Chromosome Aberrations in Uterine Smooth Muscle Tumors: Potential DiagnosticRelevance of Cytogenetic Instability1
Jonathan A. Fletcher,2 Cynthia C. Morton, Karen Pavelka, and Janice M. Lage
Department of Pathology, Brigham and Women's Hospital [J. A. F., C. C. M.. K. P., J. M. L.]; the Department of Pediatrie Oncology, Dana-Farber Cancer Institute andthe Division of Hematology/Oncology, The Children 's Hospital [J. A. F.J; Harvard Medical School, Boston, Massachusetts 02115
ABSTRACT
Cytogenetic studies were carried out on a low-grade metastatic uterineleiomyosarcoma and on a large degenerating uterine leiomyoma. Theleiomyosarcoma and leiomyoma were hyperdiploid and hypodiploid, respectively, and both tumors contained multiple consistent chromosomeaberrations. In the patient with leiomyosarcoma, flow cytometric studiesof proliferative foci from a previously resected uterine leiomyoma revealed near triploidy, suggesting that the leiomyosarcoma was metastaticfrom an unrecognized malignant uterine primary lesion. The leiomyosarcoma was characterized by extreme Cytogenetic instability,whereas the leiomyoma demonstrated cytogenetic stability. The presentcases and review of the literature on leiomyosarcomas and leiomyomasreveal cytogenetic instability to be very common in leiomyosarcomas(present in 8 of 10 cases) and uncommon in leiomyomas (present in 1 of25 cases). A grading system is described which might be useful inevaluating the diagnostic and prognostic relevance of cytogenetic instability in uterine, and other, malignancies.
INTRODUCTION
Uterine leiomyomas are extremely common neoplasms, having an incidence of nearly 40% in women older than 50 years(1); these benign tumors rarely undergo malignant transformation and in general are easily distinguished from low-gradeleiomyosarcomas. It is widely accepted that uterine smoothmuscle neoplasms with fewer than 5 mitoses/10 high-powerfields behave in a benign fashion, whereas those with greaterthan 10 mitoses/10 high-power fields will often pursue a malignant course (2). In the absence of cellular atypia, however, itcan be difficult to predict the behavior of uterine smooth muscletumors having intermediate mitotic activity (5 to 10 mitoses/10 high-power fields). Accordingly, it has been suggested thatthese neoplasms be designated "smooth muscle tumors of unknown malignant potential" (1-3). Particularly difficult to categorize are the so-called "benign metastasizing leiomyomas"
which are histologically benign neoplasms having little or nomitotic activity. It is uncertain whether such cases might represent malignant tumors which are misclassified due to inadequate sampling or malignant tumors in which metastatic phe-notype is dissociated from mitotic rate and cellular atypia;alternately, these tumors might represent multicentric benignneoplasms or benign neoplasms which have been disseminatedby mechanical means, such as surgical implantation (4-6).Herein, we describe a pelvic leiomyosarcoma in which kary-otypic analysis revealed aneuploidy, multiple consistent structural chromosome aberrations, and extreme cytogenetic instability. Correlation of the cytogenetic findings with flow cytom-etry data suggests that this leiomyosarcoma is metastatic froma uterine smooth muscle neoplasm that had been resected 5
Received 1/24/90.The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This research was supported in part by a Physician Scientist Program inAging Award (NIA-AG00294) to J. A. F.
2To whom requests for reprints should be addressed, at Department ofPathology. Brigham and Women's Hospital, 75 Francis Street, Boston, MA
02115.
years earlier. The karyotypic aberrations and cytogenetic instability in this leiomyosarcoma are contrasted with those in alarge degenerating uterine leiomyoma from another patient,and with those in previously reported uterine leiomyomas andleiomyosarcomas.
MATERIALS AND METHODS
Cytogenetic Analysis. Tissues were minced with scalpels, and disaggregated for 12 h in a 200 units/ml collagenase (Gibco) solution,according to the method of Limon et al. (7). The disaggregated cellclusters were cultured in T25 flasks, using RPMI 1640 (Gibco) with16% fetal calf serum, 1% L-glutamine, and 1% penicillin-streptomycinin a 5% CO2 incubator at 37°C.After 5 to 8 days, the adherent cells
were exposed to colcemid (0.01 ug/m\) for 1 h, lifted from the flaskswith trypsin, treated in a 0.075 M KC1 hypotonie solution for 10 min,and then fixed with two changes of methanol:acetic acid (3:1). Slideswere made by conventional techniques, using steam to assist in metaphase spreading. After 2 to 3 days of incubation on a slide warmer at60°C,the chromosomes were banded by the GTG method (8).
Cytogenetic Stability Grading. In order to assess cytogenetic instability in a standardized manner, we have devised a "cytogenetic stability"
grading system. This stability grading system is patterned after theconventional histopathological grading systems in which Grade I denotes a low grade and Grade III or IV a high-grade malignancy. In thecytogenetic context, grade refers to the percentage of cells within agiven tumor population for which additional and unique cytogeneticevents, beyond those in the stem line, are observed. These unique eventsmay include both structural and numerical aberrations. However, numerical aberrations that likely result from technical artifact, e.g., random loss of whole chromosomes in overspread metaphases, are notcounted as unique events. Also, groups of identical metaphases thathave arisen from the stem line by clonal evolution are counted as onlyone event. The stability grade is applied only when a minimum of 10metaphases from a given stem line are available for analysis, and isincluded in the karyotypic description of a given tumor. Stability GradesI, II, III, and IV indicate unique cytogenetic events in 0-10%, 11-49%,50-90%, and greater than 90% of metaphases, respectively. As ahypothetical example, "45,XX,-20 [stability grade I]" would be the
cytogenetic designation for a tumor in which each of at least 10metaphases was monosomic for chromosome 20 in the absence ofadditional chromosome aberrations. "46,XX,del(l)(p32) [stabilitygrade llj" would be the designation for a tumor in which 5 of 10
metaphases had the del(lp) only (stem line karyotype), 4 metaphaseshad del(lp) and trisomy 8 (one additional event), and 1 metaphase haddel(lp), trisomy 6, and trisomy 11 (a second additional event).
Flow Cytometry. For fixed tissues, paraffin-embedded tissue blockswere deparaffinized, rehydrated, and pepsin digested by using modifications of the Hedley technique (9, 10). Adjacent normal myometriumserved as an internal control. For fresh tissues, nuclei were mechanicallydissociated by using a modification of a method described by Thorn-thwaite et al. (11); normal peripheral lymphocytes were added to one-half of the specimen to provide an internal control (12). Nuclei werestained with propidium iodide and analyzed on a FACS SCAN (BectonDickinson, Mountain View, ÇA). DNA histograms were generatedfrom analysis of 5000 nuclei and were displayed as linear fluorescence.The DI3 was calculated as the ratio of the aneuploid G0/Gi peak channel
to that of the normal internal control G0/G, peak channel (13). A DI
of 1.00 was assigned, in either fixed or frozen tissues, if no Go/G, peakdistinctly different from control cells was detected. The coefficient ofvariation of the normal GO/G! peak was 9.1% for fixed tissues and3.2% for fresh tissues.
CASES AND RESULTS
Case 1. In October 1988, a 68-year-old woman was noted tohave a lower abdominal mass. At laparotomy, a 14- x 11-x 6-cm partially encapsulated and multicystic tumor was resectedfrom the pelvic side wall. Microscopically, the tumor containedshort, ill-defined fascicles composed of round to slightly pleo-morphic cells with perinuclear halos (Fig. \A). Mitotic activityvaried considerably throughout the tumor, with the most cellular areas containing 6 mitoses/10 high-power fields, and anoverall average of 3 mitoses/10 high-power fields. Immunoper-oxidase studies revealed diffuse staining for desmin, and electron microscopy demonstrated abundant microfilaments, pin-ocytic vesicles, subplasmalemmal linear densities, and stretchesof external lamina. There was no evidence of epithelial differentiation and a diagnosis of low-grade leiomyosarcoma was
made.Cytogenetic analysis of the leiomyosarcoma yielded 28 me-
taphases, of which 16 were diploid (46,XX) and 12 were aneu-ploid. Diploid metaphases derived presumably from nonneo-plastic stromal and vascular elements. Aneuploid metaphasesshowed several consistent chromosome rearrangements andstriking cytogenetic instability (Figs. 2 and 3). Counts in aneu-ploid metaphases ranged from 37 to 156 chromosomes (median
and modal chromosome counts of 78 and 80, respectively), andeach aneuploid metaphase contained unique chromosome abnormalities, in addition to consistent aberrations. The kary-otypic description, including only structural aberrations sharedby all metaphases, was 37-156,XX,cx,der(l)(s::lcen—>Iq42::lq32->lqter),der(l)(5pter->5pll::lcen-»lq42::lq32-»Iqter),der(4)(?::pl2->qter),der(6)(6pter^6q21::?lq31-»1qter),del(6)(q 15q25),del(7)(q 11),t( 10; 17)(q22; 12 or 21) [stability grade IV].
Four years previously, this patient had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy following a clinical diagnosis of "22-week fibroid uterus." The
pelvic side walls were unremarkable and the resected uterus,fallopian tubes, and ovaries had a combined weight of 1470 g.The posterior uterine wall was distended by a 20-x 12-x 9.5-cmpartially cystic transmural mass which was consistent with adegenerating leiomyoma. Inspection of the uterine cavity revealed diffuse thickening of the endometrium and two endo-metrial polyps. Microscopy revealed a clinically unsuspectedwell-differentiated (Grade I, International Federation of Gyne-cology and Obstetrics) endometrial adenocarcinoma with minimal myometrial invasion (less than 1 mm). The entire endometrial tumor was examined histologically and no evidence ofsarcoma was identified. Postoperatively, the patient receivedadjuvant radiation therapy via a vaginal cylinder which delivered 5000 cGy to the mucosa.
When the pelvic leiomyosarcoma was resected, microscopicsections of the antecedent hysterectomy specimen were reex-
Fig. 1. A, Case 1, leiomyosarcoma involving pelvic sidewall. Broad fascicles of proliferating smooth muscle are interspersed between paucicellular foci. H&E; x550. B, Case 1. previously resected uterine smooth muscle neoplasm. Histology is virtually identical to pelvic sidewall recurrence. H&E: X 550.
Fig. 2. Karyolype of pelvic leiomyosarcoma (Case 1). This metaphase contains 80 chromosomes, of which 20 are structurally abnormal. Arrows indicate consistentchromosome rearrangements observed in all tumor metaphases; these consistent rearrangements include der(l)(s::lcen—»Iq42::lq32—»qter),der(l)(5pter—>5pll:lcen—»1q42:: 1q32->lqter),der(4)(?::4p 12->4qter).der(6)(6pter-.6q21::? 1q31—1qter),del(6)(q 15q25),del(7)(q 11),and t(10; 17)(q22;q 12 or 21). Structural rearrangements notdesignated by arrows (e.g.. the 9q+ chromosome) were not present consistently and reflect the genetic instability of this neoplasm.
amined. Rare foci within the large degenerating transmural"leiomyoma" were composed of well-formed fascicles of prolif
erating smooth muscle (Fig. IB). In the most active areas, upto 9 mitoses/10 high-power fields were found, with 1 high-power field containing 3 mitoses. In this small area the averagemitotic rate was 6 mitoses/10 high-power fields. The mitoticallyactive areas were confined to the leiomyoma and no cellularatypia or vascular invasion were identified. The histology of theproliferative foci was identical to that of the subsequent leiomyosarcoma (Fig. \A).
Due to the fixatives used, flow cytometry could not be carriedout on the pelvic side wall leiomyosarcoma. However, flowstudies on the large degenerating uterine smooth muscle tumorwere performed by using the paraffin-embedded block demonstrating mitotically active foci. The DNA histogram had ananeuploid peak with a DI of 1.35, suggesting a near-triploidDNA content (Fig. 4); 12.8% of cells were contained withinthis peak. The finding of the aneuploid peak by flow cytometryis concordant with the cytogenetic approximation of DNAcontent in the subsequent pelvic side wall leiomyosarcoma.
Case 2. In June 1989, a 45-year-old woman was admitted toBrigham and Women's Hospital for evaluation of a lower
abdominal mass that had progressively increased in size overthe prior year. The clinical diagnosis was fibroid uterus. Totalabdominal hysterectomy revealed an 11-cm posterior, fundal,subserosal mass. On microscopy, this lesion was a degenerating
leiomyoma with hyalinization, low mitotic activity (0-2 mitoses/10 high-power fields) and no nuclear atypia. Fourteenmetaphases were analyzed following short-term cultures of theleiomyoma, and each metaphase contained multiple consistentchromosome aberrations. The karyotype was 42,XX,-2,-8,-10,-13,der(l)(?::p33->qter),der(3)(?::pll->q26::?),dic(5)(?::cen->qter),der(6)(?::p 11->qter),inv(6)(p21 q26),der(?)(7pter-»7pll::?),der(19)(pter^ql3::?) [stability grade I]. Additional chromosome aberrations were noted only in one cell,which had trisomy 8, trisomy 20, and monosomy 22, as well asthe stem line changes described above. Flow cytometric analysisof nuclear DNA from fresh tissues demonstrated a hypodiploidDNA content as compared to normal peripheral lymphocytes.The DI was 0.9.
DISCUSSION
We have presented cytogenetic and flow cytometric data fora low-grade metastatic uterine leiomyosarcoma (Case 1) andfor a large, degenerating, uterine leiomyoma (Case 2). Thosedata demonstrate that both benign and malignant uterinesmooth muscle tumors may have complex cytogenetic aberrations; the data also suggest that certain malignancies may havestriking genetic instability despite a low-grade histopathologicalappearance.
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Fig. 3. Karyotype of pelvic leiomyosarcoma (Case 1. same han est as in Fig. 2). This metaphase contains 156 chromosomes, of which 43 are structurally abnormal.Arrows indicate consistent rearrangements; descriptions of these consistent rearrangements are provided in Fig. 2. The bizzare 7p+ chromosomes and numerousunidentified markers were unique to this cell.
leiomyosarcoma are controversial, several factors, includingmitotic rate, histológica! grade, nuclear atypica, and vascularinvasion, can be useful in distinguishing uterine leiomyomasfrom leiomyosarcomas (1-3, 14, 15). Nonetheless, a minorityof uterine smooth muscle tumors appear histologically to be"borderline" lesions which are of uncertain malignant potential.
A recent flow cytometric study demonstrated that nuclei ofuterine leiomyosarcoma characteristically have aneuploid orpolyploid DNA patterns ( 16). In that study aneuploid/polyploidpatterns were also found in several uterine leiomyomas, and18% of the leiomyosarcomas were diploid. Based on those data,it appears that DNA ploidy alone does not reliably predictbiological behavior in uterine smooth muscle tumors. Cytoge-netic findings in the low-grade leiomyosarcoma, reported here,included aneuploidy, multiple consistent chromosome rearrangements, and a striking component of genetic instability.Those findings, in aggregate, are characteristic of aggressivelymalignant neoplasms, whereas benign tumors typically havenormal karyotypes or noncomplex cytogenetic aberrations (17,18). The discovery of pronounced genetic instability in theleiomyosarcoma suggested that this tumor was a fully malignantlesion. That suspicion was confirmed by microscopic reassess
ment of a smooth muscle tumor in a previously resected uterinespecimen. Although that uterine tumor was inadequately sampled (three histológica! sections) originally, the mitotically active foci present on the same slide as the leiomyoma are consistent with a leiomyosarcoma arising within a leiomyoma (15).Had the foci of increased mitotic activity been recognized inthe leiomyoma at the time of original diagnosis, further sampling might have yielded diagnostic leiomyosarcoma based onmitotic counts (2). Flow cytometric analysis of nuclear DNAcontent in this leiomyoma demonstrated a hyperdiploid DNAcontent comparable to that in the subsequent pelvic leiomyosarcoma.
Cytogenetic aberrations have been described previously in 10cases of leiomyosarcoma (19-27). The most consistent aberrations, identified in four of those leiomyosarcomas, are rearrangements involving chromosome bands 1pi2-13 (19, 22,24, 27); those rearrangements result in monosomy for the distalportion of Ip. Of interest, the present case contained twodistinct derivative chromosomes 1 of this nature. Becausedel(lp) has been observed in 50% of cytogenetically studiedleiomyosarcomas, it is possible that a tumor suppressor gene(s),located on chromosome Ip, might be critical to the genesis
Fig. 4. Case 1. DNA histogram generated from paraffin-embedded tissues oforiginal uterine tumor depicted in Fig. 1B. Abscissa indicates fluorescence channelnumber which stoichiometrically corresponds with DNA content. In addition tothe normal diploid peak, an aneuploid peak with near triploid DNA content isfound.
Only 1 of 10 previously described leiomyosarcomas was auterine neoplasm (21), and that tumor had a single cytogeneticaberration, 46,XX,t(10;17)(q22.1;pl3). Rearrangements involving chromosome bands 10q22 or 17pl3 were not seen inany of the nonuterine leiomyosarcomas, but a consistent rearrangement involving 10q22, t(10;17)(q22;q21), was also observed in the metastatic uterine leiomyosarcoma described inthis report. Although it would be premature to conclude that10q22 rearrangements characterize uterine leiomyosarcomas,additional cytogenetic studies of uterine and nonuterine leiomyosarcomas might test this interesting observation.
Several characteristic cytogenetic aberrations have been described recently in uterine leiomyomas. Those events includerearrangements at 12ql4-15 and 14q22-24, as well as deletionsinvolving the long arm of chromosome 7 (29-38). The leiom-yoma reported herein was characterized by monosomy for theentire long arm of chromosome 7; cytogenetic aberrations werenot detected, however, in either copy of chromosomes 12 and14.
Cytogenetic instability has not been assessed previously inleiomyosarcomas, and the prognostic implications of this finding are unclear. In other varieties of malignancy, however,genetic instability is believed to promote successive mutationswhich facilitate the acquisition of malignant phenotypic andclinical features (39-41). In this light, it is interesting that the
low-grade leiomyosarcoma (Case 1) had "high-grade" cytoge
netic instability, whereas the large degenerating leiomyoma(Case 2) did not evidence instability. It is possible that radiationexposure, 5 years earlier, contributed to the marked cytogeneticinstability in the metastatic leiomyosarcoma. It is unlikely,however, that the leiomyosarcoma represented a de novo radiation-induced primary tumor, because radiation-associatedleiomyosarcomas are extremely uncommon (42, 43). A literature review revealed cytogenetic studies of 24 additional uterineleiomyomas in which clonal aberrations were detected and forwhich available data were sufficient for us to to assign a cytogenetic stability grade (29-38). Twenty-three of those leiomyomas were stability grade I (29-38), whereas the remainingtumor appeared to be stability grade II or III (36). Of note, thislast tumor was a cellular leiomyoma with slight nuclear atypiain which some areas showed 3 to 4 mitoses/10 high-powerfields. Accordingly, that tumor might have had borderline malignant potential. In contrast, among nine leiomyosarcomas(19-27, 35-38), two are assigned stability grade I (19, 21), onegrade II (22), and one grade III (27). The remaining five casesare assigned grades II-IV, although exact grade cannot bedetermined from data provided (20, 23, 24-26). These datasuggest that smooth muscle tumors of unknown or borderlinemalignant potential having high-grade cytogenetic instabilitymight manifest aggressive clinical behavior. Accordingly, it ispossible that cytogenetic instability will prove to have diagnosticand prognostic utility among uterine smooth muscle tumors.
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