Endolymphatic Sac Tumors in von Hippel-Lindau

In 1994 members of the VHL Family Alliance began reporting to us quite a number of issues with hearing. At the time nothing was known about an aspect of VHL that might involve hearing. While many people with VHL had hearing issues, patients were usually told these hearing changes were not associated with VHL, or were the result of brain surgery or medication reactions.

Spurred by insistence of the Alliance that we felt there was more to it, the U.S. National Institutes of Health began a survey of their patients in 1994, which culminated in an important paper in 1997 clearly connecting endolymphatic sac tumors (ELST) with VHL. Despite descriptions of petrous-bone lesions by Brandt(2) and Lindau(3) in the 1920s and periodic reports of ELST in patients with VHL disease, ELSTs were not formally recognized as part of von Hippel-Lindau disease until publication of the Manski paper in 1997.(4) [2483-4]

Since that time the distinguished team of physicians who have authored these three new papers has compiled a significant amount of information and experience working with people with VHL who have been seen at the Clinical Center of the U.S. National Institutes of Health. They have analyzed reported hearing changes, worked out screening guidelines for people to detect changes early, and developed surgical techniques to remove tumors and preserve hearing.

ELSTs are very rare in the general population. In people with VHL, however, they are not rare. In fact, they can be seen on MRI or CT in 11-16% of people with VHL. [p. 2484] When the tumor can be seen, patients usually have symptoms:

• 95% have hearing loss
• 92% have tinnitus (ringing in the ears)
• 62% have vertigo (dizziness) or disequilibrium (balance problems)
• 29% have a fullness in the ears
• 8% have weakness or slackness of the nerve that runs through the cheek of your face.

Hearing loss may occur gradually over a period of 3-6 months or longer, or in some cases it may occur suddenly. Once hearing is lost it is very difficult to regain. Here again, it is very important to watch for early symptoms and address the problem carefully in order to preserve hearing.

In almost 60% of people with VHL who have subtle hearing changes, there is no evidence on imaging of an ELST. The cause of these symptoms is not known, but the authors believe that the symptoms may be due to a microscopic tumor. In this tiny area, even a microscopic tumor can cause some disturbance.

Microscopic analysis of the lesions has shown clearly that they are caused by the same mechanism that causes other VHL tumors. Everyone has two copies of the VHL gene. In people who have the condition called VHL, one of those two copies has an alteration that causes it not to work correctly. As long as the second copy is working correctly, all is well. When something happens to cause a change or deletion in that second copy of the VHL gene, a process begins in that one cell that may result in a tumor.

Figure 1. The inner ear, showing the endolymphatic sac (ELS). In the inset, you can see that the ELS is right up against the dura, the fibrous membrane that covers the brain. The bony structure is the petrous bone. Illustration courtesy of Dr. Lonser.

In the case of an ELST, the tumor forms either in the endolymphatic sac itself, or in the petrous bone. The endolymphatic duct runs from the inner ear to the back surface of the petrous bone and ends beneath the dura at the boundary of the brain as a flattened expansion, the endolymphatic sac. (See Figure 1.) This tiny structure is filled with fluid (called endolymph) and has a delicate system of pressure regulation that is responsible for one’s sense of balance and equilibrium. Menière’s disease is another condition that is caused by a disturbance in this area, and ELST’s are often misdiagnosed as Menière’s disease. It was previously thought that hearing loss from ELST resulted from invasion by the tumor of inner-ear structures. Based on their analysis, however, the authors believe that hearing loss and vestibular symptoms are more likely caused by hemorrhaging of the tumor inside the ear, and resulting damage from the bleeding and subsequent inflammation.

Fluid accumulation (called hydrops) may explain the Menière’s-like symptoms (hearing loss, tinnitus, and vertigo) in patients with ELST. Hydrops may result from blockage of the reabsorption of endolymph in the endolymphatic sac, inflammation in response to hemorrhage, or excessive production of fluid by the tumor. Fluid production is typical also of other VHL tumors.

Complete surgical resection of the ELST can make all the symptoms go away and can be performed with the preservation of hearing. Untreated, an ELST can lead to sudden profound hearing loss, which is not reversible. Early surgical intervention is important to prevent permanent damage to hearing and balance. Therefore early diagnosis on the basis of regular screenings is very important. Once there are symptoms that indicate an ELST may be present, high-resolution imaging can be used to detect small tumors or hemorrhage in the inner ear. Further advances in imaging techniques may also improve our ability to detect these tumors early.

Patients who have a visible tumor but who can still hear require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present, to prevent worsening of their balance problems. Further study is needed to determine whether patients with clinical symptoms of ELST, but without evidence of a tumor or hemorrhage on imaging, should undergo surgery to prevent hearing loss or to alleviate symptoms.

References:

1. Russell R. Lonser, M.D., H. Jeffrey Kim, M.D., John A. Butman, M.D., Ph.D., Alexander O. Vortmeyer, M.D., Daniel I. Choo, M.D., and Edward H. Oldfield, M.D., “Tumors of the Endolymphatic Sac in von Hippel-Lindau Disease.” N. E. J. Med. 2004 350:2481-2486. Dr. Kim is with the National Institute on Deafness, Dr. Butman is with the Radiology Department in the Magnuson Clinical Center at NIH, and Dr. Choo is with the Department of Otolaryngology, Children’s Hospital Medical Center, University of Cincinnati. See text PMID 15190140
CA Megerian, DI Choo, et al, “Hearing Preservation Surgery for small Endolymphatic Sac Tumors in patients with von Hippel-Lindau syndrome.” Otol Neurotol 2002; 23:378-387. See text PMID 11981399
Daniel I. Choo, et al, “”Endolymphatic Sac Tumors in von Hippel-Lindau Disease.” J. Neurosurg, 2004; 100:480-487. See text PMID 15796386
2. R. Brandt, “Zur Frage der angiomatosis retinae.” Von Graefes Arch Opthalmol 1921; 106:127-136.
3. Arvid Lindau, “Studien über Kleinhirncysten: Bau, Pathogenese und Beziehungen zur Angiomatosis Retinae.” Acta Path Microbiol Scand Suppl 1926; 1:1-128.
4. T.J. Manski, Gladys M. Glenn, Edward H. Oldfield, et al., “Endolymphatic sac tumors: a source of morbid hearing loss in von Hippel-Lindau disease.” JAMA 1997; 227:1461-1466. See text PMID 9145719

As printed in the VHL Family Forum 12:2, August/September 2004. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.