Abstract
Objective: To estimate the incidence of meningiomatosis and schwannomatosis, and their familial occurrences and relation to type 2 neurofibromatosis (NF2) in a well-defined population.
Methods: Patients with histologically verified intracranial, spinal, or peripheral schwannomas or meningiomas, who were residents of the Helsinki University Hospital catchment area (population, 1,713,000) from January 1, 1985, to December 31, 1995, were included in the study. The Population Register Center was used to identify relatives of all the patients, and their data were linked further to the Finnish Cancer Registry to find NF2-related tumors. Detailed pedigrees were constructed for the patients with NF2, schwannomatosis, meningiomatosis, patients with relatives with histologically verified schwannomas or meningiomas, and patients younger than 25 years of age at the time of diagnosis.
Results: Approximately 3% (12 of 455) of the schwannoma patients had multiple schwannomas in association with NF2, and 2% (11 of 455) had schwannomatosis without NF2. Two of the patients with schwannomatosis (2 of 11) had familial schwannomatosis. Approximately 1% (7 of 823) of the patients with meningioma had multiple meningiomas in association with NF2, and 4% (29 of 823) had meningiomatosis without NF2. No families with meningiomatosis were found among the 823 patients with meningioma studied. The birth occurrence of NF2 was 1 in 87,410.
Conclusions: The current diagnostic criteria of type 2 neurofibromatosis (NF2) seem valid because NF2 patients were differentiated rather easily from patients with sporadic schwannomatosis and meningiomatosis. Familial meningiomatosis, if it truly exists, is very rare, and familial schwannomatosis is uncommon.
Schwannomas and meningiomas usually occur as single and benign (World Health Organization [WHO] grade I) slow-growing tumors in otherwise healthy individuals. The presence of multiple tumors and familial clustering of patients suggest involvement of genetic factors in accordance with several known familial cancer syndromes.1 Type 2 neurofibromatosis (NF2), inherited in an autosomal dominant manner with high penetrance, predisposes at an early age to multiple schwannomas, meningiomas, and spinal ependymomas, with bilateral vestibular schwannomas as the classic diagnostic hallmark.2-4 Approximately 50% of patients have no family history and carry new mutations.2,3 NF2 is caused by mutations in the NF2 tumor suppressor gene on chromosome 22q12, the inactivation of which plays a crucial role in the tumorigenesis of sporadic schwannomas and meningiomas.5 The severity of the disease ranges from mild (late onset, slow-growing vestibular schwannomas, few other tumors) to aggressive (early onset, multiple rapidly growing schwannomas and meningiomas causing early death).2,3 There is a heterogeneous and poorly defined group of patients who do not have bilateral vestibular schwannomas but present with other features suggestive of NF2—namely, multiple meningiomas or schwannomas, or meningiomas or schwannomas in their relatives. These patients are rather uncommon but they are problematic in terms of prognosis, therapy, follow-up, and genetic counseling. Multiple tumors and familial cases may be coincidental, but they may also represent segmental NF2 or, in theory, a syndrome caused by another gene defect.
The patient with schwannomatosis typically has multiple spinal, peripheral nerve, or subcutaneous schwannomas, without bilateral vestibular schwannomas, and the disease is segmental or localized to a certain body part in approximately one third of patients.6,7 Schwannomatosis is rarely familial, and when familial occurrence is seen, incomplete penetrance is common,8,9 which is in distinct contrast to NF2. Genetically, schwannomatosis may include patients with a clinically very mild NF2, segmental NF2 (i.e., a mosaically distributed defect of the NF2 gene), and those with an undefined mechanism that makes the NF2 gene susceptible to mutations without germline inactivation.8,9 The portion of patients with multiple meningiomas is between 1 to 5% in surgical series,10,11 and from 8 to 16% in autopsy12,13 and neuroradiologic series.14 Familial meningiomatosis with no signs of NF2 is assumed to be very rare.15 A family with multiple meningiomas has been reported that did not show linkage to chromosome 22q,16 suggesting that NF2 and meningiomatosis may be genetically distinct entities.
There is no population-based data on meningiomatosis and schwannomatosis, and their familial occurrences and relation to NF2. Surprisingly, epidemiologic data on NF2 is also scarce. Only one study on the occurrence of NF2 in a defined population in the United Kingdom has been published.17 We performed a register-based study on the occurrence of single, multiple, familial, and NF2-related meningiomas and schwannomas in a defined Finnish population of 1.6 million using CT and MRI.
Methods.
Study area.
The study area was the catchment area of the Helsinki University Central Hospital (HUCH), which consists of 100 municipalities around the city of Helsinki in southern Finland. The mean population of the area was 1,557,200 (743,600 men and 813,600 women) during the 11 years of the study from January 1, 1985, to December 31, 1995. The study area was served by the Department of Neurosurgery at HUCH as the unit with population responsibility. CT has been in routine use since 1977, and MRI (1 T) since 1988.
Patients and tumors.
The patient cohort consisted of all patients diagnosed with primary histologically verified intracranial, spinal, or peripheral schwannomas or meningiomas who were residents of the HUCH catchment area at time of the diagnosis. Patients were identified from the following sources: 1) the operation list and files of the Department of Neurosurgery, HUCH; 2) the discharge and outpatient files of the HUCH; 3) the files of the Department of Pathology, University of Helsinki; and 4) the files of the Finnish Cancer Registry (FCR). All available clinical data, including patients’ medical records and radiographic (CT and MRI scans) and autopsy data, were reviewed to record the occurrence of multiple schwannomas and meningiomas or other features suggestive of NF2. When necessary, the files of the regional hospitals in the HUCH catchment area were also reviewed. Meningiomas and schwannomas had been classified histologically by a consulting neuropathologist, according to the WHO classification of 197918 or 1993,19 and the histologic diagnoses were not reevaluated.
A total of 1,318 patients with primary meningioma or schwannoma had been diagnosed between 1985 and 1995 in the HUCH catchment area. The total number of patients analyzed was 1,278, because 40 patients (3.0%) were discharged for missing case records (n = 11) or no histologic verification (n = 29). The latter patients were diagnosed radiographically either by CT (n = 24) or MRI (n = 5). The histologic diagnoses were based on tissue samples obtained during operation (n = 1,178) or autopsy (n = 100). All 100 autopsied subjects had an intracranial meningioma (69 women and 31 men) with a median age of 77 years (range, 21 to 93 years), including six patients with multiple meningiomas. Of these 100 subjects, 86 shared the meningioma first at autopsy. In the remaining 14 subjects, it was already known (via CT or MRI) but had not been operated.
Population Registry Center (PRC) and FCR.
The PRC, founded in 1969, is an official, nationwide computer-based organization containing information on all Finnish citizens and foreigners residing permanently in Finland. In 1973, the information about family relations was transferred to the PRC from the parish registries. Information about parents, which is also needed to identify siblings, was recorded in the registry only if the person resided with his/her parents in 1973 or after. The information regarding family relations other than a person’s own children is incomplete for persons older than 45 years.
The FCR was founded in 1952, and it covers the whole population of Finland. Physicians, hospitals, and pathologists are obliged to report all new cancer cases (benign and malignant intracranial and spinal tumors included) to the FCR, which also receives information from all death certificates that mention cancer. However, there is no obligation to report benign cutaneous or peripheral nerve tumors to the FCR. Registration has been reliable and virtually complete: More than 99% of the 63,722 solid tumors diagnosed in Finland between 1985 to 1988 were recorded at the FCR.20 Conditions for a population-based study are good in Finland because the population is stable, the statistics are reliable, and the unique 10-digit personal identification numbers enable computer links between different registers.
A total of 4,530 relatives of the 1,278 patients were found from the files of the PRC, and the files of the FCR were searched to find all neoplasms diagnosed among these 4,530 relatives.
Pedigree analysis.
A detailed pedigree with all first- and second-degree relatives were constructed further for the following 79 patients using the parish records: NF2 patients (n = 17), patients with two or more schwannomas or meningiomas (n = 40), patients with relatives with histologically verified schwannomas or meningiomas (n = 5), and patients younger than 25 years of age at time of diagnosis (n = 17). A total of 1,419 relatives of the 79 patients were found and linked further with the files of the FCR.
Diagnostic criteria.
Patients were considered to have NF2 or schwannomatosis if they fulfilled the criteria (definite or probable) presented in the Appendix.21 Meningiomatosis was diagnosed in a patient with two or more discrete intracranial or spinal meningiomas.
Incidence rates and statistical methods.
The annual age-adjusted incidence rates (per 100,000 persons) were calculated by the direct method22 using the world standard population as a standard. During statistical analyses, the median and range were used to describe distributions, and the Mann–Whitney U or chi-square tests were used to compare groups.
Results.
Multiple tumors.
Patients with multiple meningiomas or schwannomas, with or without NF2, were identified by reviewing the clinical, imaging, and autopsy reports. Table 1 classifies the 1,278 patients with meningiomas or schwannomas into three groups: patients with a single tumor, with multiple tumors, and with NF2. Meningiomas were multiple in 4% of patients (29 of 823) in the absence of clinical NF2 and in 1% of patients (7 of 823) with NF2. Schwannomas were multiple in 2% of patients (11 of 455) without NF2 and in 3% of patients (12 of 455) with NF2.
Familial ties among 1,278 patients with histologically verified meningiomas or schwannomas
Familial cases.
Familial cases (see table 1)—meningiomas or schwannomas in relatives to the index patients—were identified by reviewing the clinical reports and by linking relatives to the FCR. A computer-based search in the PRC revealed 4,218 relatives for the 1,221 patients with a single schwannoma or meningioma without clinical NF2. Manual construction of the pedigrees for the 40 patients with multiple meningiomas or schwannomas but no NF2 (table 2) resulted in 730 relatives for the 40 index cases in the search for familial meningiomatosis and schwannomatosis.
Clinical characteristics of 40 patients with meningiomatosis or schwannomatosis and corresponding annual incidence rates per 100,000 persons
Single sporadic meningioma or schwannoma.
Table 3 summarizes the clinical characteristics of the patients with a single meningioma (n = 788) or schwannoma (n = 433). The link from PCR to FCR identified one meningioma patient (1 of 788) with a relative with a meningioma (1 of 2,322), but the overall pedigree (n = 18) and cranial MRI of the index patient excluded classic NF2 (table 4). This pairing was regarded as coincidental.
Clinical characteristics of 1,221 patients with a single sporadic meningioma or schwannoma and corresponding annual incidence rates per 100,000 population
Clinical characteristics of 5 patients with a single schwannoma or meningioma and a relative with a single meningioma or schwannoma
Four patients with schwannoma (4 of 433) had a relative (4 of 1,896) with a meningioma (n = 3) or schwannoma (n = 1). MRI excluded classic NF2 in two of these patients, but in the other two patients no adequate cranial and spinal imaging had been performed (see table 4). Pedigree analysis of these four patients did not reveal any other affected relatives among the 120 relatives screened. Therefore, this pairing was also regarded as coincidental.
Six relatives (6 of 4,218) had an intracranial glioma without any other signs of familial cancer syndrome.
Meningiomatosis.
Patients with meningiomatosis (n = 29) included six elderly patients (median age, 85 years; range, 77 to 91 years) who were diagnosed incidentally at autopsy (see table 2). After exclusion of the six autopsy subjects, the median age of patients with a single (n = 788) and multiple meningiomas (n = 23) was similar (58 versus 61 years). Likewise, the female-to-male ratio (2.9 versus 3.6, p > 0.05) and the proportion of grade II to grade III meningiomas (8% versus 9%, p > 0.05) did not differ significantly. None of the patients with meningiomatosis had a history of schwannoma, ependymoma, glioma, or any other NF2-associated lesion. All patients, with meningiomatosis, younger than 50 years at the first surgery (n = 8) had an MR image negative for vestibular schwannoma. The linkage to FCR was performed for 491 relatives, and no families with meningiomatosis were found.
Schwannomatosis.
Eleven patients with schwannomatosis were identified who fulfilled the criteria of definite or probable schwannomatosis (see the Appendix and table 4). The patients with a single (n = 434) and multiple schwannomas (n = 11) did not differ significantly by median age (48 years versus 45 years, p > 0.05) nor by the female-to-male ratio (1.4 versus 0.8, p > 0.05). The link to the FCR was performed for 244 relatives, and two potential families with schwannomatosis were found. In the first family, the proband was 45 years old at the first tumor removal and has had numerous subcutaneous schwannomas removed, but MRI did not show any intracranial or spinal tumors. Her brother had a single malignant peripheral nerve schwannoma removed at 42 years. The brother, who later died of pulmonary embolism, did not have any intracranial tumors on autopsy. No other affected relatives were found. The proband of the second family with schwannomatosis has had several subcutaneous schwannomas removed and was operated for suprasellar meningioma at the age of 50 years, but MRI did not show any vestibular schwannomas. Her father has had one schwannoma removed, and her siblings have had two peripheral schwannomas removed. No other affected relatives were found among the 40 relatives screened.
NF2 patients.
The basic series of 1,278 patients included 10 novel NF2 patients (four familial patients from three different families) diagnosed between 1985 to 1995 in the catchment area, and seven NF2 patients diagnosed before the study period. The 17 NF2 patients were younger (median age, 36 years) than the sporadic patients with single or multiple schwannomas (p = 0.003; p = 0.042) or meningiomas (p < 0.001; p < 0.001). There were eight familial NF2 patients (five women and three men) from five different families. Four women had a severe form of NF2 with multiple intracranial and spinal schwannomas and meningiomas. All NF2 patients fulfilled the defined NF2 criteria presented in the appendix.
The occurrence of NF2.
The annual age-adjusted incidence of the new diagnoses of NF2 was 0.50/1,000,000 (world standard population, 1/2,004,000). The proportion of NF2 patients among newborns was estimated as published previously.17 The median birth year of the 10 NF2 patients diagnosed from 1985 to 1995 was 1955 (range, 1933 to 1976). Using the annual birth rates for Finland from 1950 to 1960 (874,103 live births), the occurrence of NF2 would be 1 in 87,410 live births in southern Finland.
Discussion.
We assessed the occurrence of single, multiple, familial, and NF2-related meningiomas and schwannomas in the CT/MRI era in a large population-based series using the accurate register data of Finland. In the absence of classic NF2, meningiomas were multiple (meningiomatosis) in 4% of patients with meningiomas, and schwannomas were multiple (schwannomatosis) in 2% of patients with schwannomas. The patients with meningiomatosis and schwannomatosis resemble those with single tumors in terms of average age at diagnosis, female-to-male ratio, and proportion of malignant forms. Our results indicate that familial meningiomatosis, if it truly exists, is very rare (0 of 823 patients with meningioma), and familial schwannomatosis is uncommon (2 of 455 patients with schwannoma). Our data suggest that meningiomas and schwannomas may coincide in the relatives of the patients with apparently sporadic single meningioma (1 of 788) or schwannoma (4 of 433).
The current series encompasses virtually all intracranial and spinal meningiomas and schwannomas diagnosed and verified histologically in southern Finland from 1985 to 1995, because all benign intracranial and spinal tumors must be reported to the FCR. We used several overlapping search strategies to collect the existing data on the patients, including the FCR, hospital discharge records, neurosurgical operation lists and reports, neuroradiology reports, and pathology and autopsy reports. Unfortunately, there is no obligation to report benign peripheral or subcutaneous tumors to the FCR, and therefore the incidence of peripheral and subcutaneous schwannomas is merely a hospital-based estimate. Some patients with schwannomatosis with a disease localized to the subcutaneous tissue may have been missed.
We present this series to evaluate the familial occurrence of meningiomas and schwannomas in a defined population. We used the PRC to identify relatives for the index patients and linked their data further with the FCR. First-degree relatives were obtained easily for patients younger than 45 years of age, but due to the structure of the PRC (see Methods), few relatives were found for the older patients. A detailed pedigree with all first- and second-degree relatives was constructed for patients with NF2, meningiomatosis, or schwannomatosis, and for patients with a relative with a meningioma or schwannoma using the parish records.
Schwannomatosis is a recently introduced clinical entity.6,7 Most patients with schwannomatosis are in middle age at presentation,6,7 and in our series they were older than NF2 patients, whose mean age at diagnosis was 28 years.2,3 In the current population-based series, the clinical distinction between classic NF2 and schwannomatosis was clear because we used the published clinical criteria presented in the Appendix. As a unique finding, the annual incidence of schwannomatosis was estimated to be 0.58/1,000,000 (world standard population, 1/1,808,300). Two families with schwannomatosis were found among the 455 patients with schwannoma studied. Our study supports previous reports8,9 in that there are patients with familial schwannomatosis. Their genetic background, important in terms of schwannoma biology, remains to be settled.
In 1987, the NIH outlined the diagnostic criteria of NF2.23 These criteria have been broadened21 (see Appendix, presumptive NF2). However, there are still a number of patients that do not fulfill these criteria, but in whom the possibility of NF2 seems real. These include patients who develop a single meningioma or schwannoma and who have a family history of an isolated schwannoma or meningioma. In the current series, five such patients were found (see table 4), each one having a first-degree relative with a meningioma or schwannoma. Meningiomas are not uncommon; they occur in 1.4% of autopsies, mostly as incidental findings.13 A single meningioma or schwannoma may sometimes appear to be familial but is likely to be coincidental. Wu et al.24 showed that when a patient with a vestibular schwannoma and family history of a single NF2-related tumor is investigated thoroughly, most often no additional NF2 features or NF2 germline mutations are detected.
The true occurrence of NF2 in a population is difficult to assess for several reasons. NF2 is a rare condition and therefore the calculations of the occurrence are based on small numbers of patients. The diagnostic window of NF2 is rather short between the clinical presentation (mean age at diagnosis, 28 years)2,3 and death (mean age at death, 39 years).2,3 Approximately half of the NF2 cases are familial, and when a family has a mild form of the disease, several asymptomatic NF2 patients may become known along with the proband.25 Because NF2 is an inborn condition, the number of NF2 patients per newborn is an appropriate measure rather than the incidence, which reflects new diagnoses per population and time. Only one epidemiologic study on NF2 has been published previously.17 From 1980 to 1989, 17 NF2 patients were diagnosed in the northwest region of England in a population of 4,016,100.17 Evans et al.17 assessed a birth occurrence of 1/40,562, which is clearly higher than 1/87,410 in the current series. Evans et al.17 personally visited NF2 patients, and asymptomatic relatives were screened by cranial CT or MRI whereas our series was based on existing medical records and files. The higher birth rate in southern Finland in the 1950s (87,410 live births/year) than in the northwest region of the United Kingdom (68,960 live births/year) increases further the difference in birth occurrences. Estimates that are more accurate are obtained only by a uniform NF2 screening program in a large population.
Appendix
Diagnostic criteria
Neurofibromatosis 2 (NF2; from Gutmann et al.21)
Definite NF2
-
1. Bilateral vestibular schwannomas or
-
2. Family history of NF2 (first-degree family relative) plus (a) unilateral vestibular schwannoma, at age < 30 years, or (b) any two of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
Presumptive or probable NF2
-
1. Unilateral vestibular schwannoma, at age < 30 years, plus at least one of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
-
2. Multiple meningiomas (two or more) plus (a) unilateral vestibular schwannoma, at age < 30 years, or (b) one of the following: glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
Schwannomatosis (from Jacoby et al.8)
Definite schwannomatosis
-
1. Two or more pathologically proved schwannomas, plus
-
2. Lack of radiographic evidence of vestibular schwannoma, at age > 18 years
Presumptive or probable schwannomatosis
-
1. Two or more pathologically proved schwannomas, without symptoms of eight nerve dysfunction, at age > 30 years, or
-
2. Two or more pathologically proved schwannomas in an anatomically limited distribution (single limb or segment of the spine), without symptoms of eight nerve dysfunction, at any age
Acknowledgments
Supported by a grant from the Maire Taponen Foundation.
Acknowledgment
The authors thank Mrs. Aira Lindeman for her skillful technical assistance.
Footnotes
-
See also page 4
- Received May 26, 1999.
- Accepted July 29, 1999.
References
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