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Correlations between clinical and cytogenetical data in 180 human meningiomas
Correlations between Clinical and Cytogenetical Data in 180 Human Meningiomas H. Zankl and K. D. Zang
ABSTRACT: Certain clinical data appeared to be correlated with the cytogenetic findings in a series of 180 meningiomas. A higher degree of hypodiploidy and atypical chromosome loss was observed in 12 of 18 tumors that had invaded the skull, and in 8 of 19 recurrent meningiomas. A correlation was also found between the site of the tumor origin and the karyotype of the tumor: tumors located at the convexity of the brain showed mostly an increased hypodiploidy (two or more chromosomes missing) and tumors at the base of the brain a normal karyotype. Meningiomas in the spinal canal had, with one exception, always lost one chromosome #22; in the skull, however, the #22 monosomic meningiomas were found in roughly similar frequencies at the convexity and the base of the brain. Meningiomas with normal karyotypes or monosomy 22 clearly predominated in women, whereas tumors with an increased hypodiploidy or atypical chromosome loss were found as frequently in men as in women. The possibility is discussed that the loss of #22 and the well-known predominance of meningiomas in females might be caused by an environmental factor which affects both sexes in the same way.
INTRODUCIION Meningioma is one of the few human tumors that has been studied intensively by cytogenetic techniques in recent years. Such investigations have been possible because meningioma cells have a high proliferation rate in vitro, thus a chromosome analysis after a few days of culture is possible. Zang and Singer [12] were the first to report that the loss of a G-group chromosome is the most common chromosome aberration in meningiomas. The missing G chromosome was identified by banding techniques as a chromosome #22 [4,16]. Meanwhile, the karyotypes of more than 200 meningiomas were analyzed [3,15]. The loss of one chromosome #22 has been found in about 70% of all such tumors studied so far. In nearly half of the #22 monosomic meningiomas, further chromosomes were missing. Chromosomal abnormalities without monosomy 22 were seldom found. The relatively large number of meningiomas that we have studied cytogenetically in the past 12 years made it possible to consider the chromosomal findings in relation to some clinical data associated with these tumors.
From the Institute of Human Genetics, University of Saarland, Saar, Federal Republic of Germany. Address requests for reprints to: Prof. Dr. H. Zankl, Institute of Human Genetics, 8850 Homburg/Saar, Federal Republic of Germany. Received May 25,1979; accepted July 19,1979.
University
of Saarland,
@Elsevier North Holland, Inc., 1980 0165-4606/60/02035106$02.25
Cancer Genetics and Cytogenetics
1, 351-356
(1980)
351
352
H. Zankl
and K. D. Zang
Hum an Meningiomas:
Clinical
and Cytogenetical
Data
353
H. Zankl and K. D. Zang
354
MATERIAL
AND METHODS
The karyotypes of 180 meningiomas were analyzed. In 62 tumors, chromosome banding was performed. At the beginning of our studies chromosome preparations were made directly on cover slips on which particle cultures were grown in roller tubes. Because the resulting mitoses were not so suitable for banding techniques, we changed the culture method. The biopsy material is now trypsinized and a cell suspension is seeded into stationary culture flasks. The mitoses are harvested after colchicine treatment by trypsinization, and chromosome preparation is performed as in blood cultures. For details see Zankl et al. [17]. The clinical data concerning the patients were taken from the hospital reports of the Munich and Homburg neurosurgery clinics, which kindly provided us with biopsy material. We collected the following data: the sex and age of the patient, the time between the occurrence of the first symptoms and the operation, the site of tumor growth, and the tumor size. It was also noted whether the tumor had infiltrated the surrounding tissue, especially the bony skull, and whether the meningioma had recurred after surgical removal. RESULTS
AND DISCUSSION No correlation was found between the karyotype of the tumor and the duration of symptoms, the size of the tumor, or the age of the patient. Intensive infiltration of the skull in 18 meningioma patients (10% of our whole series) was observed. Only three of these tumors had normal karyotypes and three had monosomy 22 as their only abnormality, whereas twelve tumors had lost chromosomes in addition to a #22 or (in four cases) showed an atypical chromosome loss in which chromosomes #22 were not involved. These abnormalities were clearly overrepresented in the invasive meningiomas; in the whole series, only about 113 of the tumors showed an increased hypodiploidy, and atypical chromosome loss was very rare. Russel and Rubinstein [7] reported that most invasive meningiomas belong histologically to the syncytial type, whereas, in fibromatous meningiomas, invasive growth is rarely observed. This finding is in agreement with our observation that an increased hypodiploidy of the karyotype is most often found in syncytial meningiomas [13]. For the whole series of 180 meningiomas in only 10 cases (5.6%) was it known from the hospital reports that a meningioma had already been removed from the same site of the brain. In eight of these recurrent meningiomas there was a higher degree of hypodiploidy; only one of the ten had a normal karyotype and one had a monosomy 22 as its only abnormality. This finding shows that in recurrent meningiomas also, karyotypes with increased hypodiploidy are found more often than expected. Correlations between recurrence and invasiveness are also indicated by the observation that three of the recurrent tumors had additionally infiltrated the skull. The same correlation was observed by Skullerud and Loken [8]and Jellinger and Slowik [I]. In Table 1, 121 meningiomas are summarized in which the site of tumor origin was known and a normal #22 monosomic, or more hypodiploid, karyotype was found. In order to get groups of usable size we did not consider the sites according to all clinically important locations, but condensed them into three main groups. By this method it was shown that the tumors with more than one chromosome missing were nearly all located on the convexity of the brain, whereas the meningiomas with normal karyotypes were mostly found at the base of the brain. On the spinal cord, with one exception, all meningiomas had only a monosomy 22. In the skull, however, no preferred location for #22 monosomic meningiomas could be observed. The
Human Meningiomas: Clinical and Cytogenetical Data
355
Table 1 Correlation between the site of tumor origin and the karyotype Tumor site Convexityof brain Base of brain Spinal cord
46,XX(XY) 15(5) 28(11)b 0
45,XX(XY),-22
44 - 3g,XX(XY),-22;qthers 36(9)b 3 1
17(8) ll(4) lO(3)
‘Number of tumors studied by banding techniques is listed in parentheses. *p < 0.01
(chi square test).
Table 2
Correlation between the sex of the patients and the karyotype of the menintiomas
Sex
Tumors with increased hypodiploidy or atypical chromosome lossa
Female Male
30(8) 25/71
Tumors with a normal or a X22 monosomic
karyotypea
80(29) 28l’llIb
ONumberof tumors studied by banding techniques is listed in parentheses. bp < 0.02 (cbi square test].
concentration of this particular karyotype in the spinal canal may be correlated with the finding of Weber [9] and Lapresle et al. [2] that most spinal meningiomas are histologically of the psammomatous type. We made the same observation for our material. In Table 2 the sex of the patients is correlated with the karyotypes of the meningiomas. Tumors showing a hyperdiploid or pseudpdiploid karyotype were excluded. It can be seen from this table that in tumors with a normal or a #22 monosomic karyotype the female:male ratio of the patients was 4:l. However, the sex ratio was equal in the meningiomas with a higher degree of hypodiploidy or an atypical chromosome loss. It is well-known from the literature that meningiomas are much more frequent in women than in men. The ratio ranges from 2:l to 5:4. (For a review see Ziilch [18].) It is still totally unknown why meningiomas occur preferentially in female humans. Our observation, that this predominance does not exist for tumors with increased hypodiploidy or atypical chromosome loss may help to answer this question. We propose the hypothesis that such meningiomas may be caused by environmental agents that affect both sexes equally. One such agent might be an SV-4O-related Papova virus which has been detected in several meningiomas in recent years [10,14]. The loss of small acrocentric chromosomes associated with further chromosome loss was also observed by several investigators in human cell cultures experimentally transformed by SV-40-virus [6,11]. It has been reported that in experimental tumors specific chromosomal aberrations indicate the action of different oncogenic agents [5]. It would be of great interest if the existence of similar correlations in human tumors could also be proven, This study was supported by a grant of the Deutsche Forschungsgemeinschaft (Za 32/16). The authors wish to thank Prof. Dr. F. Marguth, Dr. W. Weidenbach, Dr. M. Schmidberger, and Prof. Dr. F. Loew, of the Clinics for Neurosurgery in Munich and Homburg, for their support of this study.
356
H. Zankl
and K. D. Zang
REFERENCES 1. Jellinger K, Slowik F (1975): Histological mas. J Nemo1 208,279- 298. 2. Lapresle J, Netsky MG, Zimmermann 121 cases. Am J Path01 28, 757- 791.
subtypes and prognostic
problems
in meningio-
H (1952): The pathology of meningiomas:
A study of
3. Mark J (1974): The human meningioma: a benign tumor with specific chromosome characteristics. In: Chromosomes and Cancer, J. German, ed. J. Wiley and Sons, New York, pp. 481-495. 4. Mark J, Levan G, Mitelman F (1972): Identification by fluorescence loss in human meningiomas. Hereditas 71,163 -168.
of the G chromosome
5. Mitelman
F, Mark J. Levan G, Levan A (1972):Tumor etiology and chromosomal Science 176,1340-1341.
pattern.
6. Moorhead
P, Saksela E (1963): Non-random chromosomal aberration in SV 40 transformed human cells. J Cell Comp Physio162, 57- 83. 7. Russel DS, Rubinstein LJ (1977): Pathology of Tumors of the Nervous System. Edward Arnold, London. 8. Skullerud K, Loken AG (1974): The prognosis 337- 344.
9. Weber E (1938): Uber den Bau der Meningiome.
in meningiomas. Z Neuroll61,
Acta Neuropathol
29,
211-214.
10. Weiss AF, Portmann
R, Fischer H, Simon J, Zang KD (1975): Simian virus-40 related antigens in three human meningiomas with defined chromosome loss. Proc Nat1 Acad Sci USA 72,609- 613.
11. Yerganian G, Shein HM, Enders JF (1962): Chromosomal disturbances observed in human fetal renal cells transformed in vitro by simian virus 40 and carried in culture. Cytogenetics 1,314-324. 12. Zang KD, Singer H (1967): Chromosomal
constitution
of meningiomas.
Nature 216,84-85.
13. Zang KD (1970): Cytological and cytogenetical studies in human meningiomas. ternat Congr Neuropathol, Paris, pp. 982 -983.
Proc VI In-
14. Zang KD, May G, Fischer H (1979): Expression of SV 40 related T-antigen in cell cultures of human meningiomas. Naturwissenschaften 66,59. 15. Zankl H (1979): Der Karyotyp des Meningioms. gie Heft 111 G. Fischer Verlag, Berlin.
In: Veroffentlichungen
aus der Patholo-
16. Zankl H, Zang KD (1972): Cytological and cytogenetical
studies on brain tumors: IV. Identification of the missing G chromosome in human meningiomas as no. 22 by fluorescence technique. Humangenetik 14,167- 169.
17. Zankl H, Ludwig B, May G, Zang KD (1979): Karyotypic
cell cultures under different in vitro conditions.
variations in human meningioma J Cancer Res Clin Oncol93, 165 - 172.
18. Ziilch KJ (1956): Biologie und Pathologie der Hirngeschwiilste. rurgie, vol. 3. Springer, Berlin.
In: Handbuch der Neurochi-
ABSTRACT: Certain clinical data appeared to be correlated with the cytogenetic findings in a series of 180 meningiomas. A higher degree of hypodiploidy and atypical chromosome loss was observed in 12 of 18 tumors that had invaded the skull, and in 8 of 19 recurrent meningiomas. A correlation was also found between the site of the tumor origin and the karyotype of the tumor: tumors located at the convexity of the brain showed mostly an increased hypodiploidy (two or more chromosomes missing) and tumors at the base of the brain a normal karyotype. Meningiomas in the spinal canal had, with one exception, always lost one chromosome #22; in the skull, however, the #22 monosomic meningiomas were found in roughly similar frequencies at the convexity and the base of the brain. Meningiomas with normal karyotypes or monosomy 22 clearly predominated in women, whereas tumors with an increased hypodiploidy or atypical chromosome loss were found as frequently in men as in women. The possibility is discussed that the loss of #22 and the well-known predominance of meningiomas in females might be caused by an environmental factor which affects both sexes in the same way.
INTRODUCIION Meningioma is one of the few human tumors that has been studied intensively by cytogenetic techniques in recent years. Such investigations have been possible because meningioma cells have a high proliferation rate in vitro, thus a chromosome analysis after a few days of culture is possible. Zang and Singer [12] were the first to report that the loss of a G-group chromosome is the most common chromosome aberration in meningiomas. The missing G chromosome was identified by banding techniques as a chromosome #22 [4,16]. Meanwhile, the karyotypes of more than 200 meningiomas were analyzed [3,15]. The loss of one chromosome #22 has been found in about 70% of all such tumors studied so far. In nearly half of the #22 monosomic meningiomas, further chromosomes were missing. Chromosomal abnormalities without monosomy 22 were seldom found. The relatively large number of meningiomas that we have studied cytogenetically in the past 12 years made it possible to consider the chromosomal findings in relation to some clinical data associated with these tumors.
From the Institute of Human Genetics, University of Saarland, Saar, Federal Republic of Germany. Address requests for reprints to: Prof. Dr. H. Zankl, Institute of Human Genetics, 8850 Homburg/Saar, Federal Republic of Germany. Received May 25,1979; accepted July 19,1979.
University
of Saarland,
@Elsevier North Holland, Inc., 1980 0165-4606/60/02035106$02.25
Cancer Genetics and Cytogenetics
1, 351-356
(1980)
351
352
H. Zankl
and K. D. Zang
Hum an Meningiomas:
Clinical
and Cytogenetical
Data
353
H. Zankl and K. D. Zang
354
MATERIAL
AND METHODS
The karyotypes of 180 meningiomas were analyzed. In 62 tumors, chromosome banding was performed. At the beginning of our studies chromosome preparations were made directly on cover slips on which particle cultures were grown in roller tubes. Because the resulting mitoses were not so suitable for banding techniques, we changed the culture method. The biopsy material is now trypsinized and a cell suspension is seeded into stationary culture flasks. The mitoses are harvested after colchicine treatment by trypsinization, and chromosome preparation is performed as in blood cultures. For details see Zankl et al. [17]. The clinical data concerning the patients were taken from the hospital reports of the Munich and Homburg neurosurgery clinics, which kindly provided us with biopsy material. We collected the following data: the sex and age of the patient, the time between the occurrence of the first symptoms and the operation, the site of tumor growth, and the tumor size. It was also noted whether the tumor had infiltrated the surrounding tissue, especially the bony skull, and whether the meningioma had recurred after surgical removal. RESULTS
AND DISCUSSION No correlation was found between the karyotype of the tumor and the duration of symptoms, the size of the tumor, or the age of the patient. Intensive infiltration of the skull in 18 meningioma patients (10% of our whole series) was observed. Only three of these tumors had normal karyotypes and three had monosomy 22 as their only abnormality, whereas twelve tumors had lost chromosomes in addition to a #22 or (in four cases) showed an atypical chromosome loss in which chromosomes #22 were not involved. These abnormalities were clearly overrepresented in the invasive meningiomas; in the whole series, only about 113 of the tumors showed an increased hypodiploidy, and atypical chromosome loss was very rare. Russel and Rubinstein [7] reported that most invasive meningiomas belong histologically to the syncytial type, whereas, in fibromatous meningiomas, invasive growth is rarely observed. This finding is in agreement with our observation that an increased hypodiploidy of the karyotype is most often found in syncytial meningiomas [13]. For the whole series of 180 meningiomas in only 10 cases (5.6%) was it known from the hospital reports that a meningioma had already been removed from the same site of the brain. In eight of these recurrent meningiomas there was a higher degree of hypodiploidy; only one of the ten had a normal karyotype and one had a monosomy 22 as its only abnormality. This finding shows that in recurrent meningiomas also, karyotypes with increased hypodiploidy are found more often than expected. Correlations between recurrence and invasiveness are also indicated by the observation that three of the recurrent tumors had additionally infiltrated the skull. The same correlation was observed by Skullerud and Loken [8]and Jellinger and Slowik [I]. In Table 1, 121 meningiomas are summarized in which the site of tumor origin was known and a normal #22 monosomic, or more hypodiploid, karyotype was found. In order to get groups of usable size we did not consider the sites according to all clinically important locations, but condensed them into three main groups. By this method it was shown that the tumors with more than one chromosome missing were nearly all located on the convexity of the brain, whereas the meningiomas with normal karyotypes were mostly found at the base of the brain. On the spinal cord, with one exception, all meningiomas had only a monosomy 22. In the skull, however, no preferred location for #22 monosomic meningiomas could be observed. The
Human Meningiomas: Clinical and Cytogenetical Data
355
Table 1 Correlation between the site of tumor origin and the karyotype Tumor site Convexityof brain Base of brain Spinal cord
46,XX(XY) 15(5) 28(11)b 0
45,XX(XY),-22
44 - 3g,XX(XY),-22;qthers 36(9)b 3 1
17(8) ll(4) lO(3)
‘Number of tumors studied by banding techniques is listed in parentheses. *p < 0.01
(chi square test).
Table 2
Correlation between the sex of the patients and the karyotype of the menintiomas
Sex
Tumors with increased hypodiploidy or atypical chromosome lossa
Female Male
30(8) 25/71
Tumors with a normal or a X22 monosomic
karyotypea
80(29) 28l’llIb
ONumberof tumors studied by banding techniques is listed in parentheses. bp < 0.02 (cbi square test].
concentration of this particular karyotype in the spinal canal may be correlated with the finding of Weber [9] and Lapresle et al. [2] that most spinal meningiomas are histologically of the psammomatous type. We made the same observation for our material. In Table 2 the sex of the patients is correlated with the karyotypes of the meningiomas. Tumors showing a hyperdiploid or pseudpdiploid karyotype were excluded. It can be seen from this table that in tumors with a normal or a #22 monosomic karyotype the female:male ratio of the patients was 4:l. However, the sex ratio was equal in the meningiomas with a higher degree of hypodiploidy or an atypical chromosome loss. It is well-known from the literature that meningiomas are much more frequent in women than in men. The ratio ranges from 2:l to 5:4. (For a review see Ziilch [18].) It is still totally unknown why meningiomas occur preferentially in female humans. Our observation, that this predominance does not exist for tumors with increased hypodiploidy or atypical chromosome loss may help to answer this question. We propose the hypothesis that such meningiomas may be caused by environmental agents that affect both sexes equally. One such agent might be an SV-4O-related Papova virus which has been detected in several meningiomas in recent years [10,14]. The loss of small acrocentric chromosomes associated with further chromosome loss was also observed by several investigators in human cell cultures experimentally transformed by SV-40-virus [6,11]. It has been reported that in experimental tumors specific chromosomal aberrations indicate the action of different oncogenic agents [5]. It would be of great interest if the existence of similar correlations in human tumors could also be proven, This study was supported by a grant of the Deutsche Forschungsgemeinschaft (Za 32/16). The authors wish to thank Prof. Dr. F. Marguth, Dr. W. Weidenbach, Dr. M. Schmidberger, and Prof. Dr. F. Loew, of the Clinics for Neurosurgery in Munich and Homburg, for their support of this study.
356
H. Zankl
and K. D. Zang
REFERENCES 1. Jellinger K, Slowik F (1975): Histological mas. J Nemo1 208,279- 298. 2. Lapresle J, Netsky MG, Zimmermann 121 cases. Am J Path01 28, 757- 791.
subtypes and prognostic
problems
in meningio-
H (1952): The pathology of meningiomas:
A study of
3. Mark J (1974): The human meningioma: a benign tumor with specific chromosome characteristics. In: Chromosomes and Cancer, J. German, ed. J. Wiley and Sons, New York, pp. 481-495. 4. Mark J, Levan G, Mitelman F (1972): Identification by fluorescence loss in human meningiomas. Hereditas 71,163 -168.
of the G chromosome
5. Mitelman
F, Mark J. Levan G, Levan A (1972):Tumor etiology and chromosomal Science 176,1340-1341.
pattern.
6. Moorhead
P, Saksela E (1963): Non-random chromosomal aberration in SV 40 transformed human cells. J Cell Comp Physio162, 57- 83. 7. Russel DS, Rubinstein LJ (1977): Pathology of Tumors of the Nervous System. Edward Arnold, London. 8. Skullerud K, Loken AG (1974): The prognosis 337- 344.
9. Weber E (1938): Uber den Bau der Meningiome.
in meningiomas. Z Neuroll61,
Acta Neuropathol
29,
211-214.
10. Weiss AF, Portmann
R, Fischer H, Simon J, Zang KD (1975): Simian virus-40 related antigens in three human meningiomas with defined chromosome loss. Proc Nat1 Acad Sci USA 72,609- 613.
11. Yerganian G, Shein HM, Enders JF (1962): Chromosomal disturbances observed in human fetal renal cells transformed in vitro by simian virus 40 and carried in culture. Cytogenetics 1,314-324. 12. Zang KD, Singer H (1967): Chromosomal
constitution
of meningiomas.
Nature 216,84-85.
13. Zang KD (1970): Cytological and cytogenetical studies in human meningiomas. ternat Congr Neuropathol, Paris, pp. 982 -983.
Proc VI In-
14. Zang KD, May G, Fischer H (1979): Expression of SV 40 related T-antigen in cell cultures of human meningiomas. Naturwissenschaften 66,59. 15. Zankl H (1979): Der Karyotyp des Meningioms. gie Heft 111 G. Fischer Verlag, Berlin.
In: Veroffentlichungen
aus der Patholo-
16. Zankl H, Zang KD (1972): Cytological and cytogenetical
studies on brain tumors: IV. Identification of the missing G chromosome in human meningiomas as no. 22 by fluorescence technique. Humangenetik 14,167- 169.
17. Zankl H, Ludwig B, May G, Zang KD (1979): Karyotypic
cell cultures under different in vitro conditions.
variations in human meningioma J Cancer Res Clin Oncol93, 165 - 172.
18. Ziilch KJ (1956): Biologie und Pathologie der Hirngeschwiilste. rurgie, vol. 3. Springer, Berlin.
In: Handbuch der Neurochi-