnosis
VHL 2 type correlation
Distribution head %, body %, tail – %
uncinate process– «hotspot» for pNETs
O(I) blood
Association of Type O Blood with Pancreatic Neuroendocrine Tumors in Von Hippel–Lindau Syndrome. Ann Surg Oncol (2012) 19:2054–2059

20. symptoms (biliary compression, pain) 17 %
VHL SCA
symptoms (biliary compression, pain) %
Need for surgical procedure %
Neither IPMN no MCN publication in VHL
There is no malignancy potential
every 2 years as part of a natural history monitoring protocol for VHL associated SCA
can rarely develop endocrine or exocrine pancreatic insufficiency
Evaluation and management of pancreatic lesions in patients with von Hippel–Lindau diseaseNat Rev Clin Oncol Sep;13(9):

21. VHL pNETs Synchronously multiple pNETs 53 %
The incidence rate of new pNETs in patients with VHL disease has been reported to be one lesion per 112 patient months
Natural history of VHL-associated pNET
% - enlargement
20% - stable
20% - decrease
Malignancy , %
pNETs associated death , %
VHL pNETs versus sporadic pNETs:
Mean age manifestation vs 56 лет
Malignant potential vs %
Contrast CT surveillance Annual
Evaluation and management of pancreatic lesions in patients with von Hippel–Lindau diseaseNat Rev Clin Oncol Sep;13(9):

22. Diagnosis Chromogranin А low efficacy in VHL unlike in sporadic NETs.
CT + iv contrast sensitivity – 94 %
Endoscopic ultrasonography, with or without needle -biopsy sampling, should be reserved for use in patients with difficult-to‑diagnose pancreatic or peripancreatic lesions, or in patients with renal insufficiency and contraindications to intravenous contrast injection for CT and/or MRI
Functional visualization
68Ga DOTATATE PET CТ - sensitivity % и specificity 91%, use for:
1.diff ds: SCA и pNETs , 2. distant mets, 3. сN+, 4. G1, и G3 pNETs
18F FDG PET CТ distant mets, сN+, detect only G3 pNETs
indium‑111 pentetreotide (OctreoScan) sensitivity 60% due to low somatostatine receptor expression type 2 (only 47% VHL pNETs)

23. Indications for surgery
Criteria* :
diameter ≥3 cm (or ≥2 cm if located in the pancreatic head);
rapid growth (doubling time of <500 days);
and/or suspicion of regional lymph-node metastasis
Excluded 3 exon mutation (this item was in Blansfield 2007)
Indeed 1/3 – 2/3 of VHL patient with pNETs had surgery:
- enucleation %
- Distal pancretectomy %
- PD %
- TPDE %
*strength of recommendation: strong; quality of evidence: low

24. Approaches to the surgical management of pNETs
• pNET in pancreatic head: enucleation if away from pancreatic duct, otherwise Whipple procedure
pNET in pancreatic body/tail: enucleation if away from pancreatic duct, otherwise distal or central pancreatectomy
Total pancreatectomy only in the very rare scenario of multiple tumours meeting resection criteria that cannot be safely enculeated
Additional smaller pNETs (≤1.5 cm) identified during surgery do not need to be removed
cN+: lymphadenectomy and enucleation or anatomic resection
Показания для хирургического управления VHL-связанными pNETs.
Риск злокачественного развития - ключевое показание для хирургическая резекция pNETs. Несмотря на то, что злокачественное развитие для VHL-связанного pNETs меньше чем 20% были сообщены в большинстве исследований, уровень хирургического вмешательства для твердых поражений поджелудочной железыу пациенты с VHL колебались от 36% до 64%
В настоящее время ограниченные данные существуют для определения оптимальных показании для хирургической резекции VHL-связанных, локализованных твердые поражения поджелудочной железы в соответствии с риском злокачественного развития.
pNETs ≥3 cm в диаметре, которые расположены в теле или хвост поджелудочной железы должен быть резецирован потому что такие поражения связаны с высоким риском метастатической болезни: опухоли ≥3 см в диаметре были найдены в 67% пациенты (6 из 9) с метастатической болезнью, сравненной с тем, только 19% пациентов (19 из 99), в кого метастатический болезнь не диагностировалась на imaging15,20. Опухоли
≥2 см в диаметре, которые расположены в головке поджелудочной железы должен также быть оценен на хирургическую резекцию. Мы рекомендуем этот более низкий пороговый размер для опухолей в головке поджелудочной железы, особенно если наблюдается рост опухоли поскольку энуклеация часто более выполнима для pNETs этого размера, по сравнению с большим pNETs в этой области. Опухоли с диаметром 2 см обычно достаточно отдаленный от главного протока поджелудочной железы, чтобы избежать потребность в панкреатикодуоденэктомии и, таким образом, осложнений и потенциальной смертности связанной с ПДР
Дополнительные, критерии : удвоение опухоли и наличие мутаций зародышевой линии в экзон 3 ; однако, более свежий отчет не сделал подтвердил ассоциацию между определенными генетическими альтерациями в VHL и злокачественности . Наконец, хирургический резекция pNETs с метастазами лимфатического узла, инвазия locoregional или отдаленные метастазы должна быть рассмотренный, если технически выполнимый и если 90% опухоли массы может быть removed63 (ТАБЛИЦА 2). Мы предложили алгоритм лечения на основе критериев обсужденных выше (РИС. 3).

25. Bakhrushins Hospital experience
Aim
To assess the demographics and results of major pancreatic surgery in patients with VHL
Reflect the significance of accepting of the international guidelines for VHL pancreatic tumors treatment
Methods
Retrospective analysis of 4 cases pancreatic resection in VHL patients from Department of Surgical Oncology database 2013 – 2015
Literature review PubMed, Cochraine collaboration, UpToDate, Clinical Key, MedSape, GeneReviews, OMIM,

26. Case 1. F. 57 Post resection diagnosis of VHL type 1 (mutation c
Case 1. F.57 Post resection diagnosis of VHL type 1 (mutation c.551T→C (p.L184P) : head & tail pNETs on total serous cystadenoma pancreatic involvement ; history of RCC treated by right-sided nephrectomy in 2006 Abdominal pain. Duodenal obstruction. Diabetes mellitus type 2.
Died 8 months after surgery
from RCC mets
TPDE 2013

27. Indication for surgery
Abdominal pain.
Duodenal obstruction ( -10kg during 6 months)
Diabetes mellitus type 2 decompensation
Suspect malignancy
Difficult to diagnose VHL syndrome due to:
The absence of visual impairment and neurological disturbances
Right nephrectomy histological conclusion is unknown. Medical Documents are not available.
Mother 82 years old is in good physical condition. His father passed away in 60 years, the cause is unknown.
Children 21 and 25 years old are healthy
Verification of serous cystadenocarcinoma by leading experts pathologists
But the doubts have remained and after discharge patient was directed to medical genetic specialist

28. Reason of misdiagnosing - mets of ccRCC in pancreas with cystic parenchyma replacement
Experience of MROI named after PA Herzen 5 patients with VHL

29. 31.08.15 Central-sparing pancreatic resection, left adrenalectomy
Case 2 F, 51: VHL type 2b (no detectable mutations): CNS hemangyoblastomas; G1(ki67<1%,<2m/10HPF) pNETs head & tail mpT3(5см,2см)рN0(0/6)M0; G1(ki67 1%) pheochromocytoma of left adrenal gland; history of partial resection of the left adrenal gland for Pheochromocytoma (1989) and right adrenalectomy for Pheochromocytoma (1992); polycythemic syndrome. Somatic mosaicism. Diagnosis have been approved clinically ;
Central-sparing pancreatic resection, left adrenalectomy
In accordance to Blansfield 2007 criteria
POPF В, hospital stay 29
Time of survilence = DFS = 13 мес

30. Case 3 M, 45: VHL type 2b (mutation 695 G → A (p
Case 3 M, 45: VHL type 2b (mutation 695 G → A (p.R161Q): spine hemangyoblastomas resected in 2010;
G2 (ki67 3%, 2m/10HPF) pNEC pT3рN1(3/13)M0, L1P1, R0 IIB; history of bilateral adrenalectomy for Pheochromocytoma and nephrectomy 2008, 2009
Whipple procedure, Surveillance time = DFS 9 months

31. Case 4. M, 29: VHL тип 2b ( 3 exon mutation c.499C>T (p.R167W):
G1(ki67-1%, 0/10HPF) pNEТ хвоста pT1(15мм)N0M0, IA; history of bilateral adrenalectomy for Pheochromocytoma and partial left nephrectomy 2004, 2015
3 exon mutation – moderate risk of metastases (Blansfield 2007)
Thereby there are indication for close CT surveillance but the patient has had inisisted on operation
We declined from enucleation because it is near the pancreatic duct. Distal pancreatectomy

32. 10.03.16 Distal pancreatectomy Hospital stay 7
Case 4. M, 29: VHL тип 2b ( 3 exon mutation c.499C>T (p.R167W):
G1(ki67-1%, 0/10HPF) pNEТ хвоста pT1(15мм)N0M0, IA; .
Intraoperative US : tumor was located on the body and tail border 1.3 cm in greatest dimension nearby main pancreatic duct. There were no any other lesions
Distal pancreatectomy
Hospital stay 7
Surveillance time = DFS 7 months

33. Results Pancreatic neuroendocrine carcinoma was verified in one case
n Age MHS Morbidity Died Working ability Me ST Exon
Resections
Major * months 3
Parenchyma-sparing
POPF grade A (distal pancreatectomy)
В ( central sparing pencreatectomy)
*8 months from ccRCC mets
Results

34. Conclusion
Multidisciplinary approach. Necessity of National register and comprehensive care centers of VHL
Extensive surgery should be reserve only for malignancy suspected cases (accordance to criteria) and/or life-threatening complications
Surveillance, parenchyma – sparing and minimally invasive surgery – treatment of choice for VHL associated pNETs
pT3N1(3/13)M0, G2 (2 митоза на 10 полей зрения), P1, R0 IIB

35. Thank You for Your attention
Contacts
Egorov VI, tel ,
Beltsevitch DG, tel ,
Petrov RV , tel ,