LETTERS TO THE EDITOR Mitotic Spindle Failure in Human Cancer
Partial s p i n d l e failure resulting in m u l t i p o l a r mitoses is a well k n o w n feature of neoplastic cells. It is seen, for instance, in both the preinvasive and invasive stages of carcinoma of the cervix uteri [1]. Complete s p i n d l e failure with no polar m o v e m e n t of the separating chromatids seems to be a less well recognized p h e n o m e n o n ; our observations, however, suggest that it occurs quite frequently in at least some forms of neoplastic disease. Thus, we observed metaphases in w h i c h the c h r o m a t i d s had c o m p l e t e l y separated in three s e m i n o m a s of the testis, studied directly or after culture for 24 hours. In one of these, a large number of m e t a p h a s e s were present in the c h r o m o s o m e preparations; in 31 of 308 (10.1%), the c h r o m a t i d s had c o m p l e t e l y separated and could no longer be paired with one another, while in a further eight (2.6%), the c h r o m a t i d s of some c h r o m o s o m e s had separated but others r e m a i n e d in apposition. A n e x a m p l e from a s e m i n o m a is s h o w n in Figure 1. We have occasionally seen the same p h e n o m e n o n in carcinomas at various sites. It appears, however, to be a fairly regular occurrence in samples of bone marrow, peripheral blood, or l y m p h node tissue from patients with myeloproliferative or l y m p h o p r o l i f e r a t i v e disorders. Thus, we have seen it in ten patients who had the following diagnoses: chronic m y e l o m o n o c y t i c leukemia, acute myeloid l e u k e m i a (three cases), myeloproliferative disorder (two cases), suspected myeloproliferative disorder (two cases), myelofibrosis, and p o l y m o r p h o u s T-cell non-Hodgkins l y m p h o m a . Our findings suggest that m e t a p h a s e s in w h i c h the chromatids have c o m p l e t e l y separated are quite frequent in s e m i n o m a s and some other forms of neoplastic disease, e.g., of the h e m a t o p o i e t i c system. It appears that this phen o m e n o n has hitherto received little attention. The number of c h r o m a t i d s in a m e t a p h a s e spread will, of course, usually be about twice, or a higher m u l t i p l e of, the basic chromosome n u m b e r of the neoplastic clone. Where the chromatids have c o m p l e t e l y separated, the metaphase may be passed over because it is mistakenly considered to be a p o l y p l o i d variant. Also, little notice may be taken of it because, as we have found, the c h r o m a t i d s tend to be rather contracted and, in b a n d e d preparations, to shout little band-
ing. However, careful attention to the m o r p h o l o g y of the chromatids and c o m p a r i s o n with the c h r o m o s o m e s of any metaphases that show separation of some but not all the c h r o m a t i d s (as in Fig 1) s h o u l d leave no doubt as to their true identity. The p h e n o m e n o n of s p i n d l e failure resulting in "c-mitoses," w h i c h follows the a p p l i c a t i o n of s p i n d l e poisons such as colchicine, has long been studied. Levan, in 1954 [2], observed that every c h r o m o s o m e modification i n d u c e d by colchicine could also be found in untreated tumors, only more rarely. {We do not c o n s i d e r that the c o l c e m i d used in the pretreatment of our chromosomes, only 0.2 /xg/ml for 30 to 45 minutes, has any bearing on our findings). Complete s p i n d l e failure may be of interest for at least two reasons. First, although the fate of the cells showing this p h e n o m e n o n is u n k n o w n , it seems likely that a common sequela is the p r o d u c t i o n of a viable cell with a doubled c o m p l e m e n t of chromosomes. Second, although we cannot rule out the possibility that some of the m e t a p h a s e s with separated c h r o m a t i d s we have observed in bone marrow samples from patients with leukemias or p r e l e u k e m i a s are nonneoplastic, e.g., megakaryocytes, this p h e n o m e n o n , if its association with n e o p l a s i a is confirmed by further studies, may prove to be a useful marker for neoplasia. We thank David Smith for photographic services. Supported by a grant from the Association for International Cancer Research. NIELS B. ATKIN MARION C. BAKER
Department of Cancer Research Mount Vernon Hospital Northwood, M i d d l e s e x HA6 2RN, U.K.
REFERENCES
1. Moricard R, Cartier R (1959): Chromosomal and cytoplasmic cytopathology of intraepithelial squamous-cell epithelioma of the cervix uteri. In: Cancer of the cervix. Diagnosis of early forms, GEW Wolstenholme and M O'Connor, Eds. Ciba Foundation Study Group No. 3. J & A Churchill Ltd, London, pp. 28-43. 2. Levan A (1954): Colchicine-induced c-mitosis in two mouse ascites tumours. Hereditas 40:1-64.
106 Cancer Genet Cytogenet 62:106 107 (1992) 0165-4608/92/$05.00
~ 1992 Elsevier Science Publishing Co.. Inc. 655 A v e n u e of the Americas, New York, NY 10010
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Figure 1 (A) Metaphase from semmoma showing 194 completely separated chromatids The modal chromosome numbm was 95. Unbanded: Giemsa stain. (B) Part of regular metaphase from the same slide preparation as (A), for comparison.
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Partial s p i n d l e failure resulting in m u l t i p o l a r mitoses is a well k n o w n feature of neoplastic cells. It is seen, for instance, in both the preinvasive and invasive stages of carcinoma of the cervix uteri [1]. Complete s p i n d l e failure with no polar m o v e m e n t of the separating chromatids seems to be a less well recognized p h e n o m e n o n ; our observations, however, suggest that it occurs quite frequently in at least some forms of neoplastic disease. Thus, we observed metaphases in w h i c h the c h r o m a t i d s had c o m p l e t e l y separated in three s e m i n o m a s of the testis, studied directly or after culture for 24 hours. In one of these, a large number of m e t a p h a s e s were present in the c h r o m o s o m e preparations; in 31 of 308 (10.1%), the c h r o m a t i d s had c o m p l e t e l y separated and could no longer be paired with one another, while in a further eight (2.6%), the c h r o m a t i d s of some c h r o m o s o m e s had separated but others r e m a i n e d in apposition. A n e x a m p l e from a s e m i n o m a is s h o w n in Figure 1. We have occasionally seen the same p h e n o m e n o n in carcinomas at various sites. It appears, however, to be a fairly regular occurrence in samples of bone marrow, peripheral blood, or l y m p h node tissue from patients with myeloproliferative or l y m p h o p r o l i f e r a t i v e disorders. Thus, we have seen it in ten patients who had the following diagnoses: chronic m y e l o m o n o c y t i c leukemia, acute myeloid l e u k e m i a (three cases), myeloproliferative disorder (two cases), suspected myeloproliferative disorder (two cases), myelofibrosis, and p o l y m o r p h o u s T-cell non-Hodgkins l y m p h o m a . Our findings suggest that m e t a p h a s e s in w h i c h the chromatids have c o m p l e t e l y separated are quite frequent in s e m i n o m a s and some other forms of neoplastic disease, e.g., of the h e m a t o p o i e t i c system. It appears that this phen o m e n o n has hitherto received little attention. The number of c h r o m a t i d s in a m e t a p h a s e spread will, of course, usually be about twice, or a higher m u l t i p l e of, the basic chromosome n u m b e r of the neoplastic clone. Where the chromatids have c o m p l e t e l y separated, the metaphase may be passed over because it is mistakenly considered to be a p o l y p l o i d variant. Also, little notice may be taken of it because, as we have found, the c h r o m a t i d s tend to be rather contracted and, in b a n d e d preparations, to shout little band-
ing. However, careful attention to the m o r p h o l o g y of the chromatids and c o m p a r i s o n with the c h r o m o s o m e s of any metaphases that show separation of some but not all the c h r o m a t i d s (as in Fig 1) s h o u l d leave no doubt as to their true identity. The p h e n o m e n o n of s p i n d l e failure resulting in "c-mitoses," w h i c h follows the a p p l i c a t i o n of s p i n d l e poisons such as colchicine, has long been studied. Levan, in 1954 [2], observed that every c h r o m o s o m e modification i n d u c e d by colchicine could also be found in untreated tumors, only more rarely. {We do not c o n s i d e r that the c o l c e m i d used in the pretreatment of our chromosomes, only 0.2 /xg/ml for 30 to 45 minutes, has any bearing on our findings). Complete s p i n d l e failure may be of interest for at least two reasons. First, although the fate of the cells showing this p h e n o m e n o n is u n k n o w n , it seems likely that a common sequela is the p r o d u c t i o n of a viable cell with a doubled c o m p l e m e n t of chromosomes. Second, although we cannot rule out the possibility that some of the m e t a p h a s e s with separated c h r o m a t i d s we have observed in bone marrow samples from patients with leukemias or p r e l e u k e m i a s are nonneoplastic, e.g., megakaryocytes, this p h e n o m e n o n , if its association with n e o p l a s i a is confirmed by further studies, may prove to be a useful marker for neoplasia. We thank David Smith for photographic services. Supported by a grant from the Association for International Cancer Research. NIELS B. ATKIN MARION C. BAKER
Department of Cancer Research Mount Vernon Hospital Northwood, M i d d l e s e x HA6 2RN, U.K.
REFERENCES
1. Moricard R, Cartier R (1959): Chromosomal and cytoplasmic cytopathology of intraepithelial squamous-cell epithelioma of the cervix uteri. In: Cancer of the cervix. Diagnosis of early forms, GEW Wolstenholme and M O'Connor, Eds. Ciba Foundation Study Group No. 3. J & A Churchill Ltd, London, pp. 28-43. 2. Levan A (1954): Colchicine-induced c-mitosis in two mouse ascites tumours. Hereditas 40:1-64.
106 Cancer Genet Cytogenet 62:106 107 (1992) 0165-4608/92/$05.00
~ 1992 Elsevier Science Publishing Co.. Inc. 655 A v e n u e of the Americas, New York, NY 10010
..... ~ i~
I
~!i¸¸ ~!
|i: ¸
i!iil!~! ' ~!~ii !j' j ;i~
ii ~
'i
....
~ t¸
A
Figure 1 (A) Metaphase from semmoma showing 194 completely separated chromatids The modal chromosome numbm was 95. Unbanded: Giemsa stain. (B) Part of regular metaphase from the same slide preparation as (A), for comparison.
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