Supernumerary Ring Chromosomes in Five Bone and Soft Tissue Tumors of Low or Borderline Malignancy Charlotte 0rndal, Nils Mandahl, Anders Rydholm, Helena Will,n, Otte Brosj6, Sverre Heim, and Felix Mitelman
Five tumors (two myxoid malignant fibrous histiocytoma, two dermatofibrosarcoma protuberans, and one parosteal osteosarcoma) with ring chromosomes as the sole cytogenetic a n o m a l y or as the only structural rearrangement were observed in a series of 60 karyotypically abnormal, nonlipogenic bone and soft tissue tumors (BST). All five tumors were of borderline or low malignancy. These findings support the suggestion that supernumerary ring chromosomes as the sole structural chromosomal aberration are not associated with any particular histopathologic diagnosis but m a y characterize a group of BST of borderline or low malignancy. ABSTRACT:
INTRODUCTION In contrast to most hematologic malignancies, a high proportion of solid tumors have multiple, both numerical and structural, chromosome aberrations. Highly malignant neoplasms generally appear to have more complex changes than low-malignant and benign tumors. This has been quantitatively shown for epithelial tumors; borderline and low-malignant carcinomas often had only simple numerical changes, whereas the more aggressive carcinomas had massive rearrangements . A similar association has been observed in mesenchymal tumors, but with some prominent exceptions. The highly malignant synoviai sarcoma and Ewing's sarcoma sometimes have only simple translocations [2-5]. On the other hand, the benign tumors lipoma and uterine leiomyoma may, although they mostly carry only simple aberrations, occasionally have multiple changes [6-9]. Ring chromosomes have been observed in less than 3% of the more than 14,000 reported neoplasms with abnormal karyotypes . In bone and soft tissue tumors (BST) supernumerary rings have been observed as the sole anomaly, as one of few changes, and as part of massively rearranged karyotypes. The tumor types in which rings have been most frequently observed are malignant fibrous histiocytoma (MFH) and lipogenic tumors. Both borderline malignant groups, atypical lipoma and well-differentiated liposar-
From the Departments of Clinical Genetics (C. (3., N. M., S. H., F. M.), Orthopedics (A. R.), and Clinical Pathology (H. W.), University Hospital, Lund, Sweden, Department of Orthopedics (0. B.), Karalinska Hospital, Stockholm, Sweden, and Department of Medical Genetics (S. H.), Odense University,. Odense, Denmark. Address reprint requests to: Dr. Charlotte Orndal, Department of Clinical Genetics, Lund University Hospital, S-221 85 Lund, Sweden. Received October 15,1991; accepted January 8, 1992. 170 Cancer Genet Cytogenet60:170-175 (1992) 0165-4608/92/$05.00
coma, are characterized by supernumerary rings [11, •2], in contrast to typical lipoma and myxoid liposarcoma, which have other structural changes [6, 13, 14]. Mandahl et al.  suggested that unidentifiable supernumerary ring chromosomes, as the sole change or as one of few simple changes, characterize a group of borderline malignant and low-malignant musculoskeletal tumors. To test this hypothesis further, all cases with supernumerary ring chromosomes and simple changes were selected from a series of BST to determine if low-malignant tumors predominated in this karyotypic subgroup.
MATERIALS AND METHODS
The operational definition of simple changes was that no other structural aberrations than ring chromosomes should be present, i.e., only cases with at least one clone with a ring as the sole anomaly or with rings and numerical aberrations were accepted. All lipogenic tumors were excluded from consideration because the pattern with ring chromosomes in atypical lipoma and well-differentiated liposarcoma has already been established. Soft tissue was defined according to Enzinger and Weiss : nonepithelial, extraskeletal tissue including the peripheral nervous system, but excluding the reticuloendothelial system, glia, and the supporting tissue of parenchymal organs. Five tumors with one or mare supernumerary ring chromosomes as the sole structural change were thus found in a series of more than 60 karyotypically abnormal, unpublished, nonlipogenic BST. Clinical data for the five patients are shown in Table 1. None of the patients had received cytotoxic treatment. All five tumor samples were obtained flesh postoperatively or after overnight transportation in isotonic saline (case 1). After mechanic and enzymatic disaggregation, the tumor cells were cultured on glass chamber slides in RPMI © 1992 Elsevier Science Publishing Co., Inc. 655 Avenueof the Americas,New York,NY 10010
S u p e r n u m e r a r y Ring Chromosomes in BST
1/M/18 2/M/35 3/M/80 4/F/47 5/M/53
Distal femur Upper arm Groin Shoulder Groin
Size (cm) 10 3 14 1 2
x x x × x
5 2 8 1 2
x × x x x
5 2 8 1 2
D D D S S
P P P R R
Parosteal osteosarcoma M-MFH/II M-MFH/II Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans
S, superficial; D, deep; P, primary; R. recurrence, no cytogenetic investigation of the primary lesion; M-MFH, myxoid malignant fibrous histiocytoma. a A four-grade malignancy scale was used.
1640 m e d i u m w i t h HEPES buffer, s u p p l e m e n t e d w i t h glutamine, antibiotics, and 17% fetal bovine serum . After 3 - 7 days, the cultures were harvested in situ. Wright stain was used for G-banding. PATHOLOGIC AND CYTOGENETIC FINDINGS Case 1 Case 1 was a low-grade parosteal osteosarcoma, primary tumor. Histopathologic e x a m i n a t i o n showed tumor tissue w i t h n e w - w o v e n bone, fibrous connective tissue, and osteoblasts. The cell d e n s i t y was variable but mostly moderate. A l t h o u g h in some areas cellular p o l y m o r p h i s m was noted, the cells were uniform in most parts. Two a b n o r m a l clones were present: 47,XY, + r in 13 cells and 4 6 - 4 7 , X Y , - 13, + 1 - 2 r in 11 cells (Fig. 2), suggesting that the ring was the p r i m a r y change. Two cells had a normal karyotype. Case 2 Case 2 was a m y x o i d MFH, grade II, p r i m a r y tumor. The t u m o r was gray-white, soft, and myxoid. Light m i c r o s c o p y s h o w e d that the t u m o r was of low cellularity, myxoid, with thick, irregular vessels. A few atypical mitotic figures were
Figure 1 Histologic section from case 3, a malignant fibrous histiocytoma with low cell density and a few multinucleated giant cells. (H&E, x 230)
observed. The tumor cells were triangular or s p i n d l e shaped with h y p e r c h r o m a t i c , slightly atypical nuclei. O n l y a few m u l t i n u c l e a t e d t u m o r ceils were observed. Two different samples from the operation s p e c i m e n were investigated. In the cultures from the first sample, 10 mitoses with a normal male karyotype were noted. Nineteen cells were analyzed from the s e c o n d sample: two cells had the karyotype 47,XY, + r; the r e m a i n i n g 17 cells h a d a normal karyotype. Case 3 Case 3 was a m y x o i d MFH, grade II, p r i m a r y tumor. Crosssection s h o w e d the t u m o r to be lobular, gray-white, a n d partly sclerotic. Light m i c r o s c o p i c e x a m i n a t i o n s h o w e d a highly vascularized t u m o r w i t h t h i c k irregular vessels, a rich collagenous background, a n d low cell density. The tumor cells were either s p i n d l e - s h a p e d or m u l t i n u c l e a t e d , with atypical nuclei and e o s i n o p h i l i c c y t o p l a s m (Fig. 1). The t u m o r was m a i n l y myxoid; but in some areas a distinct storiform pattern was noted. Neither lipids, x a n t h o m a cells, hemosiderin, nor hemorrhage were observed. Three samples (A, B, and C) were taken from different parts of the tumor. A b n o r m a l cells were observed in all three samples; 49 of 50 cells from A, 34 of 50 from B, and 22 of 24 from C. The aberrations were loss of the chromosomes Y and 22, and gain of two to seven s u p e r n u m e r a r y ring chromosomes. One third of the a b n o r m a l cells from sample A also had loss of c h r o m o s o m e 18. Thus, the t u m o r karyotype was 46-51,X, - Y , - 22, + 2 - 7 r / 4 5 - 5 0 , X , -Y,- 18,-22,+2-7r. N o n c l o n a l structural changes, i n c l u d i n g telomeric associations, were also observed. Some of the small markers interpreted as rings m a y have been ring fragments. The r e m a i n i n g 19 cells had a normal karyotype. Case 4 Case 4 was a dermatofibrosarcoma protuberans, local recurrence. The p r i m a r y t u m o r was 3 cm in d i a m e t e r and infiltrated into dermis and subcutaneous fat. A local recurrence a p p e a r e d 6 months after the initial surgery. The recurrent tumor was gray-white and hard. Histologically it consisted of uniform fibroblastlike cells and h a d high cellularity, a storiform cell pattern, a n d infiltrated fat. I m m u n o h i s t o chemistry by the indirect p e r o x i d a s e m e t h o d s h o w e d negative reaction for d e s m i n and S-100 p r o t e i n antibodies, but
C. O r n d a l et al.
Metaphase cell from case 1, a parosteal osteosarcoma, with the karyotype 46,XY,- 13, + r.
scattered cells with positivity for a l - a n t i t r y p s i n and 0:1a n t i c h y m o t r y p s i n were observed. In four cells with a h y p e r t e t r a p l o i d chromosome number, a ring was observed as the sole structural anomaly, giving the karyotype 93,XXXX, + r. That only one copy of the ring was present indicates that the p o l y p l o i d i z a t i o n occurred before the ring was acquired, but loss of one ring after d u p l i c a t i o n cannot be excluded. A normal karyotype was observed in 25 cells. Case 5 Case 5 was a dermatofibrosarcoma protuberans, local recurrence. A cutaneous tumor was removed from the patient's right inguinal region. Eight months later, the tumor recurred locally and a reoperation was performed. Both tumors had similar histology, with infiltrative growth into cutis and subcutis, s p i n d l e - s h a p e d cells in a storiform pattern, and scattered mitotic figures. Immunohistochemical investigation of the recurrent tumor showed negative reaction for d e s m i n and S-100 protein but focal positivity for a l - a n t i t r y p s i n and a l - a n t i c h y m o trypsin. In 11 of 67 analyzed metaphases, the karyotype 47,XY, + r was observed. The remaining cells had a normal karyotype.
Of the more than 14,000 n e o p l a s m s w i t h c h r o m o s o m e aberrations listed by M i t e l m a n ~ less than 400 are BST, 2,600 are other solid tumors (OST), and 11,000 are hematologic neoplastic disorders (HND). The subsets w i t h ring chromosomes in these three groups are 8% in BST, 3% in OST, and 2% in HND. The difference between the t u m o r groups becomes even more p r o n o u n c e d if one considers only the fraction of n e o p l a s m s with rings as the sole structural aberration; the frequency in BST is 10 times higher than in both OST and HND, (3 vs 0.3%; Table 2). In OST, one fourth of the cases with rings have c o m p l e x karyotypes as c o m p a r e d with 6% in BST and only 3% in HND. In BST, 90% had rings that consisted of u n k n o w n c h r o m o s o m e material as c o m p a r e d with 50% in both HND and OST. Nine OST with ring c h r o m o s o m e s as the sole structural change have been reported (Table 3). These tumors span all levels of malignancy: four benign tumors (two meningiomas, one mixed salivary gland tumor, and one uterine leiomyoma), two well-differentiated carcinomas (endometrial a d e n o c a r c i n o m a and a d e n o c a r c i n o m a of the lung), two highly malignant tumors (renal cell c a r c i n o m a and W i l m s ' tumor), and one k i d n e y c a r c i n o m a for w h i c h information about histologic malignancy grade was lacking. The two meningiomas also had - 2 2 , the characteristic p r i m a r y
S u p e r n u m e r a r y Ring Chromosomes in BST
Number of cases with ring chromosomes. Data extracted from the Registry of Chromosome Aberrations in Cancer [10, updated]. The five n e w cases of this report have also been included.
Group of neoplasms
No. of cases with cytogenetic aberrations
BST BST excluding lipogenic tumors Lipogenic tumors OST All solid tumors HND
Cases with ring chromosomes
Cases with rings as the sole structural aberration
71 2,572 2,963 11,186
7(10) 89(3) 120(4) 212(2)
13(3) 9(3) 4(6) 9(0.3) 22(0.7) 36(0.3)
BST, bone and soft tissue tumors; OST, other solid tumors;HND,hematologicneoplasticdisorders.
aberration in that tumor type [17, 18], and the ring was probably a secondary aberration in both cases. Ring chromosomes, of w h i c h about 50% are r(1), have been observed in 12 uterine leiomyomas [7, 9, 19-22]; the rings are most often found together with other rearrangements and are thus considered secondary changes . Altogether n i n e n o n l i p o g e n i c BST (five in the present report, four previously reported) with rings as the sole structural aberration are n o w known: four myxoid MFH, four dermatofibrosarcoma protuberans, and one parosteal osteosarcoma (Table 4). A cytogenetic subgroup of MFH, characterized by the presence of unidentifiable s u p e r n u m e r a r y ring chromosomes, was recently s h o w n to have low relapse risk .
Other solid tumors than those of bone and soft tissues with ring chromosomes as the sole structural aberration
Karyotype 43,XX, - 14, - 19, - 22/44,XX, - 1 4 , - 19,-22,+r 45,XX,r(19), - 22 46,XX, - 4, + r(4p) 49,XX, + 2, + 7, + r
46,XX,r(3)(p25q27)/92, XXXX,r(3),r(3) 47,XY, + 7/50,X, - Y, + 3, + 7 , + 8 , + 12,- 15,+16, +r/51,X,-Y,+ 3,+ 7,+ 8, + 1 2 , - 1 5 , + 1 6 , + 17,+r 47,XY, + r
48,XX, + 5, + 5, + 7, - 17/49, XX,+ 5,+ 5,+ 7 , - 17,+r 46,XX,r(1}
Of the 13 MFH with rings that have been reported [25, 26, present study], four had rings as the sole structural aberration in at least one clone (Table 4). All four were of the myxoid subtype, and these tumors are generally of lower malignancy [16, 27]. Of the other n i n e MFH with rings, eight (six storiform-pleomorphic and two myxoid tumors) had multiple additional aberrations, whereas one pleomorphic MFH had somewhat less massive changes . Dermatofibrosarcoma protuberans is a fibrohistiocytic tumor of borderline malignancy. It tends to recur locally but rarely sets distant metastases . All four cytogenetically examined cases [15, 28, present study] had ring chromosomes as the sole structural r(1) in one. In one tumor, the ring appeared to be a secondary change, following + 8, and
Nonlipogenic bone and soft tissue tumors with ring chromosomes as the sole structural aberration
Meningioma Pleomorphic adenoma Endometrial adenocarcinoma, well differentiated Renal cell carcinoma Renal cell carcinoma, highly malignant
47,XY, + r/46-47,XY, - 13, + 1 - 2r
47,XY, + r 45-51,X, - Y, - 22, + 2-7r/45-50,X, - Y, - 18,- 22,+ 2-7r 93,XXXX, + r
Wilms' tumor, unfavorable histology Adenocarcinoma of the lung, well differentiated Uterine leiomyoma
48-49,XY, + 2, + 1-2r 47,XY, + r 47,XY, + 8/48,XY, + 8, + r
47,XY, + r(1)(cen--~ q44::?::p36-*cen)
Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans M-MFH/III M-MFH/II Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans
M-MFH.myxoid malignantfibroushistiocytoma. QFour-grademalignancyscale.
Reference Present report, Case 1 Case 2 Case 3
Case 4 Case 5    
in another (case 4) acquisition of the ring appeared to be secondary to polyploidization. Parosteal osteosarcoma is a low-malignant variant of osteosarcoma . None of the previously reported 10 cytogenetically characterized osteosarcomas has been of the parosteal type [30-34], and case I of the present series is therefore the first description of a parosteal osteosarcoma with karyotypic abnormalities. Three of the osteosarcomas that have been reported had ring chromosomes as part of complex karyotypes . The data presented above appear to support the hypothesis that s u p e r n u m e r a r y ring chromosomes as the sole structural a n o m a l y characterize tumors of borderline or low malignancy, not only in lipogenic tumors [6, 11, 12], but also in n o n l i p o g e n i c BST. No similar correlation is discernible in other solid tumors or in HND. The cause b e h i n d the association with low malignancy level may not be the presence of s u p e r n u m e r a r y rings themselves, but instead the simplicity of the karyotypic changes. However, in atypical and typical sporadic lipomas, it is the presence of rings in the former and other changes in the latter tumors [6, 8, 35], not the general karyotypic complexity, that appears to be the p h e n o t y p e - d e t e r m i n i n g cytogenetic difference. Furthermore, some MFH have had simple chromosome changes without rings: two cases had only the numerical changes + 7 and + 17 , one case had +i(8p) as the sole change , and one case had numerical changes, t(11;?), and a few n a n - r i n g markers . All four tumors were highly malignant pleomorphic MFH. The available data therefore indicate that among BST s u p e r n u m e r a r y rings as the sole structural aberrations, rather than a low n u m b e r of karyotypic changes in general, is associated with low malignancy.
C. Orndal et al.
This work was supported by grants from the Swedish Cancer Society, the John and Augusta Persson Foundation for Medical Research, and the Lund University Medical Faculty.
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