von Hippel-Lindau Disease: A Genetically Transmitted Multisystem Neoplastic Disorder Carole Hennessy Martz

ON HIPPEL-LINDAU (VHL) disease is a rare hereditary disorder in which affectedindividuals are genetically predisposed to develop certain types of tumors and cysts in multiple organs. Estimates of incidence range from one per 36,000 to 50,000 persons.l-3 Kindreds from nearly every continent have been identified.2*4*5von Hippel-Lindau disease has received recent scrutiny, along with other hereditary cancers, in hopes of identifying those individuals at risk of developing diseasemanifestations prior to symptom development.

VON

MANIFESTATIONS OF HIPPEL-LINDAU DISEASE

von Hippel-Lindau diseaseis a multisystem disorder characterized by the presenceof tumors or tumor-like cysts, most of which are not malignant but may undergo malignant transformation6 The six most common manifestations of VHL disease are associatedwith the greatestmorbidity and mortality: cerebellar, spinal, and medullary hemangioblastomas(HBLs); retinal angiomas;renal cell carcinomas (RCCs); and pheochromocytomas (PCAS).~-~ The most commonly identified pathologic lesions associated with VHL disease are listed in Table 1. Variability in expressionis characteristic. Progressionof lesions is highly variable and long mean latent periods between manifestations are common.’ Consequently, there is no age at which a family member can be consideredfree of risk of developing somemanifestation of the diseasewithout precise genetic marker analysis showing absenceof the diseasegene.‘,’

of clinical evaluation.8”’ The phenomenonof genetic anticipation may also occur. This meansthat clinical manifestations of VHL disease may become apparentat an earlier age in successivegenerations.6.7 The VHL disease gene has been mapped to a small region on the short arm of chromosome3 at 3~25~26.‘~~‘~ Tightly linked DNA markers, including flanking markers, have been identified. Recent analysis of VHL diseasefamily data suggests that distinct clinical subtypes of the disease may exist and raises the possibility that mutant alleles on the VHL diseasegene, yet located within the samelocus, may produce the variety in clinical expression.‘,14In addition, a linear arrangementof several different adjacentunits has been suggested as the mechanismresponsiblefor the various manifestations noted in different families. l5 DIAGNOSIS AND TREATMENT OF VON HIPPEL-LINDAU DISEASE

A positive diagnosis of VHL disease requires the presenceof two characteristic lesions in one individual or in two related persons. To fit Melmon and Rosen’s traditional classification, one of these lesions must be either a central nervous system (CNS) hemangioblastomaor a retinal angioma (RA).6 However, for individuals with a family history of VHL disease,finding one of the more common pathologic lesions of VHL diseaseis considered diagnostic. In those individuals in whom VHL diseaseis diagnosedand no family history of the diseasecan be elucidated, the individual must be consideredto have developed a new VHL diseasemutation.g A list of clinical situations leading

GENETICS AND MOLECULAR BIOLOGY OF VON HIPPEL-LINDAU DISEASE

Similar to many hereditary cancer syndromes, VHL diseaseis transmitted in an autosomal dominant manner. The VHL disease gene appearsto function as a tumor suppressorgeneand to fall into the category of hereditary tumor development proposed by Knudson. lo Penetranceof the gene may near 100% with advancing age and thoroughness Seminars

in Oncology

Nursing,

Vol 8. No 4 (November),

1992:

pp 281-287

From the Radiation Therapy Department, Elmhurst Memorial Hospital, Elmhurst. IL. bole Hennessy Martz, MS, RN, OCN: Oncology Clinical Nurse Specialist, Radiation Therapy, Elmhurst Memorial Hospital. Address reprint requests to Carole Hennessy Martz, MS, RN, OCN, 314 S. Wille St, Mt Prospect, IL 60056. Copyright 0 1992 by W.B. Saunders Company 0749-2081/92/0804-C009$5.0@/0

281

CAROLE H. MART2

Table 1. Pathologic Lesions Associated Hippel-Lindau Disease6*8,s

with

von

HBLs of the central nervous system (cerebellar, medullary, spinal) Retinal angiomas Renal cysts, adenomas, carcinomas, and angiomas Pancreatic cysts, carcinomas, islet cell tumors, and adenomas PCAs and paraganglioma Cystadenoma and cysts of the epididymus

to suspicion of VHL diseaseand requiring further evaluation is provided in Table 2. Family pedigree analysesare integral to the investigation of risk for individuals suspectedas having VHL diseaseprior to diagnostic testing. For a positive diagnosis to be made, the proband and all first-degree relatives should undergo a thorough screening evaluation to detect asymptomatic lesions. As you can see from the pedigree of the VHL diseasefamily shown in Figure 1, diagnosis is often missed until several manifestations have been identified in a family, often over several generations. In this family, the proband had sought medical attention for increasing visual floaters. Initially diagnosed with a retinal detachment, he was referred to a large midwestem medical center. On detailed ophthalmologic examination, he was found instead to have several unilateral retinal angiomas. Having seen these lesions previously in families with VHL disease, the physician questioned the young man about his family diseasehistory. On informing the physician that both his father and paternal grandfather had died from renal cell carcinoma, the diagnosis of VHL diseasewas made. In addition, the mother indicated that the young man’s father had also had a testicular cyst. Subsequent evaluation of the proband’s siblings Table 2. Clinical Situations Suspicious for von Hippel-Lindau Disease and Requiring Further Evaluation Family history of VHL Family history of PCA Family history of RCC Epididymal cystadenoma Bilateral multifocal RCC Bilateral PCA, ectopic PCA RCC in a person under the age of 30 years Pancreatic cysts Multiple HBLs of the CNS Retinal angiomas Bilateral, multifocal renal cvsts Reprinted

with permission?

i

RCC 67

ii

h RA EC

Fig 1. Pedigree of a family with VHL disease. 0, Female; deceased; PA, retinal angioma; EC, 0, male; n , affected;‘* epididymal cyst; RCC, renal cell carcinoma; AODM, adult onset diabetes mellitus; & , proband.

found a younger brother affected with asymptomatic, bilateral retinal angiomas and a testicular cyst. His other two siblings were later screenedat the National Institutes of Health and found to be free of disease manifestations. In addition, their DNA blood analysesindicate they did not inherit the diseasegene. The proband has since refused further screening while his younger brother continues to follow annual screening recommendations. It is not yet known whether the proband’s infant son has inherited the diseasegene. Presentingsymptomsof VHL diseaseare dependent on the location and size of lesions. Symptoms associatedwith the more common manifestations of VHL diseaseare listed in Table 3. Early identification of involvement is critical to prevent or delay life-threatening complications. Diagnostic evaluation should include a search for all of the more commonly occurring VHL disease lesions. Diagnosis tests recommendedfor this purpose and associatedfindings are listed in Table 4. Age of onset of lesions varies, but, in general, retinal angiomas and HBL are the earliest to appear. Visceral lesions are often silent and rarely clinically apparentuntil late in the diseasecourse. Renal cell carcinomasare typically the last manifestation displayed.7-9 RETINAL ANGIOMAS

Retinal angiomas (also referred to as von Hippel’s tumor) are detectedin roughly one half of all diagnosedcasesof VHL disease.The averageage of onset is 25 years, with a range of 2 to 67 years.3v7,8These angiomas are histologically benign but may be multiple, bilateral, and recurrent.

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DISEASE

Table 3. Symptoms Disease

Organ

of the Most

Involvement

Manifested Earlv

Lesions

of von Hippel-Lindau

Spinal cord6s.‘8,‘9

Late SvmPtoms

Gait disturbances, slurred speech, papilledema, dizziness, decreased visual acuity, nystagmus, rarely mental changes Motor deficits, muscle wasting, anesthesia, paraplegia, subarachnoid hemorrhage Subarachnoid hemorrhage, sensory and motor deficits, urinary incontinence

Leg weakness, loss of sensation, impaired proprioception, back pain, syncope, incontinence, vertigo Headache, nausea, vomiting, ataxia, nystagmus Decreased visual blurred vision

angioma

Disease

Svmptoms

Occipital or frontal headaches, intermittent nausea and vomiting

HBL

Retinal

Commonly

acuity, floaters,

Pain, cataracts,

glaucoma,

blindness

RCC

Kidney6.8.9.22.23

Microscopic

PCA

Adrenal

Intermittent blood pressure elevations, throbbing headaches, episodic palpitations, episodic flushing, tachycardia, nervousness

Sweating, tremors, postural dizziness, weight loss, palpable mass, nausea

intermittent abdominal

Nausea and vomiting, palpable abdominal mass, diabetic symptoms

Pancreatic

gland”s~20~2’~24

cvsts

Epididymal cystadenoma and cysts

hematuria

Gross hematuria. mass

nausea and vomiting, fullness

None

Palpable

flank pain, palpable

mass, possible

infertility

Adapted from the Oncology Nursing Forum with permission from the Oncology Nursing Press, Inc. Martz CH: von Hippel-Landau disease: A genetic condition predisposing tumor formation. Oncol Nurs Forum 18:545-551, 1991.

Ocular symptoms vary on the size, location, and secondary effects of the tumor. Diagnosis requires a detailed eye examination that should include indirect ophthalmologic examination, fluorescein angiography, and tonometry. Left untreated, these lesions may progress to retinal detachment, glaucoma, and blindness. Treatment involves the use of surgery consisting of laser photocoagulation or cryotherapy. Advanced lesions may require enucleation. Careful follow-up is imperative to prevent or delay visual ~oss.~,‘~.‘~ Table 4. Tests Used in the Diagnosis Organ Involvement CNS Kidney Adrenal

gland

Primarv

of Lesions

CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMAS

Hemangioblastomas of the CNS occur in one half to two thirds of all cases of VHL disease and are known to cause the greatest mortality,h-8 Average age at diagnosis is 29 years, with a range of 12 to 65 years. Most commonly located in the cerebellum (referred to as Lindau’s tumor), HBL may also occur in the spine and brain stem at the craniocervical junction.’ Associated

With von Hippel-Lindau

Tests

Disease’,’

Additional

Tests or Findinas

MRI, brain and spinal cord*

Neurologic

examination,

CT scan or ultrasound,

Urinalysis,

polycythemia

CT scan, adrenalst; catecholamines;

kidneyt

Hypertension,

24-hour urinary serum catecholamines

Pancreas

CT scan, pancreast

Retina

Fluorescein

angioscopy,

Testicle

Ultrasound,

scrotum

*Immediate reporting of neurologic symptoms screening. tcomputed tomography scans of the abdomen abdominal ultrasound is used.

Endocrine indirect

Palpable

are performed

by some

hypercalcemia,

or exocrine

enlarged

thyroid

tests

Tonometry

ophthalmoscopy

is suggested

polycythemia

physicians

on patients

mass, infertility

in lieu of annual

age 20 years or greater.

MRI scans following

initial

Under the age of 20 years

CAROLE

Hemangioblastomasmay be cystic, solid, hemorrhagic, or mixed. Although generally histologically benign, they may result in hemorrhage, obstructive hydrocephalus, increased intracranial pressure, and death. Symptoms vary by site, size, and history of previous surgical resections. Progression of symptoms is highly variable.‘*18 Neumann et all9 reported that an averageinterval of 25 weeks occurs between the initial onset of symptoms and the diagnosis of HBL. Gadoliniumenhancedmagnetic resonanceimaging (MRI) has beenfound to be superior to computedtomography (CT) scanning in the diagnosis of these lesions.18 It has been noted that patients diagnosed with HBL are frequently polycythemic. Recent studies analyzing the content of cystic fluid from resected CNS lesions have detectedhigh levels of erythropoietin, which may gain accessto the bloodstream directly from the tumor or indirectly via leakage into the CNS.26A return of erythrocytosis following surgical removal of an HBL may signal recurrence, incomplete resection of the tumor, or development of another manifestation of VHL disease, such as RCC. Microsurgical removal of HBL is recommended when symptomatic or life-threatening. Asymptomatic lesions may be monitored closely. However, the VHL disease patient and family must be informed of the importance of reporting the onset of focal neurologic symptoms.9*‘9*27Surgical outcomeis very much dependenton the location, size, and nature of the lesion.’ von Hippel-Lindau disease hemangioblastomastend to be multiple and recurrent, and may be scattered,making complete surgical excision impossible in some cases. Conventional or stereotactic irradiation may be useful in thesesituations or with inoperable lesions. Ventriculoatrial shunts are occasionally used to managehydrocephalussecondaryto tumor obstruction. Prior to any surgical procedure, however, the presence of occult pheochromocytomasmust be evaluated to prevent potential anesthetic complications.20’21 RENAL CYSTS AND CARCINOMAS

Renal cell carcinomasoccur in nearly half of all personsaffected with VHL diseaseand are the second leading cause of death in this population.‘,” Simple renal cysts occur more commonly. Average age at diagnosis is 37 years, with a range of 20

H. MART2

to 67 years. It is projected that as more people survive treatment for HBL, more will succumb to death from renal carcinomasbecausediagnosis of RCC is often delayed due to the absenceof symptoms until late in the diseasecourse. As a result, the presence of metatasis to the retroperitoneal lymph nodes or lung at diagnosis is not uncommon.‘s8 Close follow-up of individuals diagnosed with other manifestations of VHL diseaseis indicated to detect the development of renal carcinomas in the early stages. Annual abdominal CT scansor abdominal ultrasounds are the tests used for diagnosis. Recent studies suggestthat atypical renal cysts, as opposedto simple cysts, may be on a morphologic continuum with a progression to cancer over time. Rapidity of progression and the best method for distinguishing between simple and atypical cysts have not been established but may lead to earlier identification of at-risk individuals in the future.28,29 Like the hemangioblastomas associated with VHL disease,RCCs also tend to be multiple, bilateral, and recurrent, and may causepolycythemia secondaryto secretion of erythropoietin by the tumor or cyst. Surgeons now recommend renalconserving surgeries, such as partial nephrectomy or cyst enucleation, as opposed to total nephrectomy.22,23Renal cell carcinomas tend to be radioresistant and respond poorly to conventional chemotherapy. As yet, the inclusion of these patients into clinical trials using interleukins and other investigational drugs has not been attempted due to unknown effects on other VHL diseasetarget organs.3oIt has not yet been attempted, but it may becomefeasible one day for personsaffected with VHL diseaseRCCs or premalignant conditions to undergo bilateral nephrectomyand receive a donor kidney from a sibling who is known not to have acquired the diseasegene.3 PHEOCHROMOCYTOMAS

Pheochromocytomaoccurrence in VHL disease tends to be clustered in certain predisposedfamilies. The overall incidence appearsto be 12% to 18%. Age at onset is variable, but in affected families PCAs generally occur sometime in the early 30s with a rangeof 10 to 56 years.“* Lesions often occur bilaterally, may be multiple, and recur after surgical excision. Time lapse betweenthe onset of symptoms and diagnosis averages 1 year. Symp-

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285

toms are frequently dismissed as psychosomatic (refer to Table 3). These lesions may secrete a variety of catecholamines, thereby explaining the diversity in presentation. Ninety percent of PCAs occur in the chromaffin cells of the adrenal medulla. The remainder occur in extra-adrenal chromaffin tissues (called paraganglioma).” Diagnosis of PCA in VHL disease is made through analysis of blood pressure(recumbentand standing), serum calcium, serum and urinary catecholamines, and abdominal ultrasound or CT scan. Occasionally, a ‘311-MIBG(metaiodobenzylguanidin) scan may be used to assist in detecting extra-adrenal catecholamine-secretingtumors.8,24 Elevated blood pressure, serum and urinary epinephrine and norepinephrine levels, and hypercalcemia, as well as radiographic evidenceof an adrenal mass, tend to substantiate the diagnosis of PCA. The associatedhypercalcemia is thought to be related to the action of catecholamines either indirectly via releaseof parathyroid hormone or by direct action on the bone. Enlargement of the thyroid gland may also occur.20Y2’,31 Occasionally, PCAs are symptomatic, but a definite lesion cannot be identified. Conversely, some individuals have radiographic evidence of tumor but maintain normal blood pressure, calcium, and catecholamine levels.*O,*’,24 Surgery is the treatment of choice for symptomatic PCA and lesions greater than 5 cm in size. Metastasisrarely occurs. Preoperativepreparation requires adrenergic blocking agents, such as phenoxybenzamine hydrochloride (Dibenzyline; Smith Kline Beecham, Philadelphia, PA), 10 mg twice daily beginning 2 weeks prior to surgery. This drug prevents excessivecatecholaminesecretion during surgery. If there is a history of cardiac arrhythmias or a heart rate over 110 beats/min, a beta blocker such as propranalol may be added. If bilateral adrenalectomy becomes necessary, lifetime adrenal hormone replacementtherapy will be necessary.Recurrent elevations of serum calcium or catecholamines may signify incomplete resection of the PCA or new tumor formation, necessitating further work-up. 9,20,2 ’ PANCREATIC CYSTS, ADENOCARCINOMAS, ISLET CELL TUMORS

AND

Pancreatic lesions in VHL diseasemay consist of cysts and/or a variety of solid tumors: cystade-

nomas, islet cell tumors, and carcinomas. Occasionally, cysts and tumors are diagnosedsynchronously. Pancreatic cysts occur in approximately 85% of all VHL diseasecasesbut are also found in the normal population. I4 Mean age at onset or detection of these cysts is 37 years, with a range of 15 to 49 years.7*31Rarely symptomatic, their existence is typically found incidentally or during screening for VHL disease lesions. Studies used for diagnosis are listed in Table 4. Surgical excision is advised when pancreatic adenocarcinomas are detectedor if islet cell tumors becomehormonally active.9.25 EPIDIDYMAL CYSTADENOMAS

AND CYSTS

Epididymal cystadenomas occur in approximately 10% of VHL diseasemales and epididymal cysts occur in 7% of affected men. Lesions are frequently bilateral. Diagnosis is made by palpation on physical examination or via ultrasound of the scrotum. Because of the high prevalence of epididymal cysts in the general male population, they are no longer consideredaffirmative evidence of VHL disease in at-risk individuals in the absenceof other diseasemanifestations. Due to the benign nature of these lesions, no treatment is required.9.‘5 SCREENING RECOMMENDATIONS

It is extremely important that health care providers persist in pursuing further evaluation of a patient who presentswith any of the clinical indicators suspicious for VHL diseaseas listed in Table 2. This is particularly true for any individual who has been diagnosed with a CNS hemangioblastoma, PCA, or early onset RCC (under the age of 30 years). A pedigreeanalysis is a good starting point and may quickly elucidate whether an individual should be considered as affected. Any patient diagnosedwith an HBL, PCA, or early onset RCC should also undergo a thorough diagnostic screeningevaluation to rule out other target organ involvement. Involvement of a geneticist will facilitate coordination of the screening tests required. If any of the testsas outlined in Table 4 are positive, subsequentscreening of all first-degree family membersis advised. These tests should be performed on affected individuals on an annual basis. At-risk relatives should receive physicals and detailed eye examinations annually and other

CAROLE

286

screening tests at 2 to 3-year intervals. Should a person become symptomatic, however, the frequency of testing is increased.’ It is essential that all family members and their physicians realize that screening of a single systemis inadequatebecauseit is not possible at this time to predict which manifestations of VHL diseasewill develop over time. The ageat which screeningof at-risk individuals should commencevaries. A detailed eye examination should be performed annually beginning within the first 2 years of life. Baseline evaluation for the presenceof CNS lesions using gadoliniumenhancedMRI is suggestedbeginning at 10 years of age. Some physicians suggest delaying further MRI examinations until CNS symptoms occur. Screening for abdominal manifestations of VHL disease should commence in the early teens. For persons under the age of 18 years abdominal ultrasoundis suggested.After the ageof 18 yearsCT of the abdomen is the diagnostic procedure of choice.99’8 NURSING IMPLICATIONS

As with the diagnosis of any potentially lifethreatening illness, the family diagnosed with VHL disease experiences a variety of emotions ranging from denial and rage to guilt and outright fear. These emotions may vary greatly from one family member to another and from one week to the next. The oncology nurse is in an ideal position to assist families in coping with the enormous physical, emotional, financial, and psychosocial strains that may be placed on them. Integral to this approach is supplying them with accurate and timely information. Emphasizing a senseof hope and clarifying the need for early diagnosis are essential.32 The nurse can also assist the family in understanding which symptoms should be reported, the schedule for screening tests, and any required preparation. Multiple surgeries are often necessary.30

ii. MAR-f-2

Many people diagnosed with familial diseases develop fatalistic attitudes about their risks of developing disease manifestations. This is particularly true if the family’s only experience with the diseasehas been the loss of a loved one. Ventilation of feelings and concerns should be encouraged. Support renderedthrough contact with other families affected with VHL disease can be very beneficial. Families may require more intense counseling regarding personal and financial matters as well. Referral of families to medical centers* where researchersare diligently working to isolate the VHL diseasegeneand study diseasecharacteristics can often afford these families with the most upto-date information. At present, however, predictions regarding inheritance of the disease gene must be basedon a detailed clinical and diagnostic examination in combination with DNA polymorphisms analysis. CONCLUSION

von Hippel-Lindau disease is a rare hereditary diseasethat can greatly impact a family’s senseof emotional and physical well-being. Easily misdiagnosed,VHL diseaseis a lifelong diagnosis that requires intense follow-up for multiple and often recurrent tumors. Oncology nurses must maintain an index of suspicion for such hereditary conditions whenever they seepatients who present with unusual diseasemanifestationsand early age onset cancers. In doing so, potential family cancer syndromes will becomeidentified earlier, thereby affording families the best possible medical care. ACKNOWLEDGMENT The author gratefully acknowledges the assistance of Dr Zbar in reviewing this manuscript for accuracy.

*Dr Zbar, National Institutes of Health, Bethesda, MD; Dr Seizinger, Massachusetts General Hospital, Boston, MA; and Dr Vance, University of North Carolina at Chapel Hill.

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3. Glenn GM, Linehan WM, Hosoe S, et al: Screening for von Hippel-Lindau disease by DNA polymorphism analysis. JAMA 267:1226-1231, 1992 4. Go RCP, Lamiell JM, Hsia YE, et al: Segregation linkage analysis of von Hippel-Lindau disease among 220 descendants from one kindred. Am J Hum Genet 36:131-142, 1984

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