Introduction
von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBLs) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts [
1]. The diagnosis of VHL disease in the absence of a family history of CNS or retinal HBL requires the presence of multiple (at least two) HBLs or one HBL and any one of the described visceral manifestations. For a patient with a family history of CNS or retinal HBL, the diagnosis of VHL disease requires only the presence of one HBL or other manifestations of this disease. Genetic analysis can confirm the diagnosis of VHL disease in a patient manifesting the clinical symptoms but may or may not meet the aforementioned diagnostic criteria [
2]. In clinical practice, VHL disease is classified according to the absence (type 1) or presence (type 2) of pheochromocytoma in other family members and may be subdivided according to the absence (type 2A) or presence (type 2B) of renal cell tumor [
3,
4].
The clinical manifestation of VHL disease varies. Some reports have shown that HBL of the CNS is one of the most common tumors affecting 60% to 80% of patients with VHL disease [
5]. Although these tumors are benign, they may be associated with peritumoral edema or cysts and are the major causes of morbidity [
6,
7]. VHL-associated renal lesions are often multiple and bilateral [
8]. RCC is the major malignant neoplasm in VHL disease; VHL-associated RCC is the primary cause of inherited renal cancer with varied morbidity [
9]. Other studies have shown that 35% to 70% of patients with VHL disease exhibit pancreatic cysts, cyst adenomas, and PETs [
1,
10]. The frequency of PETs occurs by approximately 8% to 17%, and the liver is the most common site of metastasis of these tumors [
11–
14]. Adrenal pheochromocytomas arise in 10% to 20% of the patients with VHL disease, and these carcinomas tend to be bilateral in a significant number of cases [
15].
Systematic family screening is an important procedure to study a hereditary disease. Such a screening procedure is also important to detect hereditary diseases in asymptomatic patients. In addition, early diagnosis is an important prognostic step. However, few studies on VHL disease, particularly about a large VHL family, are available in Chinese literature [
16,
17]. Furthermore, no previous report on VHL-associated PETs in the Chinese population has been presented. Thus far, the family considered in the present study was the largest family with VHL disease in the world; two cases of PETs from this family were reported for the first time. In this study, a detailed systematic report of this VHL family in terms of their epidemiological and clinical features was provided. The importance of family screening to diagnose VHL disease was also emphasized.
Materials and methods
Self-designed questionnaire
A questionnaire was designed to collect the sociodemographic profile of the family members, including name, age, gender, region, educational background, habits, medical history, marital history, and so on.
Screening of family members
We conducted a detailed physical examination of the family members and focused on the susceptible organs. We also performed a preliminary family screening by abdomen B ultrasonography examination. The suspected patients were then subjected to cranial computerized tomography (CT), abdominal CT examinations, and fundus examination.
Retrospective study of VHL cases in the family
To keep the family record complete, we obtained the information of dead suspected cases by interviewing the insiders and made a comprehensive decision. We also obtained the information of the living patients by visiting hospitals and checking their medical records.
Statistical analysis
All of the collected data were transcribed in a Microsoft Excel spreadsheet and analyzed using SPSS 18.0. The results were expressed as mean±standard deviations. Continuous variables were compared by ANOVA, and categorical variables were compared by Chi-square test. P≤0.05 was considered statistically significant.
Results
Epidemiological characteristics of the VHL family
The simple family genogram and the detailed sociodemographic characteristics of the Chinese VHL family are presented in Fig. 1 and Table 1, respectively. A total of 63 lineal descendants (34 males and 29 females) in 6 generations (generations O, A, B, C, D, and E) were traced. Nine dead suspected cases (6 males and 3 females) and 10 living cases (2 males and 8 females) were traced; the rest of the members were healthy or asymptomatic. The age of the family members (cut-off age) ranged from 1 year to 61 years (34.9±5.18 years), in which the age of the living and dead members ranged from 1 year to 61 years (32.2±4.75 years) and from 21 years to 56 years (40.00±8.89 years), respectively. The following patients were included in each generation: 1 male patient in generation O; 1 male and 1 female in generation A; 4 males and 2 females in generation B; 3 males and 7 females in generation C; and none in generations D and E. Significant differences (P<0.05) were observed between the members of generations B and C in terms of gender, age at diagnosis, and morbidity of the disease (Table 1).
Clinical characteristics of the patients with VHL disease
The clinicopathological features of the 19 patients with VHL disease and their cumulative survival function curves are presented in Table 2 and Fig. 2, respectively. The age at diagnosis of the dead suspected patients ranged from 12 years to 50 years (36.67±9.56 years). For the living patients, the age at diagnosis ranged from 24 years to 41 years (32.4±5.40 years). A total of 7 HBLs, 2 PETs, 3 pancreatic cysts, 4 RCCs, 4 renal cysts, 11 pheochromocytomas (5 unilateral, 6 bilateral; 9 pathologically confirmed, 2 suspected), and 2 paragangliomas (including the suspected and definitive cases) were observed. Among the ten living patients, 4, 2, 3, 1, 4, 8, and 2 patients manifested cerebellar HBL, PETs (1 splenic metastasis from PETs), pancreatic cysts, RCC, renal cysts, pheochromocytomas (4 unilateral, 4 bilateral, total 8), and paragangliomas, respectively. For the dead suspected patients, cerebellar HBL (suspected in 3 patients), RCCs (manifested in 3 patients), and pheochromocytomas (1 unilateral, 2 bilateral, total 3; detected in 3 patients) were observed. Surgery was the definitive mode of management in 14/19 patients. The median survival time following diagnosis of the patients with VHL disease was 4.90 years and the 10-year survival rate was 39%.
Detailed case reports of the VHL patients
Dead suspect cases
O1: A 45-year-old male was suspected to have died from RCC according to the description provided by the family members.
A1: A 40-year-old male suffered from a sudden death presumably because of a cerebellar HBL.
A2: A 50-year-old female died two years after brain surgery presumably because of a cerebellar HBL.
B1: A 52-year-old female died seven years after brain surgery presumably because of a cerebellar HBL.
B7: A 36-year-old male suffered from a sudden death presumably from bilateral adrenal pheochromocytomas.
B8: A 50-year-old male died one year after right nephrectomy presumably because of a recurrent RCC.
B9: A 42-year-old male suffered from a sudden death presumably from RCC.
C5: A 23-year-old male died 11 years after he was diagnosed with right adrenal pheochromocytoma.
C21: A 21-year-old female suffered from a sudden death presumably from bilateral adrenal pheochromocytomas.
Living cases (from local hospitals)
B3: A 56-year-old female was evaluated for hypertension 17 years ago and later diagnosed with bilateral adrenal tumors based on radiological evaluation. The pathology of the resected adrenal specimens revealed pheochromocytomas. She was diagnosed with cerebellar HBL after one year.
B5: A 45-year-old female was evaluated for intermittent headache. Bilateral adrenal masses were detected based on radiological evaluation. The pathology of the resected adrenal specimens was consistent with pheochromocytomas.
C10: A 28-year-old female was diagnosed with cerebellar HBL (pathologically confirmed).
C22: A 42-year-old female was evaluated for intermittent back pain. Right adrenal pheochromocytoma was detected by radiological and pathological evaluation.
C24: A 32-year-old female was diagnosed with a tumor in the right adrenal gland in a routine physical examination. The histopathological examination of the resected specimen was consistent with pheochromocytoma.
C27: A 42-year-old female was diagnosed with cerebellar HBL and a right-sided RCC.
Living cases (from our hospitals)
C2: A 42-year-old hypertensive female was evaluated for intermittent headache and manifested lesions in the right adrenal, spleen, and pancreas. Cysts were also detected in the pancreas and both kidneys. Masses were also found around the inferior vena cava based on radiological evaluation. The pathology of the resected specimens revealed PETs, splenic metastasis from PETs, right adrenal pheochromocytoma, and paragangliomas.
C3: A 37-year-old female was evaluated for hypertension 12 years ago and masses were found in bilateral adrenals. The pathology of the resected specimen revealed bilateral pheochromocytomas. Radiological evaluation from the previous month revealed masses in the pancreas, kidneys, and between the inferior vena cava and the abdominal aorta. The pathology of the resected specimens revealed PETs, pancreatic and renal cysts, and paraganglioma.
C4: A 33-year-old female was evaluated for intermittent headache. Masses were detected in her right adrenal, pancreas, kidneys, and cerebellum based on radiological evaluation. The pathology revealed pheochromocytoma, cysts in the pancreas and kidneys, and HBL.
C11: A 24-year-old male was diagnosed with bilateral adrenal masses based on routine radiological evaluation; his histopathological examination result showed pheochromocytoma.
The typical clinical imaging data of the patients affected with VHL disease are presented in Fig. 3.
All of the four patients from our hospital manifested pheochromocytomas and showed biochemical evidence of endocrinological abnormalities (Table 3).
Discussion
It took a long time for the clinicians to know the VHL disease. In 1911, von Hippel first described retinal angiomatosis in a patient. After 10 years, Brand reported the autopsy findings of the same case revealing hypernephromas, tumors in the cerebellum, and cysts in the kidney, epididymis, and pancreas. In 1926, Lindau collected data of 40 patients with cerebellar cysts and RCC. This compilation of clinical features is currently known as VHL syndrome [
18].
VHL disease is an autosomal dominant neoplasia syndrome resulting from a germ line mutation in VHL gene located in the short arm of chromosome 3 (3p25–26); this mutation can lead to the development of multiple benign or malignant tumors and cysts in many organs and systems [
5]. The most important diseases in the VHL family we investigated include HBLs of the CNS, adrenal pheochromocytomas, and PETs.
The HBLs of the CNS are the characteristic lesions, either multiple or multifocal, observed in patients with VHL disease. In a previous study, the average age of diagnosis of VHL-associated HBL is 33 years, a decade earlier than sporadic lesions [
6,
7]. Some reports have also shown that cerebellar HBLs are the major causes of death in 82% of the patients. Most HBLs in the craniospinal axis can be safely and completely excised by surgery, which is the preferred modality of patient management [
19]. Although microsurgical techniques have considerably been improved in recent years, post-operative outcomes in patients with VHL-associated HBLs may not always be satisfactory because multifocal tumor development and recurrences are still serious problems. Therefore, a long-term follow-up period for the patients is mandatory.
The incidence of hereditary pheochromocytomas varies from 10% to 20% in different studies, and these differences are associated with mutations in several genes such as RET, MEN-1, and VHL [
20]. VHL-associated pheochromocytomas are often small, multiple, and bilateral, showing a predilection for younger individuals with a mean age of 30 years [
21]. Walther
et al. [
22] reported that a maximum of 47% of pheochromocytomas are bilateral in the VHL family. A subset of these patients may be normotensive and asymptomatic at the time of first detection. Pheochromocytomas may be detected incidentally during routine checkups by physicians, but such manifestations can suddenly become symptomatic; life-threatening complications may also occur at the time of surgery, trauma, or pregnancy, thereby requiring urgent interventions [
23]. This tendency results in a significant increase in morbidity and mortality; hence, judicious surveillance protocols should be strictly followed to ensure appropriate detection and follow-up of these tumors. Given the characteristics of VHL-associated pheochromocytomas, which are similar to an active volcano, patients should control their emotions and undergo regular physical examination. Surgery is the definitive modality of management; partial adrenalectomy or enucleations are conducted more often to preserve the adrenal function [
24]. The criteria for recommending surgery include the following: (1)functionally active tumors; (2) abnormal uptake in meta-iodobenzylguanidine scan; and (3) size>3.5 cm [
1].
PETs have long attracted clinicians because some of these tumors may be biologically active, manifesting distinct syndromes that provide important information about human hormones. PETs are broadly classified in two groups: (1)functional PETs associated with symptoms caused by ectopic secretion of hormones and (2) non-functional PETs. However, VHL-associated PETs are almost invariably non-functional and usually asymptomatic; such PETs may occasionally cause pancreatitis or pain [
10]. This study is the first to report VHL-associated PETs in China given that only few studies have been reported worldwide. The two PET cases in the family were both females with an average age of 39 years; the median age of diagnosis was 38 years; 66% of the patients were females [
9]. PETs mostly developed in 10% to 17% of the patients with VHL disease; approximately 17% to 25% of these PETs metastasized at the time of diagnosis, in which 9% to 37% metastasized to the liver [
1]. We found that PETs could also metastasize to the spleen, and this finding had not been described previously. The treatment of PETs is mainly conducted by surgical resection, and the preservation of the functional pancreas is a key technique to ensure the quality of post-operative life [
25].
The results of our study showed that the morbidity of the patients with VHL disease was lower in younger generations than in older generations. No case of VHL disease was observed in the fifth and sixth generations (D, E) at present. This finding provided good news for the family but remains an unresolved problem. This case may be caused by the following reasons: (1) the individuals in the fifth generation are too young (<20 years) to become clinically symptomatic; (2) the mutation of VHL gene decreases with generations, and this mutation does not possibly occur after more than five generations; (3) the mutation of VHL gene may have led to embryonic death during pregnancy; and (4)an unknown gene that can possibly influence the phenotypic expression of the mutated VHL gene with age may be present. According to the data of the patients with VHL disease in our study, the prevalence of this disease possibly decreases with generations (O to E). Family screening is an important method to study a hereditary disease. In addition, early diagnosis is an important step of prognosis. Considering the features of the VHL family, we should focus the follow-up procedures on post-operative patients with VHL disease and those in the younger generation.
In summary, an epidemiological study of a large VHL family, which is probably the largest in the world, from northwest China was conducted for the first time. The HBLs of the CNS and pheochromocytomas manifested the typical characteristics described in previous studies, and PETs were very rare. We suggest that an early diagnosis of patients with VHL disease and an appropriate screening of family members are essential for appropriate management. These procedures may also help reduce the recurrence rate of lesions and improve the post-operative quality of life of patients.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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