American Jouirnial of Pathology, Vol. 142, No. 1, January 1993 Copyright © American Society for Investigative Pathology

Chromosomal Abnormalities in Leiomyosarcomas Chandrika Sreekantaiah,* John R. Davis,t and Avery A. Sandbergt From the Memorial Sloan-Kettering Institute, Laboratoty of Genetics and Cancer Genetics, * New York, New York; the Department of Pathology, University of Arizona Health Science Center,t Tucson, Arizona; and the Cancer Center qf SBRI and Genetrix, Inc.,* Scottsdale, Anizona

Thirty-eight tumors from 30 patients diagnosed as leiomyosarcoma were cytogeneticaly assessed after short term culture. The specimens were obtained from the retroperitoneum, gastrointestinal tract, and extremities. Chromosomal abnormalities were present in 18 tumors from 13 patients; 15 tumors had clonal changes, whereas 3 tumors had numerous nonclonal changes. Ten tumors from 10 patients had normal karyotypes and no results were obtained in 10 other tumors from 7 patients. Of the tumors with clonal chromosomal aberrations, 4 had near-diploid (3 hypo- and one hyperdiploid) modes, 8 were polyploid, and 3 were bimodaL No specific karyotypic charge appeared to characterize the leiomyosarcomas, although involvement of some chromosomes appeared more frequent than others. A comparison of our findings with those reported in the literature revealed certain consistent structural rearrangements involving chromosomes 1, 7, 10, 13, and 14 at bands Ip36, 1p32, Ip13, 1q32, 7pll.1-p21, 7q32, 10q22, 13q14, and 14p1l, respectively. Other bands less frequently rearranged were 3p13-p22, 3q21, 4ql3-q23, 6q15-q21, 7q11.2-q22, 12ql3-ql4, 1 7q12-q25, 19q13.3-q13.4, and 20q12-ql3.1. Numerical changes included recurrent loss of chromosomes 4, 9, 14, 15, 16, 18, 21, and 22. Identification of the abnormalities of these chromosomes is important in that it may predict the existence of oncogenes, tumor suppressor genes, and/or growth factor genes at these sites. Subsequent molecular analysis might then lead to the identification of the genes involved and ultimately to a better understanding of the pathogenesis of leiomyosarcomas. (Am J Pathol 1993,

142:293-305)

Leiomyosarcomas (LMS) are malignant neoplasms that arise from smooth muscle tissue. They occur most frequently in the female genital tract and the gastrointestinal tract. Soft tissue LMS are less common, accounting for about 7% of soft tissue sarcomas, approximately half of which occur in the retroperitoneum. LMS are a very aggressive group of neoplasms with a high rate of recurrence and metastases to the lung and liver.1 2 Although specific chromosomal rearrangements of diagnostic relevance have been described in a variety of sarcomas,3 the cytogenetic data on LMS are still very limited. The karyotypic picture in the 24 cases with chromosomal abnormalities previously reported in the literature4-19 is quite diverse, with no single change common to all or most LMS. However, among the hypodiploid tumors, the most consistent aberrations identified are involvement of 1p13-1pter in deletions and translocations with resultant partial monosomy of the distal portion of 1 p and monosomy of chromosomes 18 and 22. A majority of the tumors showed extensive numerical and structural abnormalities. Unique translocations or other abnormalities were present in a few tumors and, because they occurred as the sole change, they were considered primary for those individual tumors. The present study describes the chromosomal findings in 28 LMS obtained from the retroperitoneum, gastrointestinal tract, and extremities and compares the data with those in the published literature. Certain chromosomal aberrations were found to occur in a greater frequency, suggesting that genes of importance in the development and progression of LMS may be located at these sites.

Materials and Methods Chromosomal analysis of the tumor specimens was carried out on short-term cultures according to preSupported in part by Grant CA-41183 from the National Cancer Institute. Accepted for publication July 22, 1992. Address reprint requests to Dr. Avery A. Sandberg, The Cancer Center of SBRI and Genetrix, Inc., 6401 E. Thomas Road, Scottsdale, AZ 85251.

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Figure 1 A: Grade 1 intra-abdominal leiomyosarcoma (case 10) showing interlacing fascicles of spindle cells tightly compacted (x 166). B: A slightly myxomatous area of tumor shown in A has fairly mature elongated nuclei and little pleomorphism. Mitotic counlt u'as 2110 HPF (X 416).

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wvith moderate amount of cvtoplasm, no patterned B: Ntuclear hyperchromatism and pleomorphism are prominienlt anld mitotic figuires are numerous (X 416). This grade 2 leiomyosarcoma (same as in A) was vimentin anid actini positive anid cytoplasm was strong/v red in trichrome staini.

Figure 2 A: Round cell leiomyosarcoma of stomach (case 4) composed of epithelioid cells

arranigement, anid scant intercelluilar matrix (x 166).

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viously described techniques.20'21 Briefly, this consisted of overnight collagenase disaggregation of the tumor and culture in flasks and coverslips in RPMI 1640 medium supplemented with 17% fetal calf serum, glutamine (2 mmol/L) and penicillin/ streptomycin (50 U/ml; 50 p g/ml) at 37 0C and 5% C02. After harvest, which was individualized for each flask and coverslip, and fixation, the chromosomes were G-banded.22 A minimum of 15 to 20 metaphases were analyzed for each specimen when possible and the karyotypes expressed in accordance with the International System of Chromosome Nomenclature.23

Results Thirty-eight tumors originating from retroperitoneal and gastrointestinal sites and extremities diagnosed as LMS (Figures 1 and 2) were analyzed cytogenetically. Ten tumors showed predominantly normal karyotypes and 18 revealed karyotypic abnormalities, of which 15 were clonal and 3 had numerous nonclonal changes. Ten other tumors failed to attach and grow in culture, probably because of the necrotic nature of the specimens received. The relevant clinical, histopathological, and cytogenetic findings in the 18 LMS from 13 patients with chromo-

somal abnormalities are summarized in Table 1, and representative karyotypes depicting cytogenetic abnormalities are illustrated in Figures 3 to 7.

Clinical Data The mean age of the patients was 51 years; there were 6 women and 7 men. Apart from 3 cases (nos. 5, 9, and 13) all other tumor samples were recurrent specimens. Two specimens each were received for case 3 (recurrence and metastases), case 9 (primary and recurrence), and case 10 (recurrences), and 3 tumor specimens were received for case 5 (2 primary specimens from different areas and 1 recurrence). Histopathological grading was available for all tumors; 5 tumors were low grade lesions and 13 were moderate to high grade. The treatment of choice in all cases was surgical resection of the tumor followed by chemotherapy or intraoperative radiotherapy in some cases. Thus, some of the recurrent tumor samples were received after previous therapy. Follow-up data were not available for all patients; therefore, prognosis could not be evaluated.

Pathology The distribution of the LMS studied by us is in keeping with the observations of others, ie, these tumors

Figure 3. Representative G-banded karyotvpe from case 1 with leiomyosarcoma ofsmall bowel showing clonal gains of a number of cbromosomes. Vo strnctural changes are evident.

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Figure 4. Representative G-banded karvotipe from case 2 with invasive leiomposarcoma of stomach. Maniy numenrcal and some stnrctural chromosome chanzges are present, inzcluiditng nmarkers uwhose origin couild not be established. 7The stnrctural chaniges involve chromosomes 1, 3, and 22. See Table I for description qf the changes. Additionial nonclonal gainis are also presenit.

are widely distributed and are usually encountered in the retroperitoneal-intraabdominal soft tissue and muscular viscera (eg, uterus and stomach). The histological observations of the tumors studied by us can be generally described as follows. The soft tissue smooth muscle sarcomas (Figure 1) are spindlecell neoplasms forming interlacing bundles with generally scant intercellular matrix. Cytoplasm is abundant and longitudinal fibrils may occur. Nuclei are elongate and vary from uniform size and chromatin patterns to pleomorphic, hyperchromatic, and bizarre nuclei. Mitotic activity is characteristic but may consist of only a few per 10 high power fields. High grade sarcomas, in addition to having more aberrant nuclear and cellular abnormalities and high mitotic rates, have extensive hemorrhage and necrosis. The gastric leiomyosarcomas (Figure 2), which constituted nearly half of the cases studied, tend to have round neoplastic cells which may include foci of spindle cells. The round cells have epithelioid features in terms of plump cells with sharp outlines and central nuclei; clear cytoplasmic vacuoles are variable in presence and size. Nuclei tend to be oval to

round in low grade sarcomas, but have greater pleomorphism and size in high grade lesions. Mitoses occur at least in small numbers.

Cytogenetic Data A hypodiploid mode was present in 3 tumors, 1 tumor had a hyperdiploid mode, and 8 tumors contained near-triploid and near-tetraploid modes. The other 3 tumors had bimodal populations with counts in the near-diploid and polyploid ranges. All 3 tumors with nonclonal changes were near-diploid. Numerical changes were expressed in relation to the appropriate ploidy level. The changes in the hypodiploid and near- to hyperdiploid tumors were different when compared with the polyploid tumors. Whereas recurrent losses of chromosomes 16, 18, and 22 predominated in the former, losses of chromosomes 4, 9, 14, 15, and 21, and to a lesser extent of 10, 12, and 18, were more frequent in the latter. Structural rearrangements were not dependent on ploidy except for that of the short arm of chromosome 3, (del(3)(p11-p22)), which was observed in the polyploid tumors. Chromosome 1 was most fre-

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Figure 5. G-banded karvotipe from case 5 uwith invasive leiomynosarcoma of stomach shbuoing large marker chromosomes (possible homogeneous4v staining regionis indicated bh' arrouw) in additioni to other chanzges. The latter consisted of many nntimerical changes and 6 markers uhose identity cotuld not be established uith certaintv.

quently rearranged, particularly the short arm at bands 1p13-1p36.1. The short arms of chromosomes 7 and 14 and the long arm of chromosome 13 at band q14 were also frequently involved. Chromosome Y was not involved in structural aberrations in the present series. A normal karyotype was present in 10 tumors. Although most of the tumors were harvested between 3 and 8 days (the latest time of harvest was 14 days in 2 tumors), overgrowth of the cells by normal stromal elements cannot be ruled out. The normal karyotype may therefore not be representative of the tumor.

Discussion Considerable interest has been generated in the chromosomal constitution of solid tumors with the identification of recurrent translocations, deletions, and other aberrations in a variety of neoplastic diseases and their proven clinical usefulness.3 In the characterization of soft tissue sarcomas, in particular, cytogenetics has emerged as a very promising

diagnostic approach. Several sarcomas demonstrate consistent chromosomal rearrangements, mostly translocations, which have proved helpful in the differential diagnosis of these neoplasms.2425 The diagnostic relevance of cytogenetic studies in soft tissue tumors has been noted by us on several occasions and further stressed in a recent study.19 Among the soft tissue sarcomas, LMS comprise a small group of tumors, which are outnumbered by the more common liposarcomas and malignant fibrous histiocytomas. Consequently, the cytogenetic information on LMS is sparse. Successful karyotypic analysis has been reported in only 33 tumors from various anatomical sites.4-19 Of these, 9 were karyotypically normal. This number may be an underrepresentation, because most of the reports were single case studies with no information about the cytogenetic success rate or cases with a normal karyotype. The chromosomal changes in the 24 LMS with abnormalities were usually complex with extensive numerical and structural rearrangements. No specific primary cytogenetic abnormality characteristic of LMS has been identified, although consistent

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Figure 6. A G-banded karyotvpe from case 9a with leiomyosarcoma of abdomen and pelvis with multiple and complex chromosome changes. The latter incltuded some numerical and a large nuimber of stnrctuiral anomalies, some of rather complex nature (markers), involving chromosomes 1, 2, 7, 8, 10. 12, 14, 15, 19, 20, and 21. See Table I for descriptioni of these chaniges.

chromosomal profiles were observed and an attempt at a chromosomal classification made.12 We have successfully analyzed 28 LMS, 18 of which contained clonal and nonclonal abnormalities. A comparison of our results with published data revealed certain similarities in the chromosomal patterns and provided new information about nonrandom cytogenetic changes in this group of diverse tumors. Some of the abnormalities were noted to be ploidy-specific and others site-specific. Hypodiploidy appeared to be a common occurrence and consistent changes in this group included monosomies of chromosomes 16, 18, and 22, and recurrent structural aberrations of chromosome 1 at bands 1 p13-1 pter such that there was partial monosomy of 1 p. Loss or rearrangement of these chromosomes and chromosome regions is not restricted to LMS and has been noted in other tumors as well. Loss of chromosome 18 has been nonrandomly observed in colorectal adenomas3 and monosomy 22, long characteristic of meningiomas,26 has recently been observed in uterine leiomyomas,27 another smooth muscle tumor. As suggested previously,12 the mechanism of pathogenesis in these tumors may be loss of a tumor suppressor gene located on these chromosomes. Structural abnor-

malities of chromosome 1 are often present in a variety of neoplasms, most often resulting in extra copies of 1q, and have been suggested to be a secondary change providing cells with a selective growth advantage.27'28 In LMS, however, the high frequency of loss of the distal portion of 1 p suggests that a tumor suppressor gene(s) may be located in that region and which may be important in the initiation and progression of LMS. The near-triploid and near-tetraploid tumors were characterized by recurrent losses of chromosomes 4, 9, 14, 15, and 21 in relation to their ploidy level. Structural rearrangements, found predominantly in the polyploid tumors, included deletions of the short arm of chromosome 3 at bands 3p1 1-p22. The presence of bimodal tumors and polyploid populations of cells, with duplication of some of the marker chromosomes, in a few near-diploid tumors suggests that the higher ploidy tumors may have arisen consequent to doubling of the lower ploidy tumors. Irrespective of the ploidy level the mechanism of tumorigenesis in LMS appears to be related to loss of a tumor suppressor gene(s). Apart from the ploidy-specific changes detailed above certain site-specific changes were also observed. All five LMS of the knee examined cyto-

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Figure 7. Repre-wentative G-banded karvotpe from case 1-: with invasile leiomnovsarcoma of stoniach. soine stnrctniral changes. The t(l; 19) was a niozcklo)ial chaz,ge.

genetically10'15'19 (present report) showed extra copies of chromosomes 20; in 4 cases as trisomy 20 and in one case as an additional rearranged chromosome 20 (t(20;?)(q13;?)).15 Although no uterine leiomyosarcomas were examined by us in the present study, based on published data, rearrangements, either as deletions or translocations, of 7q, 13,16,17.19 12q, 13,16 1Oq,9,16,17 and 17q,9,15,16'17 were nonrandomly present. Since these regions are also consistently rearranged in the benign counterpart of LMS, ie, uterine leiomyomas,27'29 the genes located at these sites are most probably proliferation-related. The number of cases in each of the other sites was not large enough to permit similar identification of specifically rearranged chromosomal loci. The observation that tumors from a particular site share certain chromosomal abnormalities indicates that alternative mechanisms of initiation and progression may be operative even in tumors of similar histology. Different sets of genes may be activated either during the development of the tumor or its progression depending on tumor location. Although no specific structural abnormality in LMS in general was observed, certain chromosomal break points could be identified as being recurrently rearranged (Figure 8). The most frequently involved

7Te kar ot)pe contains many numerical antd

bands were 1p36, 1p32, 1p13, 1q32, 7p11.1-p21, 7q32, 10q22, 13q14, and 14p11.1-p11.2. Less frequently rearrangements affected bands 3p11-p22,

3q21, 4q13-q23, 6q15-q21, 7q11.2-q22, 12q13-14, 17q12-q25, 19q13.3-q13.4, and 20q12-q13.1. The specificity of involvement of these regions can be confirmed only by further cytogenetic and molecular analysis, leading ultimately to the identification of genes of importance in the tumorigenesis of LMS. The chromosomal changes in LMS may have a significance similar to that in adencarcinomas (eg, of the large bowel) in which they are thought to reflect a sequential multistep genetic process necessary for tumorigenesis and tumor progression. It is interesting that bands 13q13-q14 were involved in a number of cases. The RB gene has been localized to band 13q 1430 and loss of this gene has been implicated in the tumorigenesis of a number of cancers, including soft tissue sarcomas.3 Perhaps it has a similar role in LMS. Homogeneously staining regions were present in a number of tumors and may contribute to the pathogenesis of LMS through an amplification of oncogenes. Homogeneously staining regions have been noted in other soft tissue tumors as well.3

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siveness, metastatic spread, response to therapy, and prognosis, may ultimately lead to an improved classification of LMS.

Acknowledgments 1

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11 x

12

x

We thank Dr. C. P. Karakousis and Dr. S. P. L. Leong for supplying the tumor material, Ms. Shirley Frazzini for willing and expert secretarial assistance, and Robert Roeder and Fred Flohrschutz for expert photographic assistance. The invaluable help of Carol S. Berger, Mary Powell, and Adam Wilson is gratefully acknowledged. We also thank Diane Smith, Darcy Celeste, and Judy Krasher for help in collecting clinical information.

References 13 Fiur

pn ti 17 14 15 8. Sceaiepeetto shwigh choosml2oa

:X~~~ Figure 8. Scbematic representatiott sboulitig the cbromosomal locatioti of break poitits int this (x ) astd other piblisbed (e*) cases of LUS.

Nonclonal structural and numerical changes affecting various chromosomes were present in three cases in a high number of cells. No two rearrangements or changes were similar. The presence of such random changes reflects genomic instability and may be representative of an early stage in the clonal evolution of a tumor, although the possibility that these nonclonal aberrations resulted from previous tumor therapy should be considered. Subsequent selection may then give rise to a predominant clone. Similar nonclonal changes have been previously reported in LMS1-16 and other sarcomas31 (unpublished observations). In conclusion, the results presented extend our knowledge about chromosomal abnormalities in soft tissue sarcomas in general and LMS in particular. They also demonstrate that differences in karyotypic findings may be due to tumor heterogeneity or site and ploidy. The description of chromosomal findings in more cases of LMS of specific sites will help to determine whether our observations of specific changes characterizing specific sites is accurate. This, as well as correlations with other parameters such as grade and stage of the tumor, tumor inva-

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Genet Cytogenet 1986, 22:159-167 8. Dal Cin P, Boghosian L, Sandberg AA: Cytogenetic findings in leiomyosarcoma of the small bowel. Cancer Genet Cytogenet 1988, 30:285-288 9. Dal Cin P, Boghosian L, Crickard K, Sandberg AA: t(10;17) as the sole chromosome change in a uterine leiomyosarcoma. Cancer Genet Cytogenet 1988, 32:263-266 10. Nilbert M, Mandahl N, Heim S, Rydholm A, Will6n H, Akerman M, Mitelman F: Chromosome abnormalities in leiomyosarcomas. Cancer Genet Cytogenet 1988, 34:209-218 11. Sait SNJ, Dal Cin P, Sandberg AA: Consistent chromosome changes in leiomyosarcoma. Cancer Genet Cytogenet 1988, 35:47-50 12. Boghosian L, Dal Cin P, Turc-Carel C, Rao U, Karakousis C, Sait SNJ, Sandberg AA: Three possible cytogenetic subgroups of leiomyosarcoma. Cancer Genet Cytogenet 1989, 43:39-49 13. Havel G, Dahlenfors R, Wedell B, Mark J: Similar chromosomal evolution in a uterine stromomyosarcoma and

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