Apr. 01, 2021
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This article includes discussion of von Hippel-Lindau disease, VHL disease, and von Hippel-Lindau syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
This article reviews the diverse systemic manifestations of von Hippel-Lindau disease and discusses the historical context of the disease as well as current methods employed in the diagnosis and treatment of the disorder. Classic physical and radiographic manifestations are illustrated in a clinical vignette. New recommendations for management of pancreatic lesions and for pheochromocytoma surveillance are reviewed.
• Von Hippel-Lindau disease is an autosomal dominant hereditary multisystem tumor syndrome with marked intra-and interfamilial variability.
• The tumors are highly vascular and mostly consist of hemangioblastomas of the CNS and retina, renal cell carcinoma, endolymphatic sac tumor of inner ear, and adrenal pheochromocytoma.
• There is correlation between the type of gene mutation and its phenotypic expression, particularly for pheochromocytoma and renal cell carcinoma.
• Molecular diagnostic testing for the von Hippel-Lindau gene (VHL gene) is available and can be performed on asymptomatic high-risk individuals and in high-risk pregnancies in the early prenatal period.
• Management mainly consists of excision of malignant lesions (eg, renal tumors) and surgical removal or ablation of symptomatic benign lesions (eg, hemangioblastomas), which are followed closely for possible recurrence or development of new lesions.
Panas and Remy were first to describe retinal hemangioblastoma, using the descriptive term “retinal angiomatosis” (60). Other investigators interpreted the retinal lesions as vascular malformations, including Collins, who was the first to recognize the inherited nature of this disorder (12). Von Hippel was the first to document the progressive nature of the retinal lesions (81).
The history of hemangioblastoma of the cerebellum was initiated by Hughlings Jackson in 1872 (29). Several authors subsequently noted an association between cerebellar cysts and small cysts of the pancreas and kidneys (65; 82). These associated lesions later became known as the von Hippel-Lindau complex.
Tresling described the first family with an association between retinal and cerebellar tumors (79). Lindau combined, as a single entity, the clinical-pathological hemangioblastic alterations of the retina, cerebellum, spinal cord, and lesions of the pancreas, kidneys, adrenal medulla, liver, and epididymis (37). The term "von Hippel-Lindau disease" was first used in 1936 (17) and has been in common use since the 1970s (44). Melmon and Rosen reviewed the literature on the disease and suggested the clinical diagnostic criteria (49). Möller described the heredity of the disease as an autosomal dominant trait (50). In 1988, Seizinger and colleagues demonstrated the responsible gene at short arm of chromosome 3 (73). Latif and colleagues showed that the abnormal gene of von Hippel-Lindau disease behaves as a tumor suppressor gene (36). These molecular genetic findings established the definitive criteria for the disease to confirm the diagnostic viability of the clinical criteria (78).
Von Hippel-Lindau disease is an autosomal dominant multisystem tumor syndrome with various benign and malignant neoplasms. Approximately 20% of cases of von Hippel-Lindau disease result from de-novo mutation of the VHL gene. Melmón and Rosen established diagnostic criteria for von Hippel-Lindau disease; for diagnosis, a patient must have at least 1 characteristic lesion in the central nervous system, eye, or viscera if there is a family history of an affected first-degree relative, or they must have 2 lesions in the absence of a family history (49). Since these initial criteria were established, the diagnostic criteria have been expanded to encompass molecular genetic confirmation.
The lesions are diverse and affect various organs; they vary considerably in number, size, location, and number of organs involved. The usual locations involved include the eye, central nervous system, kidney, pancreas, inner ear, adrenal gland, liver, and epididymis (male) or broad ligament (female). Given the diversity of the symptomatology corresponding to the involvement of the organs in each patient, the symptoms and clinical signs are individualized.
Eye. The typical ocular lesion is the hemangioblastoma of the retina, which was the first recognized pathological manifestation of von Hippel-Lindau disease (60). The retinal hemangioblastoma has been referred to as an angioma, hemangioma, or retinal angiomatosis and has been reported to occur in approximately 40% to 60% of patients; they are bilateral in 30% to 50% of cases with ocular involvement. Retinal lesions may become manifest at any age, including infancy. The principal symptoms or complications of retinal hemangioblastoma are glaucoma, cataracts, detachment of the retina, and sympathetic ophthalmitis, which results in unilateral or bilateral blindness in half the cases. Some tumors remain stationary and dormant for many years after diagnosis; however, the usual course is one of progressive growth at a moderate or rapid rate. Studies within the past several years indicate that the prevalence and biological progression of retinal hemangioblastoma and also other lesions in von Hippel-Lindau disease are determined in part by the specific germline mutations within the VHL gene.
The typical retinal hemangioblastomas are pink-red masses varying from less than 1 mm in maximum dimension to several disc diameters. The tumors are fed by a tortuous, dilated artery and drained by equally dilated veins that may become arterialized by capillary shunts. They may result in an inflammatory reaction and progress to exudates, hemorrhages, and retinal detachment, with extension to adjacent retinal tissue (76). The retina may become fibrotic and thickened. In the majority of cases the lesions are located in the peripheral zones of the retina, but the macular region may be affected as well. When the optic disc is affected, the lesion can resemble papilledema, papillitis, or glioma of the optic nerve head (27).
An uncommon retinal vascular lesion was reported in a group of patients with von Hippel-Lindau disease (87). This was described as a fibrovascular lesion and referred to as “retinal vascular proliferation.” The significance of this lesion as a separate entity remains to be determined by study of additional groups of patients with longer follow-up.
Central nervous system. Hemangioblastomas of CNS are the main component of von Hippel-Lindau disease. They occur in 60% to 80% of cases, are multifocal in 42% of cases, and are the presenting feature in approximately 40% of cases (45; 44; 52; 41; 67). The lesion is mainly located in the cerebellum and spinal cord, less commonly in the brainstem (84), and rarely in the cerebral hemispheres (62), optic nerve (28), pituitary gland (16), pituitary stalk, and third ventricle (39).
Hemangioblastoma of the cerebellum is the most common CNS lesion in von Hippel-Lindau disease (52; 41; 40). More than 50% of subjects with von Hippel-Lindau disease present with hemangioblastomas of the cerebellum (35). However, studies suggest that this tumor is at least as common in the spinal cord of patients with von Hippel-Lindau disease (84; 01). The diagnosis is usually made in young adults, 24 to 40 years of age, with a mean age of 32 years; it occasionally has been seen in children less than 10 years of age (26). The most frequent symptoms are generalized headaches due to increased intracranial pressure and headaches localized to the occipital and upper cervical regions; less frequent symptoms include lethargy, anorexia, gait disturbances, dementia, and visual disturbances. The usual signs of hemangioblastoma of the cerebellum are ataxia, papilledema, nystagmus, bilateral convergent strabismus, and facial paralysis; less frequent findings are impaired consciousness, paresis of the lower extremities, diminished in visual acuity, and dysarthria.
Historically, cerebellar hemangioblastomas were the cause of death in the majority of patients with von Hippel-Lindau disease (35; 52), but increased survival has been achieved due to the use of advanced diagnostic and management techniques. Early diagnosis often is possible in preclinical stages because of study of carriers or possible affected family members by molecular genetic techniques and newer methods of imaging of subjects at risk, thus, disclosing cryptic hemangioblastoma of the CNS (52; 64). Approximately 40% to 50% of patients present with multiple lesions (19). The symptoms of posterior fossa involvement with hemangioblastoma appear approximately 15 years earlier in cases of von Hippel-Lindau disease than in sporadic cases of hemangioblastoma (52; 13). The majority (80%) of cerebellar hemangioblastomas are located in the cerebellar hemispheres, 15% in the vermis, and only 5% in the floor of the fourth ventricle. Of these cerebellar tumors, 75% are cystic, usually with mural nodules (35). Approximately 10% are multiple and 10% are recurrent. Cerebellar hemangioblastomas usually produce erythropoietin, which may result in erythrocytosis (polycythemia).
Hemangioblastomas of the brainstem in von Hippel-Lindau disease usually localize to the medulla oblongata. The signs and symptoms are related to the size of the lesion and the involvement of cranial nerves and long sensory and motor pathways, particularly the pyramidal tracts.
Spinal cord hemangioblastomas present with a frequency 3 times greater than those of the brainstem (35). Symptoms include pain or alteration of function of the sensory and proprioceptive tracts, depending on the precise localization. Symptoms of spinal cord compression occur early, and pain often precedes the loss of sensation. The tumor can produce signs and symptoms related to lesions of the lateral columns, distal weakness, muscular atrophy, hyperreflexia, and spastic paraplegia. The concomitant cerebellar symptoms in many cases may confuse the diagnosis if it is not taken into account that von Hippel-Lindau disease is a multisystem disorder and may be multicentric in the CNS, requiring an investigation of all possible locations in search of multiple lesions. Advances in techniques of MR, Gd-DPTA-MR, and MR angiography have made possible an early detection of asymptomatic lesions and also have reduced the time interval between the appearance of symptoms and the diagnosis. The localization of spinal cord hemangioblastoma is intramedullary in almost two thirds of cases, extramedullary intradural in one fourth, and extradural in the rest. Half the tumors occur in the thoracic region, 40% in the cervical region, and the remainder in the lumbar segments. Rarely is the tumor encountered in the sacral region or the cauda equina. The CSF may be xanthochromic, with elevated protein and occasionally subarachnoid hemorrhage. Erythrocytosis has not been described in spinal hemangioblastoma as it has been with cerebellar lesions.
Systemic lesions. Lesions of the kidneys, pancreas, and epididymis are frequently asymptomatic and their detection may be incidental. Patients with adrenal tumors (pheochromocytomas) are more often symptomatic. The clinical presentation in a symptomatic patient varies widely depending on the extent and distribution of disease.
Kidney. The renal lesions of von Hippel-Lindau may be benign cysts or clear cell carcinomas with a partial or predominant cystic component; both present with a similar incidence. Renal cysts may be solitary or multiple. These cysts are potentially premalignant (06) and appear in adulthood. The risk of developing renal cell carcinoma varies in different clinical forms of von Hippel-Lindau disease (see classification below). In the most common forms (types 1 and 2B) this risk approaches 70% (45; 58); it is the cause of death in 20% to 50% of affected patients (35). Malignant renal cell tumors in von Hippel-Lindau disease are multiple and bilateral in 60%, an important difference from sporadic cases (59). The detection of renal cell carcinoma among multiple cystic lesions can be difficult, though new methods of MR imaging are making early and correct diagnosis much easier.
Pancreas. Lesions of the pancreas in von Hippel-Lindau disease are usually benign and cystic; more than 40% of patients with von Hippel-Lindau disease will have cystic lesions of the pancreas identified at the time of diagnosis. Pancreatic cystadenoma and familial pancreatic adenocarcinoma are less frequent (53). Pancreatic islet cell tumors (eg, insulin producing) can occur in von Hippel-Lindau disease (38). Like the renal, CNS, and retinal lesions in von Hippel-Lindau disease, pancreatic islet cell tumors are substantially vascular. Most of these lesions grow slowly and are asymptomatic, although they rarely can be malignant (14). Familial cystic or solid lesions of the pancreas should raise the suspicion of von Hippel-Lindau disease or multiple endocrine neoplasia. The majority of pancreatic lesions are asymptomatic, but some may obstruct the biliary and pancreatic ducts and result in fibrosis and atrophy of the pancreas. If there is significant loss of the cells populating the islets of Langerhans, diabetes mellitus may result. When symptomatic, patients may present with abdominal pain, mass effect in the abdomen, and endocrine and exocrine insufficiency of the pancreas. In select patients with resultant pancreatitis, pancreatectomy may be performed.
Adrenal gland. Pheochromocytomas are usually unilateral, but bilateral tumors are not uncommon. The risk of developing this tumor varies in different forms of von Hippel-Lindau disease (see classification below). The tumor may result in hypertension, unstable blood pressure, and paroxysmal headaches. High urinary concentrations of catecholamines and metanephrine are suggestive of the diagnosis. The diagnosis can be confirmed by an abnormal pressor response. Radiological study with ultrasonography, MRI, and MRA discloses the tumor.
Epididymis and broad ligament. Epididymal lesions consist of simple cysts or papillary cystadenomas; they are found in 10% to 60% of male patients with von Hippel-Lindau disease and present at an average age of 23 years (35; 09). They may be bilateral and rarely impair fertility. It can be found by routine physical examination but is often an incidental finding at autopsy. These lesions generally are not painful. Although often clinically insignificant, the presence of this tumor in a patient with a close relative with von Hippel-Lindau disease is often instrumental in performing additional studies to establish the diagnosis of that disease. Papillary cystadenoma of the broad ligament is an analogous lesion that may occur in women with von Hippel-Lindau disease. The diagnosis of this lesion can be reliably made by ultrasonography.
Inner ear endolymphatic sac tumor. These are slow-growing, low-grade papillary adenocarcinomas involving the temporal bone. Such lesions occur in an estimated 10% of patients with von Hippel-Lindau disease and are frequently bilateral (43). Symptoms of disequilibrium or aural fullness affecting patients with known von Hippel-Lindau disease may be an early indication of endolymphatic dysfunction. Abrupt hearing loss and tinnitus are other symptoms that may suggest the presence of an endolymphatic sac tumor (08; 33). Such patients should undergo CT or MRI of the internal auditory canal.
Metastasis. Metastatic involvement of the nervous system occurs relatively rarely (53), and the origin of the tumor can be any other organ (most commonly kidney). In many cases, the CNS metastases are revealed only at autopsy.
Classification. Based on the likelihood of developing pheochromocytoma, von Hippel-Lindau disease phenotypes may be divided into type 1, low risk for pheochromocytoma, and type 2, high risk for pheochromocytoma (07; 40). Type 2 accounts for 7% to 20% of von Hippel-Lindau disease cases and is further divided into 3 types: type 2A, low risk for renal cell carcinoma; type 2B, high risk for renal cell carcinoma; and type 2C, pheochromocytoma only, with the last type being the least common form. This classification is helpful in research for correlating the effect of specific mutation with pVHL function and phenotype but is less useful for clinical management due to its intrafamilial variability (44).
Many factors influence the prognosis of von Hippel-Lindau disease. The most important factors include localization, size, number, and biological nature of the tumors. CNS hemangioblastomas were the most frequent cause of death in a large French series of 215 von Hippel-Lindau disease patients (67).
Early detection of the disease and the associated lesions and management of the tumors of various organs by physicians with special expertise in these organs have markedly improved the prognosis in patients with von Hippel-Lindau disease.
A 25-year-old Caucasian woman first presented for medical care at the age of 18 years following a 2-month history of progressive difficulty with ambulating, handwriting, thinking, and blurring of vision with headache. She acutely experienced severe nausea and headache in the days preceding her admission.
Her neurologic examination was notable at that time for papilledema, right dysmetria, and right Babinski. CT scan revealed a left cerebellar 5 cm x 5 cm enhancing lesion with a cystic component compressing the fourth ventricle with early hydrocephalus.
The lesion was surgically excised without complication. The tumor was diagnosed as a cerebellar hemangioblastoma.
Given the young age of presentation and a similar tumor previously diagnosed in her mother, she received extensive medical surveillance for systemic manifestations of von Hippel-Lindau disease. MR of C-spine revealed multiple heterogenously enhancing nodular masses throughout the posterior fossa as well as cervical cord consistent with multiple hemangioblastomas.
Subsequent funduscopic examination revealed multiple bilateral retinal hemangioblastomas.
Additional evaluations in the succeeding months revealed the presence of multiple cystic lesions within the head of the pancreas as well as a solid tumor within the right mid-kidney. The renal lesion was surgically excised and diagnosed as renal cell carcinoma.
Von Hippel-Lindau disease is inherited as an autosomal dominant trait with high penetrance (over 90% by 65 years of age). The associated neoplasms are age-dependent and show allelic-specific expressivity. The disease is caused by germline mutations in the VHL gene (a tumor suppressor gene), and the associated tumors are initiated by biallelic inactivation of this gene (36; 78). Over 500 gene variants have been described to date (72).
VHL gene and pVHL. The gene is located at chromosome 3p25-26 and contains 3 exons and a coding sequence of 639 nucleotides. It is expressed in all tissues and encodes 2 protein products: a full-length form (p30, 213 amino acids) and a shorter form (p19, 160 amino acids). The VHL gene products, particularly the p19 isoforms, have been conserved throughout evolution and can be detected in all multicellular organisms examined to date (Kaelen 2007; 55). Both protein isoforms behave similarly in most functional assays, so they are referred to as pVHL. This protein has been implicated in a variety of cellular functions, including transcriptional and posttranscriptional gene expression, extracellular matrix formation, apoptosis, and ubiquitylation (30; 68; 57).
Gene mutations. Germline mutations of the VHL gene are spread throughout the 3 exons. Missense mutations are the most common, but other forms of mutation and large deletions can also occur. The inactivation of both alleles of the VHL gene is the critical event in the pathogenesis of von Hippel-Lindau disease neoplasms (15). Biallelic inactivation may occur through one of several pathways, including intragenic mutations, mitotic recombination events, and hypermethylation of the promoter region. Alteration of the VHL gene is typically due to insertion, deletions, or missense mutations (36). Mutations of the VHL gene are also common in sporadic hemangioblastomas and renal cell carcinomas.
There is correlation between certain germline mutations and particular clinical phenotypes (74). In families with von Hippel-Lindau disease type 1 (high risk for hemangioblastoma and renal cell carcinoma but low risk for developing pheochromocytoma), mutations are nonsense or truncating, which markedly disrupt the folding of pVHL (77; 44). Individuals with von Hippel-Lindau disease type 2 have a higher risk of developing pheochromocytoma, and nearly all have a missense germline mutation. This type is further divided into 3 subtypes; 2A (high risk for pheochromocytoma and hemangioblastoma but low risk for renal cell carcinoma); 2B (high risk for pheochromocytoma, hemangioblastoma, and renal cell carcinoma); 2C (pheochromocytoma only). This subtype shows a specific missense germline mutation in the VHL gene (88).
Pathogenesis. The tumors in von Hippel-Lindau disease are initiated by random somatic cell mutations, resulting in bialleic loss of the tumor suppressor VHL gene and its protein product pVHL. Among the various functions of this protein, the pVHL-deficient cells’ inability for ubiquitylation (and subsequent degradation) of hypoxia-inducible factor (HIF-1alpha and HIF-2alpha) has been implicated in the development of highly vascular tumors in von Hippel-Lindau disease (48; 11; 30; 58).
Normal pVHL binds to elongin C, which forms a complex with elongin B, Cul 2, and Rbx1. This complex, due to its ubiquitin ligase activity, interacts with the hydroxylated alpha subunits of HIF and targets them for rapid degradation by proteasomes. Under normoxic conditions and in the presence of functional pVHL, hydroxylated alpha subunits are rapidly degraded. In hypoxia, alpha subunits of HIF cannot be hydroxylated for binding to functional pVHL; this results in transient stabilization of the HIF-alpha, causing their accumulation in the cytoplasm and subsequent translocation to the nucleus, where they result in activation of the transcription factors for a variety of hypoxia-inducible genes such as vascular endothelial growth factor, erythropoietin, and transforming growth factors TGF-alpha and TGF-beta. Likewise, in von Hippel-Lindau disease, where pVHL is abnormal or absent, accumulation of HIF results in abnormal signaling, even in the presence of oxygen (31; 46; 30; 55). These chains of interactions appear to play a key role in the formation of the vascular tumors characteristic of von Hippel-Lindau disease. Studies suggest that targeted inhibition of some of these factors or their receptors may suppress the growth of tumor cells in advanced metastatic renal cell carcinoma and other von Hippel-Lindau disease-associated tumors (10). The broader concept of the role of hypoxia in inflammation and tumor progression in the context of von Hippel-Lindau disease is reviewed by Bader and Hsu (05).
Histopathology. The 2 most common tumors of von Hippel-Lindau disease hemangioblastoma and renal cell carcinoma are discussed here.
Hemangioblastoma is a fine vascular network of endothelial-lined channels or caverns, generally without the presence of neurons or glia. In the cerebellum it may be cystic and contain xanthochromic fluid. A small, highly vascular nodule is generally found in the wall of the cyst. The nodule is usually in contact with the leptomeninges at the surface of the cerebellum. The "pseudoxanthomatous" stroma consists of polygonal cells with foamy lipid-laden cytoplasm. These stromal cells are nearly indistinguishable from the clear cells of renal cell carcinoma or of retinal hemangioblastoma and are believed to be the principal neoplastic cells of hemangioblastoma (83; 63). The histogenesis of the stromal cells is not known. Studies suggest that stromal cells share protein expression and topographic distribution with hemangioblast progenitor cells (22; 61). Extramedullary hematopoiesis may be present within cerebellar hemangioblastoma, and concomitant paraneoplastic erythrocytosis has been reported (90). Hemangioblastomas are well demarcated and generally are not locally invasive, nor do they tend to metastasize.
Renal lesions may be cystic or solid. The tumors are highly vascular and consist of clear cells. The cysts are small (range from several millimeters to 2 cm in diameter), have a gray appearance, and are filled with clear liquid. They are lined by a layer of atypical cuboidal cells that are similar to those covering solid and cystic renal cell carcinomas. Renal tumors may invade neighboring zones and metastasize through venous channels to the adrenal glands, spinal cord, and other sites of the CNS.
Prior to the advent of molecular genetic testing, the reported incidence of this disease in England was estimated to be 1 in 45,500 to 1 in 36,000 live births (42; 41), and it’s prevalence in south Germany was 1 in 39,000 live births (54). The use of molecular genetic techniques combined with detailed radiological and clinical evaluation of individuals with clinical suspicion of von Hippel-Lindau disease will result in early diagnosis and thereby, may provide more detailed information for epidemiological studies.
There are no specific preventive measures for any of the neoplasms associated with von Hippel-Lindau disease. However, early diagnosis of this disease in individuals at risk results in timely management of the tumors and reduces morbidity and mortality among these patients. Also, genetic counseling of patients with von Hippel-Lindau disease and at risk individuals prior to pregnancy followed by molecular genetic confirmation of the disease is an appropriate preventive measure. Moreover, affected fetuses carrying the VHL gene can be diagnosed by DNA analysis at the beginning of the ninth week of gestation (preferably at 10 to 12 weeks on chorionic villus sample or at 15 to 18 weeks on amniotic fluid cells). Preimplantation genetic diagnosis may be carried out in pregnancies at risk for von Hippel-Lindau disease.
The differential diagnosis of von Hippel-Lindau disease includes sporadic cases with the same types of lesions as in von Hippel-Lindau disease but not associated with this disease. The differential diagnosis is not important with regard to therapy, which is the same in both isolated lesions and those that present in a patient with von Hippel-Lindau disease. Sporadic cases of hemangioblastoma generally are solitary or affect a single organ, whereas the lesions in von Hippel-Lindau disease usually are multiple and are found in several organs. Nevertheless, the clinical presentation in each organ can extend over several or many years (35).
The retinal changes of subjects with von Hippel-Lindau disease, especially those that involve the optic disc and seem to correspond to papilledema, neuritis, or tumor, also may be observed in neurofibromatosis, tuberous sclerosis, retinitis pigmentosa, sickle cell anemia, and maxillary hemangioma. The differential diagnosis includes several entities, including racemose hemangioma, cavernous hemangioma, macroaneurysm, vasoproliferative tumor-like lesions, Eales disease, atypical retinal detachment, Leber retinal telangiectasia, retinoblastoma, and Coats disease (35; 76).
The principal differential diagnosis of hemangioblastoma of the cerebellum is astrocytoma, which also may be cystic or solid. Those of the brainstem must be differentiated from syringobulbia and those of the spinal cord from cystic astrocytoma and syringomyelia.
Renal cell carcinoma in patients with von Hippel-Lindau disease is differentiated from sporadic cases by an earlier presentation, by its multifocal nature, and by its frequent cystic component.
Minimal diagnostic criteria for patients with a known family history of von Hippel-Lindau disease include the presence of a single retinal hemangioblastoma or cerebellar hemangioblastoma, renal cell carcinoma, or pheochromocytoma (14). Multiple pancreatic cysts are sufficiently rare within the general population such that their presence in an at-risk patient is a strong indication that they have inherited the mutation. In contrast, renal and epididymal cysts are generally not reliable indicators that an at-risk person carries a von Hippel-Lindau disease mutation due to the fact that they occur with a fairly high frequency within the population. However, the presence of multiple renal cysts at an early age is strongly suspicious for a diagnosis of von Hippel-Lindau disease as such a presentation is rare within the general population (14).
In the absence of a positive family history, the clinical diagnosis of von Hippel-Lindau disease can be made in a person who has at least 2 hemangioblastomas in retina, 2 in CNS, 1 in CNS, and 1 in retina, or 1 of these lesions and a characteristic visceral tumor (38). De novo mutations tend to be underrecognized compared with mutations in a familial setting.
Molecular diagnostic techniques have greatly increased the sensitivity of detection of germline mutations in individuals with von Hippel-Lindau disease. The most sensitive approach is to employ several complimentary methods including Southern blotting for entire gene deletions or gene rearrangements, fluorescent in situ hybridization to confirm deletions, and complete gene sequencing. This approach may identify germline mutations in virtually all families with von Hippel-Lindau disease (78).
A variety of diagnostic techniques has been used for the ocular hemangioblastoma (76). Indirect ophthalmoscopy is the test of choice for screening for ocular hemangioblastoma (70). Fluorescein angiography can detect lesions before they are evident by unenhanced funduscopic examination.
The diagnosis of cerebellar hemangioblastoma is easily established following MRI or MRA, which provide precise identification of the size, solid or cystic structure, site of the nodule, feeding vessels and draining veins, and relations with surrounding structures. All of these studies can be performed without surgical exploration of the posterior fossa and without the need of anesthesia or even contrast enhancement. CT and MRI without contrast have been recommended for screening for von Hippel-Lindau disease in the central nervous system and other locations (23; 71). However, the subsequent introduction of Gd-DPTA to further enhance MR studies has been shown to be the most sensitive method to detect intracranial and intraspinal hemangioblastomas (19). Gd-DTPA-enhanced MR is capable of demonstrating a larger number of lesions, can separate the tumor from the surrounding zone of edema, and can determine whether the lesion is cystic or solid. The hemangioblastoma is a highly vascular lesion with many capillary channels that enhances rapidly with contrast agents. Purely cystic lesions not enhanced by Gd-DTPA are exceptional. To maximize the contrast between lesions and the neural parenchyma, it is recommended that the injection be administered immediately before imaging. The use of MRA is critical preoperatively because it defines feeding arteries and draining veins with reliable differentiation of the vessels and further confirms the nature of the lesion. In addition, MR angiography is capable of evaluating vascular lesions anywhere in the body including the retina. However, a detailed examination of the ocular fundus is still essential to detect retinal hemangioblastomas.
Given the limitations of CT in studying the posterior fossa and spinal cord, this technique is not a reasonable alternative to MRI. It may, however, complement the MRI for the study of lesions in the abdominal organs, especially if enhanced by contrast.
Ultrasonography remains a recommended test for the study of lesions in the epididymis and may play a role in the evaluation of intra-abdominal lesions.
Ultrasound offers the advantage of real-time visualization and facilitates sampling of the tumor by fine needle aspiration or core biopsy. The diagnosis of pheochromocytoma is suggested by specific tests for this tumor, specifically the urinary elevation of catecholamines and metanephrine; biopsy or fine needle aspiration then confirms the diagnosis.
The following are considered essential steps in the management of von Hippel-Lindau disease patients, even in asymptomatic patients with genetically confirmed disease (35; 64): (1) information and advice about von Hippel-Lindau disease and its complications; (2) annual medical history and physical examination; (3) careful evaluation of any symptom attributable to this disease; (4) ophthalmological examination every 6 to 12 months beginning at the age of 6 years; (5) urine test for pheochromocytoma at least once and repeated in the event of elevation of catecholamines and metanephrine or instability of blood pressure; (6) bilateral selective renal angiography or MRA after the age of 15 to 20 years and repeated every 1 to 5 years; and (7) imaging studies by MRI and MRA of the posterior fossa and spinal cord, pancreas, and kidneys after the age of 15 to 20 years, repeated every 1 to 5 years and whenever symptoms appear that indicate evaluation sooner. Retinal hemangioblastoma may be diagnosed by careful examination of the ocular fundi. Indirect ophthalmoscopy is the screening test of choice to detect this lesion. Also, other intracranial, spinal, pancreatic, renal, adrenal, and epididymal tumors can now be detected early and diagnosed with precision using improved methods of MRI and MRA. Depending on the size, location, and nature of the tumor and the presence or absence of clinical symptomatology, the indications for surgical or other types of treatment may be established. Mathematical models to determine the optimal age for initial screening and frequency of screening for various Von Hippel-Lindau disease-associated lesions were published that propose earlier screening for adrenal lesions and delayed screening for retinal lesions (34). Revised screening criteria for children have been proposed (66).
Eyes. The management of retinal hemangioblastomas may be challenging, particularly in multiple bilateral lesions. Greater than 90% of cases can be managed by observation, laser photocoagulation, cryotherapy, plaque radiotherapy, or vitreoretinal surgery (76). The tumors in the region of optic disc should be kept under surveillance unless they show evidence of progression. Small ocular lesions diagnosed early respond well to photocoagulation and cryotherapy (02). Tumors with a diameter of less than one fourth of a disc respond better to photocoagulation. Those with a diameter between one fourth and a full disc without the complication of retinal detachment respond equally well to photocoagulation and cryotherapy. Those with a diameter greater than a disc with or without retinal detachment respond to a combination of cryotherapy and photocoagulation with xenon arc or argon laser. It seems that the argon laser can be more adequate for small lesions, the xenon arc for those with diameters between 1 and 2 discs, and cryotherapy for those that reach a diameter of 2 discs or more. Surgical excision of the tumor may be indicated in select cases. Other methods of treatment, including the use of antiangiogenic agents and photodynamic therapy, have been reported but the efficacy of these trials needs to be supported in larger studies (21; 69).
Central nervous system. Hemangioblastomas of the cerebellum are more easily approached than those of the brainstem or spinal cord. Although the resection of the solitary tumor is successful in a high percentage of cases, the final result depends on several factors, such as the nature of the hemangioblastoma, cystic versus solid (better results in cystic than in solid lesions), localization, and size. The highest mortality is observed in solid tumors of the fourth ventricle (35). Microsurgical techniques and new strategies of stereotactic radiosurgical treatment with preoperative embolization of vessels that feed the hemangioblastoma have considerably improved the prognosis of these tumors in symptomatic patients with nonresectable tumors (51; 03). The result of a study suggests infratentorial craniospinal irradiation as a potential therapeutic option for hemangioblastomas in von Hippel-Lindau disease (75). Nevertheless, the strong tendency of multifocality and recurrence remain serious problems that are incompletely resolved. Erythrocytosis, probably provoked by erythropoietin stimulation from secretions of hemangioblastoma cells, resolves after resection of the tumor and reappears in recurrent cases.
Hemangioblastomas of the brainstem are more challenging surgically, and their excision should be limited to the symptomatic tumors (86). Radiosurgery also may be used to treat symptomatic tumors that are not surgically resectable (03).
Spinal cord hemangioblastomas should be treated only if they produce progressive symptoms. The long-term results are considerably better in cases treated surgically than in those not operated (47). Moreover, diverse techniques of modern surgery, such as microsurgery, tumoral embolization, laser therapy, radiotherapy, and radiosurgery, also have provided more options for treatment.
Renal lesions. Surgical excision of benign renal cysts is usually not recommended even though doing so may prevent malignant transformation. Large carcinomas generally necessitate nephrectomy. Bilateral renal cell carcinomas generally have a poor prognosis, regardless of surgical intervention. However, it is improved after bilateral nephrectomy and transplantation if the patient survives a year free of metastatic disease (35). Radiofrequency ablation of renal lesions can also be utilized.
Pancreas. Recommendations for management of pancreatic lesions have been suggested; cystic lesions can generally be managed by observation, whereas solid lesions are of greater concern due to risk of malignancy (32). Pancreatectomy is usually not indicated, even in the presence of a completely cystic pancreas, if the patient is asymptomatic and there is no evidence of malignancy. Complete excision is indicated for mucinous cystadenoma and for carcinoma.
Pheochromocytoma. This tumor should be excised as soon as it is diagnosed and localized if the patient is otherwise stable. A few reports have advocated for adrenal-sparing surgery in pediatric patients so as to postpone steroid replacement therapy (18; 80). One recommendation is to initiate screening among von Hippel-Lindau disease patients yearly starting at age 5 (04).
Epididymis and broad ligament. In general, it is not necessary to excise cystadenomas.
Inner ear endolymphatic sac tumor. Early detection and surgical treatment of small lesions, when hearing is still present, may reduce the incidence and severity of hearing loss and vestibular dysfunction associated with these tumors (33).
Tumors of the brainstem and spinal cord carry a high risk including damage to neural tissue during surgical excision. The size of the lesion is important for selection of operative technique. A small retinal tumor may be resolved with photocoagulation or cryotherapy, whereas larger tumors often associated with secondary changes, such as retinal detachment, exudation, or hemorrhage, carry a high risk of visual loss. The cumulative probability of visual loss in all VHL gene carriers by age of 50 years was estimated to be 35% (Webster and Maher 1999). Small, solitary tumors confined to the kidney may be excised by a glomerular sparing surgery or laser ablation, whereas a large mass may require total nephrectomy. The prognosis, in spite of surgery, continues to be poor in cases where the tumor has spread outside of the kidney and in cases of bilateral renal cell carcinomas.
In select cases, pregnancy may influence the course of von Hippel-Lindau disease; additionally, it can constitute a complication in cases requiring surgical intervention (56; 25). Patients with known cerebellar hemangioblastoma may develop intracranial hypertension late in pregnancy (24), and growth of cerebellar hemangioblastoma during pregnancy has been demonstrated (20). However, another group has now shown that hemangioblastoma progression is not altered by pregnancy, which has sparked debate in the field (89). The general consensus appears to be that small patient populations are limitations in all of the studies and that a larger cohort will need to be utilized in order to fully explore the effect of pregnancy on hemangioblastoma progression in patients with von Hippel-Lindau disease.
Additional reported complications include the onset of eclampsia late in pregnancy due to inoperable pheochromocytoma (24). Improved methods of nonradiological imaging have reduced the risk to the fetus and the mother during diagnostic studies. Fundamental problems result from proximity of some structures (pancreas, adrenals, and kidneys) to the uterus and of the necessity of using general anesthesia with tumors in any location except in most ocular lesions, which can be treated under local anesthesia.
The investigation of von Hippel-Lindau disease by molecular genetic diagnostic techniques beginning at the tenth week of gestation is now possible since the identification of the carrier gene.
Any type of anesthesia may be used in patients with von Hippel-Lindau disease at any age. Standard precautions should be taken for pregnant women and hypertensive patients with pheochromocytoma.
Jennifer Baccon MD PhD
Dr. Baccon of Akron Children's Hospital and Northeast Ohio Medical University has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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