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First published on December 13, 2007
This version was published on February 1, 2008
Neuro Oncol 2008 10(1):73-78; DOI:10.1215/15228517-2007-047
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Clinical Investigations

Acoustic neuromas following childhood radiation treatment for benign conditions of the head and neck

Arthur B. Schneider, Elaine Ron, Jay Lubin, Marilyn Stovall, Eileen Shore-Freedman, Jocelyn Tolentino and Barbara J. Collins

Section of Endocrinology and Metabolism, University of Illinois College of Medicine, Chicago, IL (A.B.S., E.S.-F., J.T., B.J.C.); Division of Epidemiology and Genetics, National Cancer Institute, Rockville, MD (E.R., J.L.); Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX (M.S.); USA

Address correspondence to Arthur B. Schneider, University of Illinois College of Medicine, Section of Endocrinology, Diabetes and Metabolism (MC 640), 1819 W. Polk St., Chicago, IL 60612, USA (abschnei{at}uic.edu).


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Childhood radiation exposure has been associated with an increased risk for developing several neoplasms, particularly benign and malignant thyroid tumors, but little is known about the risk of developing acoustic neuromas. The aim of this study was to confirm whether there is a risk for acoustic neuromas and, if so, to determine its magnitude and duration. We investigated the time trend and dose-response relationships for acoustic neuroma incidence in a cohort of 3,112 individuals who were irradiated as children between 1939 and 1962. Most of the patients were treated to reduce the size of their tonsils and adenoids and received substantial radiation exposure to the cerebellopontine angle, the site of acoustic neuromas. Forty-three patients developed benign acoustic neuromas, forty of them surgically resected, far in excess of what might be expected from data derived from brain tumor registries. The mean dose (±SD) to the cerebellopontine angle was 4.6 ± 1.9 Gy. The relative risk per Gy was 1.14 (95% confidence interval 1.0-1.3). The earliest case occurred 20.4 years after exposure and the latest 55 years after exposure (mean 38.3 ± 10.1 years). Our study provides support for an association between acoustic neuromas and childhood radiation exposure. Although acoustic neuromas are usually benign and often asymptomatic, many cause significant morbidity. Following childhood radiation exposure, they appear after a long latency and continue to occur many decades afterward. Any symptoms of an acoustic neuroma in a patient with a history of radiation to the head and neck area should be investigated carefully, and the threshold for employing imaging should be lowered.

Key Words: Acoustic neuromas • dose-response relationships • radiation-related neoplasms


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
For the last 30 years, we have been studying a cohort of irradiated patients to determine health risks related to their exposure. We have reported on the increased incidences and dose-response relationships for benign and malignant thyroid tumors, benign and malignant salivary gland tumors, and benign parathyroid tumors.1-5 We also have described an increased frequency of acoustic neuromas and schwannomas in other parts of the body in this cohort.6,7 An association between radiation exposure and schwannomas, including acoustic neuromas, has been suggested by reports of cases in radiation-exposed cohorts and sporadic case reports.8-16 Only recently, however, have the dose-response relationship between radiation and schwannomas and the effects of other risk factors been investigated.17 Studies of schwannomas have been limited because the tumors are rare, and usually only symptomatic ones are clinically diagnosed. This is the first report to evaluate radiation-related acoustic neuromas specifically. We describe the dose-response relationship for acoustic neuromas and observe that cases continue to occur as late as the fifth decade after exposure.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The cohort consisted of 4,296 patients who received conventional radiation therapy for benign conditions in the head and neck area before their 16th birthday, between 1939 and 1962. We began following this cohort in 1974 and have described it, including the details of the radiation treatments, previously.3-5 Briefly, the large majority of patients were irradiated for "enlarged" tonsils and adenoids through symmetric fields centered on the posterior pharynx. Typically, treatments were delivered in three weekly sessions with a total dose of 7.5 Gy or 9 Gy. In the current study 3,112 (72.4%) subjects with adequate follow-up information, defined previously as reliable information about whether or not the subject had thyroid surgery, and estimated radiation dose to the cerebellopontine angle are included. Follow-up efforts occurred uniformly without regard to dose. Subjects were informed about the potential risk of Schwann cell tumors and specifically acoustic neuromas starting about 1986, but no early detection screening has been conducted. The diagnosis of acoustic neuroma was confirmed by a review of the operative reports, pathology reports, and, when available, original pathology slides.

Radiation doses to the cerebellopontine angle, the site of acoustic neuromas, were estimated. Approximately 12% of the study population received more than one course of treatment. Typically these subjects received retreatment to the posterior pharynx or treatment to a second area in the head and neck region. In 87 subjects (3.0%) where the doses administered to the left and right sides differed, the mean dose to the right and left sides was used for analysis.

Data were analyzed using Cox proportional hazards regression methods, as implemented by the Epicure 2.11 computer software program (Hirosoft International, Seattle, WA, USA), with age at treatment as the entry time and age at event or age at end of follow-up as the event or censoring time.18 The score test was used to test for a linear trend of risk over continuous doses.18 Dose categories for relative risks (RR) were defined as <4.45, 4.45-<4.75, 4.75-<5.35, and >5.35 Gy. These were selected according to quartiles for the cases, modified to account for cases with equal doses. Since there was no unexposed reference group available for analysis, the lowest quartile was used as the reference category. We chose to use quartiles based on the number of cases rather than the number of subjects to create a stable reference group with enough cases while emphasizing lower doses. Confidence intervals for the estimated βs by Cox analysis were computed using likelihood-based methods.19 We evaluated variations in the dose-response relationship within categories of age at first radiation exposure and sex. The Kaplan-Meier20 method was used to plot tumor-free survival. For this purpose, time to event was defined as the date of the first radiation treatment until surgery for an acoustic neuroma or the date of last contact. Nonparametric group comparisons were performed with the Mann-Whitney test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical Findings
During follow-up, 43 of the 3,112 members of the study cohort developed acoustic neuromas. Forty cases were histologically confirmed and three cases were diagnosed on the basis of radiographic evidence, without surgical confirmation. The initial acoustic neuroma was on the right side in 25 cases, the left side in 15 cases, bilateral in 1 case, and unknown in 2. No patients were treated with radiation as their primary therapy, but three recurrences were treated with gamma knife therapy. These occurred 3, 4, and 18 years after the initial surgery.

One case of bilateral acoustic neuromas was detected radiographically in a patient who had other Schwann cell tumors diagnosed earlier. It is not known whether these tumors occurred as a result of neurofibromatosis type 2 or radiation exposure. In one case, a second acoustic neuroma was diagnosed 10 years after the first, but information as to whether it was ipsilateral or contralateral was not obtained.

The demographic and treatment characteristics of the cohort and the 43 individuals who developed acoustic neuromas are shown in Table 1. No differences were observed when patients who developed acoustic neuromas were compared with the rest of the cohort, with respect to the proportion of males (62.8% vs. 60.1%) and the other demographic characteristics shown in the table.


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  		Table 1. Demographic characteristics of the individuals included in this study and those who developed acoustic neuromas

 

The distribution of radiation doses to the cerebellopontine angle is shown in Fig. 1. The dose range was narrow, with an interquartile range of 4.4-4.9 Gy. The mean dose to the cerebellopontine angle was 4.62 Gy for the 3,069 cohort members who did not develop acoustic neuromas and 5.27 for the 43 members who did. The difference between the means of the doses was significant by the t-test, and the distribution of the doses was statistically different as determined by the Mann-Whitney test (both p < 0.05). The Kaplan-Meier plot of the acoustic neuromas in Fig. 2 shows that after 20 years cases have accrued throughout the follow-up period. The first acoustic neuroma occurred 20.4 years after exposure, and the tumor with the longest latency, the time interval between exposure and the occurrence of an acoustic neuroma, occurred after 55 years.


Figure 1
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  		Fig. 1. Distribution of estimated doses (Gy) to the cerebellopontine angle for the 3,112 individuals included in this study.

 

Figure 2
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  		Fig. 2. Kaplan-Meier plot of acoustic neuroma-free survival from the time of radiation exposure. The intersecting vertical lines indicate the time points at which the population at risk decreases by 500 individuals.

 
Dose-Response Relationships
Based on Cox regression, there was a statistically significant trend with dose (Table 2). The relative risk per Gy (RR/Gy) was 1.14, with a 95% confidence interval of 1.0-1.3, and the risk was not significantly modified by gender.


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  		Table 2. Acoustic neuromas, subjects, person-years, disease rates, relative risksa (RR), and 95% confidence intervals (CI) by categories of estimated dose

 

There was a nonsignificant decrease in the magnitude of the dose-response relationship with increasing age at exposure. This relationship was seen using alternative statistical models (linear, power, linear-exponential) for the dose-response relationship (data not shown). There was no correlation between exposure dose and latency.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main findings of this study concern the association of childhood radiation exposure and acoustic neuromas. Our results are consistent with a linear dose-response relationship for acoustic neuromas and strongly support a causal role for radiation. They also show that acoustic neuromas continue to occur into the fourth and fifth decades after exposure (Fig. 2).

Recently, the secular trend for acoustic neuroma incidence in the United States has been investigated.21 The findings were derived from data obtained from 11 collaborating brain tumor registries and, independently, from the Los Angeles County Cancer Surveillance Program. The authors of this investigation concluded that the incidence has been increasing, and they suspect that it is due to the introduction of more precise diagnostic methods. Our findings presented here tentatively raise the possibility that radiation exposure may have contributed to this trend.

The data from the 11 collaborating brain tumor registries and the Los Angeles County Cancer Surveillance Program give similar estimates for the incidence of acoustic neuromas during 1995-1998, that is, 0.6 and 0.8 cases per 100,000 person-years, respectively. These estimates give a projection of <1 expected case in the cohort studied here, even uncorrected for the lower rates in prior years.

Although the dose-response relationship confirms the association of radiation with acoustic neuromas, the risk estimate appears smaller than would be anticipated considering that 43 cases were observed in the cohort versus <1 case predicted from population-based rates. However, the lack of nonexposed subjects in this study, imprecision in the dose estimates, relatively narrow dose range, and uncertainty in which model best represents the data make it inappropriate to extrapolate to zero dose. Also contributing to this apparent difference may be the characteristics of the cohort and tumor ascertainment. The cohort is quite uniform in race and ethnicity, although these are not known to be factors in acoustic neuroma incidence. Also, even though most surgically resected acoustic neuromas are symptomatic, there may be differences in how frequently they are diagnosed based on access and use of medical services. The cohort has a relatively high educational and economic level, and cohort members are aware of their radiation exposure and the associated elevated risks of thyroid and other head and neck tumors, which may result in earlier or more accurate diagnoses.22 Age at radiation treatment is a strong modifier of the dose-response relationship for thyroid tumors in this cohort.3 A decreasing risk with increasing age at exposure also was seen for acoustic neuromas, but the association was not statistically significant.

To date, the most detailed dose-response analysis for schwannomas is the study of atomic bomb survivors in Hiroshima and Nagasaki.17 In slightly more than 80,000 individuals, including 32,600 with little or no exposure, 55 cases of schwannomas (including 22 spinal schwannomas) were observed and a significant dose-response relationship was demonstrated. The relative risk at 1 Sv (sievert) was 4.5. In nearly 11,000 persons irradiated as children for tinea capitis in Israel from 1948 to 1960, three acoustic neuromas were described in a 1988 report compared to none in the nonexposed comparison population of more than 16,000 people.9 In a Rochester, NY, study reported in 1976, a cohort of children whose thymus glands had been treated with radiation during the same era as the cohort in the current report included one acoustic neuroma.12 Results from these studies, however, are not directly comparable to those presented here. The atomic bomb survivor and Israel tinea capitis studies reported results for all schwannomas, whereas we have restricted our analysis to acoustic neuromas, and the doses in the present study are several-fold higher than those in the other studies.

Acoustic neuromas have not been reported as second tumors in survivors of childhood cancers whose treatment included radiation therapy to the head and neck region. There are several possible reasons for this. Some studies of second neoplasms depend on linkage to cancer registries to ascertain subsequent tumors,23 and although some cancer registries do obtain information on benign meningiomas, very few register acoustic neuromas. Other studies obtain information on previous tumors from self-reports on surveys.24,25 How accurately these ascertain acoustic neuromas is uncertain and probably depends on the precise wording of the questions and the level of medical knowledge of the study population. Our findings (Fig. 2) and those from the Israel tinea study9 and atomic bomb survivors17 emphasize the long latency of acoustic neuromas, much longer than for meningiomas. Acoustic neuromas develop asymptomatically. When symptoms do occur, there often is a considerable lag before medical attention is sought and the diagnosis made. Thus, studies of second tumors, including the landmark Childhood Cancer Survivor Study,25 probably do not yet have sufficient follow-up to assess the occurrence of acoustic neuromas. As a result of these considerations, it should be mentioned that acoustic neuromas may emerge as a late problem in childhood cancer survivors.

Efforts have been made to identify other risk factors, besides radiation exposure, for developing acoustic neuromas. While two studies suggest that exposure to loud noise is a risk factor and one study suggests a history of nonmedullary thyroid cancer as a risk factor, no other risk factors have been identified with certainty.26-28 Much effort has gone into determining whether magnetic waves, from cell phones or occupational exposure, increase the risk for acoustic neuroma. In a recent review, Propp et al.21 did not find adequate evidence to support these associations.

In the clinical setting, an effort should be made to estimate an individual's risk. Since the present study shows a linear dose-response relation, patients with higher doses are at greater risk. However, it is rarely possible to know the precise dose to the cerebellopontine angle. Another indicator of an increased risk is the prior occurrence of a radiation-related neoplasm. Previously, we observed that of 70 individuals in this cohort with neural tumors, 7 had multiple tumors.7 We also observed a larger than expected number of individuals with multiple radiation-related neoplasms.29,30 Although we initially postulated that this was due to increased susceptibility, it now appears that known factors, including larger radiation doses, account for these findings. Nevertheless, the presence of one tumor (thyroid, parathyroid, salivary, or neural) should be taken as an indicator of an increased risk for another.

The findings in this article raise the question whether asymptomatic irradiated patients should be screened for acoustic neuromas. Screening for hearing loss has been recommended for older individuals in the general population, and in irradiated patients the possibility of an acoustic neuroma should be considered.31 One approach that has been suggested is that all patients who notice hearing loss should be tested further, and that all elderly patients should be screened with a whispered-voice test.31 In irradiated patients, hearing loss, particularly if it is asymmetric, and symptoms of vestibular disease should raise the suspicion of an acoustic neuroma. Hearing loss, tinnitus, sensory deficits, and gait disturbances were the symptoms, in decreasing order of frequency, observed among the atomic bomb survivors who developed acoustic neuromas.16

Because acoustic neuromas are continuing to occur 50 years after exposure, people who have been exposed to head or neck radiation as children should be both informed and questioned about potential symptoms so they can notify their physicians promptly if they develop any of them.


   Acknowledgments
 
We thank Rita Weathers at M. D. Anderson Cancer Center for her help in the dose reconstruction. This work was supported, in part, by NIH Research Grant CA-21518, contracts NO1-CP-85604 and NO1-CP-95614, and the intramural research program of the National Cancer Institute, NIH.

Received for publication September 6, 2006. Accepted for publication March 14, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  • Favus M, Schneider A, Stachura M, et al. Thyroid cancer occurring as a late consequence of head-and-neck irradiation. N Engl J Med. 1976;294: 1019-1025.[Abstract]

  • Fogelfeld L, Wiviott MBT, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med. 1989;320: 835-840.[Abstract]

  • Schneider AB, Ron E, Lubin J, Stovall M, Gierlowski TC. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab. 1993;77: 362-369.[Abstract]

  • Schneider AB, Gierlowski TC, Shore-Freedman E, Stovall M, Ron E, Lubin J. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab. 1995;80: 254-257.[Abstract]

  • Schneider AB, Lubin J, Ron E, et al. Salivary gland tumors after childhood radiation treatment for benign conditions of the head and neck: dose-response relationships. Radiat Res. 1998;149: 625-630.[CrossRef][Medline]

  • Shore-Freedman E, Abrahams C, Recant W, Schneider AB. Neurilemomas and salivary gland tumors of the head and neck following childhood irradiation. Cancer. 1983;51: 2159-2163.[CrossRef][Web of Science][Medline]

  • Sznajder L, Abrahams C, Parry DM, Gierlowski TC, Shore-Freedman E, Schneider AB. Multiple schwannomas and meningiomas associated with irradiation in childhood. Arch Intern Med. 1996;156: 1873-1878.[Abstract/Free Full Text]

  • Morbidini-Gaffney S, Alpert TE, Hatoum GF, Sagerman RH. Benign pleural schwannoma secondary to radiotherapy for Hodgkin disease. Am J Clin Oncol. 1005;28: 640-641.[CrossRef]

  • Ron E, Modan B, Boice JD Jr, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988;319: 1033-1039.[Abstract]

  • Rubinstein AB, Reichenthal E, Borohov H. Radiation-induced schwannomas. Neurosurgery. 1989;24: 929-932.[Web of Science][Medline]

  • Salvati M, Polli FM, Caroli E, Frati A, Missori P, Delfini R. Radiation-induced schwannomas of the nervous system: report of five cases and review of the literature. J Neurosurg Sci. 2003;47: 113-116.[Medline]

  • Shore RE, Albert RE, Pasternack BS. Follow-up study of patients treated by x-ray epilation for tinea capitis: resurvey of post-treatment illness and mortality experience. Arch Environ Health. 1976;31: 21-28.[Web of Science][Medline]

  • Sogg RL, Nikoskelainen E. Parotid carcinoma and posterior fossa schwannoma following irradiation: report of a patient treated in infancy for benign ear disease. JAMA. 1977;237: 2098-2100.[Abstract/Free Full Text]

  • Toyooka ET, Pifer JW, Hempelmann L. Neoplasms in children treated with x-rays for thymic enlargement. 3. Clinical description of cases. J Natl Cancer Inst. 1963;31: 1379-1405.[Medline]

  • Van Den Berg CJ, Edis AJ. Multicentric thyroid carcinoma, parathyroid adenomas, and vagal neurilemmoma in a young man with antecedent tonsillar radiation. Mayo Clin Proc. 1980;55: 648-650.[Medline]

  • Yonehara S, Brenner AV, Kishikawa M, et al. Clinical and epidemiologic characteristics of first primary tumors of the central nervous system and related organs among atomic bomb survivors in Hiroshima and Nagasaki, 1958-1995. Cancer. 2004;101: 1644-1654.[CrossRef][Web of Science][Medline]

  • Preston DL, Ron E, yonehara S, et al. Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst. 2002;94: 1555-1563.[Abstract/Free Full Text]

  • Preston DL, Lubin JH, Pierce DA. Epicure User's Guide. Seattle: Hirosoft International; 1993.

  • Cox DR, Hinkley DV. Theoretical Statistics. London: Chapman and Hall; 1974.

  • Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: 457-481.[CrossRef][Web of Science]

  • Propp JM, McCarthy BJ, Davis FG, Preston-Martin S. Descriptive epidemiology of vestibular schwannomas. Neuro-oncol. 2006;8: 1-11.[Abstract/Free Full Text]

  • Wong FL, Ron E, Gierlowski T, Schneider AB. Benign thyroid tumors: general risk factors and their effects on radiation risk estimation. Am J Epidemiol. 1996;144: 728-733.[Abstract/Free Full Text]

  • Macarthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Phillips N, McBride ML. Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada. Pediatr Blood Cancer. 2006;46: 339-344.[CrossRef][Medline]

  • Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. 2001;93: 618-629.[Abstract/Free Full Text]

  • Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006;98: 1528-1537.[Abstract/Free Full Text]

  • Edwards CG, Schwartzbaum JA, Lonn S, Ahlbom A, Feychting M. Exposure to loud noise and risk of acoustic neuroma. Am J Epidemiol. 2006;163: 327-333.[Abstract/Free Full Text]

  • Hemminki K, Eng C, Chen BW. Familial risks for nonmedullary thyroid cancer. J Clin Endocrinol Metab. 2005;90: 5747-5753.[Abstract/Free Full Text]

  • Preston-Martin S, Thomas DC, Wright WE, Henderson BE. Noise trauma in the aetiology of acoustic neuromas in men in Los Angeles County, 1978-1985. Br J Cancer. 1989;59: 783-786.[Web of Science][Medline]

  • Mihailescu D, Shore-Freedman E, Mukani S, Lubin J, Ron E, Schneider AB. Multiple neoplasms in an irradiated cohort: pattern of occurrence and relationship to thyroid cancer outcome. J Clin Endocrinol Metab. 2002;87: 3236-3241.[Abstract/Free Full Text]

  • Schneider AB, Shore-Freedman E, Weinstein R. Radiation-induced thyroid and other head and neck tumors: occurrence of multiple tumors and analysis of risk factors. J Clin Endocrinol Metab. 1986;63; 107-112.[Abstract/Free Full Text]

  • Bagai A, Thavendiranathan P, Detsky AS. Does this patient have hearing impairment? JAMA. 2006;295: 416-428.[Abstract/Free Full Text]


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    This Article
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    15228517-2007-047v1
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