Cytogenetic findings in phyllodes tumors of the breast: Karyotypic complexity differentiates between malignant and benign tumors

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3) (p21p23), were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.     

Cytogenetic characterization of tumors of the vulva and vagina

Neoplasms of the vulva and vagina account for less than 5% of all female genital tract cancers. Squamous cell carcinoma (SCC) represents more than 70% of the cases in both locales, followed by melanoma, basal cell carcinoma, Paget's disease, and other carcinoma subtypes. Until recently, only few cases had been analyzed by chromosome banding techniques and karyotyped, and also the number subjected to molecular cytogenetic analysis remains low. To understand better the genetic changes harbored by the neoplastic cells in cancer of the vulva and vagina, we analyzed cytogenetically 51 such tumors, finding karyotypic abnormalities in 37. All tumors were analyzed by G-banding, sometimes supplemented by multicolor fluorescence in situ hybridization, and a subset of tumors was also analyzed by comparative genomic hybridization. The two cytogenetically abnormal cases of Paget's disease both had two clones, one with gain of chromosome 7 as the sole change, the other with loss of the X chromosome among, in one case, other aberrations. The four cytogenetically abnormal malignant melanomas (three of the vulva, one of the vagina) presented complex karyotypes with aberrations involving different chromosomes but most often chromosome 1, specifically 1p12-q41. In the 31 cytogenetically abnormal SCCs, different clonal karyotypic abnormalities were seen. Intratumor heterogeneity with multiple clones was observed in 11 cases. The clones were cytogenetically unrelated in eight tumors but related in three, indicating that in the latter clonal evolution had taken place from a single malignantly transformed cell. The main chromosomal imbalances were gains of, or from, chromosome arms 3q, 5p, 8q, 9q, and 19q, and loss from 11q. Breakpoint clusters were seen in 11q13-23, 2q22-35, and 19q13, as well as in the centromeres and pericentromeric bands of chromosomes 3, 8, 9, 13, 14, and 22.     

Karyotypic findings in tumors of the vulva and vagina.

Neoplasms of the vulva and vagina together account for less than 5% of all female genital tract cancers, and very few cases have been analyzed using chromosome banding techniques. We report the karyotypic findings in a consecutive series of ten tumors of the vulva and vagina; in addition to five squamous cell carcinomas of the vulva, we present the first cytogenetic analysis of two malignant melanomas and a Paget disease of the vulva, as well as an adenocarcinoma and a squamous cell hyperplasia of the vagina. Whereas no clonal karyotypic changes were found in the squamous cell hyperplasia of the vagina, the remaining nine malignant tumors showed clonal chromosome abnormalities. An inverse correlation was found between the degree of histologic differentiation and karyotypic complexity in the squamous cell carcinomas of the vulva. The malignant melanomas had chromosomal aberrations that have previously been described in malignant melanomas occurring elsewhere, but were less karyotypically complex. Cytogenetically unrelated clones were detected in the Paget disease of the vulva but not in any of the other tumors; this finding is consonant with the interpretation that at least a proportion of Paget disease of the vulva arises multicentrically within the epidermis from pluripotent stem cells.     

Nonrandom karyotypic features in basal cell carcinomas of the skin.

Cytogenetic analysis of short-term cultured 44 basal cell carcinomas (BCC) revealed clonal karyotypic abnormalities in 38 tumors. Relatively complex karyotypes (at least four structural and/or numerical changes per clone) with unbalanced structural as well as numerical aberrations were found in eight (approximately 21%) of the BCC, while the remaining BCC (79%) had simple karyotypes (1 to 3 aberrations per clone). Numerical changes only were found in 16 tumors, 15 BCC displayed both numerical and structural aberrations, and the remaining 7 BCC showed only structural aberrations. Extensive intratumoral heterogeneity, in the form of cytogenetically unrelated clones, was found in 21 tumors, whereas related subclones were present in 10 tumors. In order to obtain an overall karyotypic picture in BCC, the findings of our previously published 25 BCC have been reviewed. Our combined data indicate that BCC are characterized by nonrandom karyotypic patterns. A large subset of BCC is characterized by nonrandom numerical changes, notably, +18, +X, +7, and +9. Structural rearrangements often affect chromosomes 1, 4, 2, 3, 9, 7, 16, and 17. A number of chromosomal bands are frequently involved, including 9q22, 1p32, 1p22, 1q11, 1q21, 2q11, 4q21, 4q31, 1p36, 2q37, 3q13, 7q11, 11p15, 16p13, 16q24, 17q21, and 20q13. When the genomic imbalance is assessed, it has been shown that several chromosome segments are repeatedly involved in losses, namely loss of the distal part of 6q, 13q, 4q, 1q, 8q, and 9p. A correlation analysis between the karyotypic patterns and the clinico-histopathologic parameters has been undertaken in the 44 BCC of the present series. The cytogenetic patterns show a significant correlation with tumor status (P=.025), that is, that cytogenetically more complex tumors are also those clinically the most aggressive. Also, the frequency of cytogenetically unrelated clones is significantly higher in recurrent BCC than that in primary lesions (P=.05). No clear-cut association has been found between the karyotypic patterns and histologic subtypes or tumor sites.     

Diverse chromosome abnormalities in squamous cell carcinomas of the skin

Short-term cultures from three invasive squamous cell carcinomas of the skin were cytogenetically analyzed. Clonal chromosome aberrations were found in all tumors. In the first case, two of three abnormal clones were related, and in the second case, two of five clones demonstrated cytogenetic similarities. Both clones detected in case 3 had a structural rearrangement in common. Several nonclonal changes were seen in all three cases in addition to the clonal aberrations. None of the rearrangements detected, clonal or nonclonal, corresponds to any of the consistently cancer-associated aberrations known from other neoplasms. The remarkably diverse karyotypic picture of the three squamous cell carcinomas, in particular the finding of unrelated clones in two of them, hints that these neoplasms may be poly-rather than monoclonal. The lack of a common cytogenetic denominator argues that if chromosomal changes are of pathogenetic importance in this tumor type, a wide variety of apparently dissimilar changes exist that are roughly equal in their capacity to malignantly transform skin epithelium.     

Karyotypic heterogeneity and clonal evolution in squamous cell carcinomas of the head and neck

Head and neck squamous cell carcinomas (HNSCC) are often characterized by complex karyotypic changes, and a substantial proportion of the reported tumors have shown intratumor heterogeneity in the form of cytogenetically related (40%) or unrelated clones (20%). In order to study intratumor heterogeneity and to distinguish the temporal order of chromosome rearrangements in these tumors, two or more samples from different areas of the same tumor were separately examined in 19 HNSCC, yielding karyotypes from a total of 42 tumor samples. Intrasample heterogeneity was observed in 16 samples. Two samples displayed both related and unrelated multiple clones, four samples showed only multiple unrelated clones, and the remaining 10 samples had only related subclones. Intersample heterogeneity was detected in all but one tumor. Five tumors showed both cytogenetically related and unrelated multiple clones, 11 were found to have only related subclones, and the remaining two tumors showed only unrelated clones. Clonal evolution could be assessed in 13 tumors. A comparison of chromosome imbalances in different subclones from these tumors suggests that partial or entire loss of 3p, 8p, 9p, and 18q and gain of genetic material from 3q and 8q are likely to be early genetic events. In contrast, loss of 1q, 6p, 7q, and chromosome 10, as well as gain of chromosome arms 5p and 7p, are most probably later genetic events. One of the examined tumors contained two highly complex clones that were cytogenetically unrelated, indicating that this tumor had a multicellular origin.     

Interstitial deletion of the short arm of chromosome 3 as a primary chromosome abnormality in carcinomas of the breast

Interstitial deletions of the short arm of chromosome 3 were found in short-term cultures of five breast carcinomas (of 41 breast cancers with clonal aberrations analyzed by us during the same period). They were the only clonal structural change in three tumors; in the remaining two, the clone with 3p– coexisted with seemingly unrelated clones that had other structural and numerical aberrations. The deletions were identical, del(3)(p12p14), in four cases. The fifth tumor seemed to have a smaller deletion, interpreted as del(3)(p13p14). Our findings constitute karyotypic evidence that 3p deletions are relatively common in breast carcinomas and concur with the molecular genetic detection of loss of heterozygosity in this chromosome arm. The fact that the deletions were found as solitary changes indicates that loss of genetic information from 3p loci is an early, possibly primary, event in tumorigenesis. © 1993 Wiley-Liss, Inc.     

Unrelated clonal chromosomal aberrations in carcinomas of the oral cavity

Short-term cultures from 12 oral squamous cell carcinomas were cytogenetically investigated. A normal karyotype was found in 3 tumors, 2 of which had many nonclonal changes. Clonal chromosome abnormalities were detected in the remaining 9 cases, in 6 of them in the form of 2 or 3 abnormal clones. In 5 cases the different clones were cytogenetically unrelated, suggesting a multiclonal origin. Numerous additional nonclonal changes were present in 4 of the 9 tumors with clonal aberrations. None of the structural aberrations, clonal or nonclonal, were found in more than one case; nor did any of the rearrangements correspond to cancer-associated aberrations known from other tumors. The aberration breakpoints of the present series and of previously reported tongue cancer clustered to bands 1p32, 1p22, 1p11, 1q21, 1q23, 1q25, 1q32, 1q42, 1q44, 2q31, 3p11, 4q35, 7p22, 11p15, 11q13, 12q24, and 17q25.     

Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions

Whether macroscopically distinct carcinomas in the same breast are clonally related (multifocal breast carcinoma) or unrelated (multicentric breast carcinoma) is no longer only a scientific-pathological issue but, because different therapeutic strategies may be preferable for cases with intramammary metastatic disease compared with cases of multiple primary breast carcinomas, one that may have profound clinical implications. We studied the evolutionary relationship among macroscopically distinct, ipsilateral breast carcinomas by cytogenetic analysis of 26 tumorous lesions from 12 patients. Sixteen of the 26 foci (62%) were found to contain clonal chromosome abnormalities. Two carcinoma foci were karyotypically abnormal in each of seven patients. Four of these cases had an evolutionarily related, cytogenetically abnormal clone in the two lesions from the same breast, whereas the remaining three cases had completely different clonal karyotypic aberrations in the separate foci. These results, together with our previous findings in five other informative cases, show that multiple, synchronous breast tumors sometimes arise through intramammary spreading of a single primary carcinoma, whereas on other occasions they are the result of the simultaneous emergence of pathogenetically independent carcinomas within the breast. In the total material, an association was seen between the proximity of the foci and the likelihood of them being karyotypically related. Genes Chromosom. Cancer 18:170–174, 1997. © 1997 Wiley-Liss, Inc.     

Nonrandom pattern of cytogenetic abnormalities in squamous cell carcinoma of the larynx

Cytogenetic analysis of short-term cultures from 105 squamous cell carcinomas of the larynx (LSCC) revealed clonal chromosome aberrations in 56 tumors. Simple karyotypic changes (less than four aberrations per clone) were found in 24 cases, and the remaining 32 tumors had complex karyotypes with multiple numerical as well as unbalanced structural rearrangements. Extensive intratumor heterogeneity, in the form of multiple related subclones or unrelated clones, was observed in a large fraction of the tumors. The structural changes most often affected chromosomes 3, 1, 11, 7, 2, 15, 5, 4, 8, and 12, with rearrangements in the centromeric regions, i.e., the centromeric bands p10 and q10 and the juxtacentromeric bands p11 and q11, accounting for 43% of the total breakpoints. The most common imbalances brought about by numerical and unbalanced structural rearrangements were loss of chromosomal region 3p21-pter, chromosome arms 4p, 6q, 8p, 10p, 13p, 14p, 15p, and 17p, and gain of chromosomal regions 3q21-qter, 7q31-pter, and 8q. Among 17 recurrent aberrations identified, the most common were i(8q), hsr(11)(q13), i(3q), i(5p), and del(3)(p11). No statistically significant association was found between major karyotypic features and histological differentiation or TNM stage. The karyotypic features of the LSCC were also compared with previously published oral SCC, a subgroup of SCC that has been more extensively characterized cytogenetically. No clear-cut karyotypic differences were found between LSCC and oral SCC, with the exception that i(8q) was significantly more frequent among the latter.     

Frequent clonal abnormalities of chromosome band 13q14 in B-cell chronic lymphocytic leukemia: multiple clones, subclones, and nonclonal alterations in 82 midwestern patients.

We performed cytogenetic analyses of peripheral blood lymphocytes from 82 Midwestern B-cell chronic lymphocytic leukemia (B-CLL) patients. The cells were cultured with mitogens for 3-4 days. At least 15 metaphase cells were analyzed in 79 (96%) cases. Fifty (63%) of the 79 patients had clonal chromosomal alterations. Structural modifications of the long arm of chromosome 13 at or near band 13q14 were the most frequent abnormalities, identified in 23 (46%) of the patients with clonal abnormalities. In several patients, the abnormality involving band 13q14 was the sole chromosomal alteration. There was a high incidence of complex karyotypes. Nine patients had multiple subclones that appeared to result from clonal evolution; seven patients had cytogenetically unrelated clones; three patients had both subclones and cytogenetically unrelated clones. Nonclonal abnormalities were also prominent. Our study confirms the high incidence of clonal abnormalities involving chromosome arm 13q and documents the clustering of abnormalities at band 13q14 in B-CLL. The evidence for clonal evolution and the presence of multiple unrelated clones in these patients suggest that B-CLL may not be a karyotypically stable disease.     

Cytogenetic comparison of primary tumors and lymph node metastases in breast cancer patients

Chromosome banding analysis of primary tumors and axillary lymph node metastases from 10 breast cancer patients revealed abnormal karyotypes in all samples with cytogenetic similarities between the primary tumor and the metastasis in all informative pairs. Although karyotypically unrelated clones were also found in the lymph node samples, they were less numerous than in the primary tumors, indicating that there was more genetic heterogeneity among the neoplastic cells in the primary than in the secondary tumors. On the other hand, some of the clones had become more complex in the metastases as a result of clonal evolution, and by and large these metastatic breast cancer cases had more karyotypic anomalies than do unselected primary breast carcinomas. Among the aberrations occurring more frequently, and that consequently may predispose to disease spread, were losses of chromosomes 17 and 22 and homogeneously staining regions, a cytogenetic sign of gene amplification. Genes Chromosomes Cancer 22:122–129, 1998. © 1998 Wiley-Liss, Inc.     

Parallel karyotypic evolution and tumor progression in uterine leiomyoma

Cytogenetic evidence of clonal evolution was detected in five uterine leiomyomas. In two tumors, two clones were found, the third tumor had four, the fourth had nine, and the fifth had 12 clones. The first tumor had trisomy 12 as the primary anomaly and a sideline that also contained a del(7)(q21q31). Both clones of the second tumor had three structural changes in common but differed by the presence in the more advanced clone of an inv(7)(q31q34). Two cytogenetically unrelated pairs of clones were seen in the third tumor. One clone had a stemline of 46 and an r(1); a sideline had developed through duplication of this clone. The other pair had a del(7)(q21q31) in common. The last two tumors both had t(12;14)(q14-15;q23-24) as the primary abnormality. They also had a high frequency of telomeric associations that involved certain chromosome arms only. One of the secondary changes in the fourth tumor was a del(7)(q21q31); the principal secondary change in the fifth case was a ring chromosome 1 of variable size in the different clones. The analysis of these five uterine leiomyomas and the collation of the results with previously obtained data lead us to conclude that del(7)(q21q31) is secondary to t(12;14) and + 12 in this tumor type, and that ring formation involving chromosome 1 material, often with duplication of segments, is a common phenomenon during clonal evolution. The fact that the tumors were classified as cellular and had an increased mitotic rate indicates a parallel development between histologically detectable tumor progression and cytogenetically recognizable clonal evolution in uterine leiomyomas.     

Uterine leiomyoma cytogenetics

Uterine leiomyoma--a benign smooth muscle tumor--has recently been found to contain tumor-specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14-15;q23-24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one-third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra-myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors--leiomyosarcoma and rhabdomyosarcoma--are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13-15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exists also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13-15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor-specific rearrangement.     

Rings, dicentrics, and telomeric association in histiocytomas

We report clonal karyotypic abnormalities in six of 12 cytogenetically investigated malignant fibrous histiocytomas. Four of eight tumors of the pleomorphic subtype had complex clonal chromosome aberrations, including ring chromosomes, dicentric chromosomes, and/or telomeric associations. No common characteristic aberration could be distinguished. Two of four myxoid tumors had clonal changes: One had one to two ring chromosomes and an extra chromosome #2; another had a supernumerary ring chromosome as the sole abnormality.     

Whole-arm t(1;16) and i(1q) as sole anomalies identify gain of 1q as a primary chromosomal abnormality in breast cancer.

Cytogenetic analysis of four ductal breast carcinomas revealed net gain of 1q in all tumors. In the first tumor, the only change was that one chromosome 16 was replaced by a derivative chromosome consisting of 16p and 1q. The same unbalanced whole-arm translocation was also found in the second tumor, as the only aberration in one of four abnormal clones. In the last two cases, which also were characterized by cytogenetically unrelated clones, an extra i(1q) was present in one clone in both tumors as the sole aberration. Our findings suggest that gain of 1q is a primary chromosomal abnormality in breast carcinomas, in the sense that it is an early event that precedes the acquisition of more complex changes.     

Nonrandom karyotypic features in squamous cell carcinomas of the skin.

We report the finding of clonal chromosome abnormalities in 13 short-term cultured squamous cell carcinomas (SCCs) of the skin. Intratumor heterogeneity, in the form of cytogenetically related (subclones) or unrelated clones, was detected in six tumors. Whereas clones with complex karyotypic changes were found in 6 tumors, clones with simple anomalies were observed in 10 tumors, and sometimes these clones coexisted with highly abnormal clones. Rearrangement of chromosome 8, in the form of isochromosome i(8q) or whole arm translocation, was the most common aberration, found predominantly in complex clones. Another recurrent feature, i.e., the centromeric rearrangement of chromosome 1, as isochromosome i(1q) or i(1p), or whole arm translocations, was always part of a complex karyotype. Homogeneously staining regions were found in two cases, one with a highly complex karyotype and the other with a simple karyotype. In order to obtain an overall karyotypic picture in SCC of the skin, the cytogenetic findings in 10 SCCs reported earlier were reviewed. The chromosomes most commonly affected were, in decreasing order, chromosomes 1, 11, 8, 9, 5, 3, and 7. Chromosomal sites most frequently rearranged were almost all pericentromeric: they were 8q10-q11, 1p10-q12, 5p10-q11, 11p15, and 9p10-q10. Recurrent anomalies were i(1q), i(8q), i(5p), i(1p), i(9p), and i(9q). Among them, only i(8q) and i(9q) might be assumed to be early genetic events, considering the fact that they could occasionally be identified in simple clones. The most frequent losses included part of or the entire chromosomes 2, 4, 9, 11, 14, 18, and 21, arm 8p, and chromosomes X, Y, and 13. Overrepresentation most frequently involved 1q, chromosome 7, and 8q. The characteristic karyotypic pattern observed in skin SCC was in line with the experience in several other carcinomas. Genes Chromosomes Cancer 26:295-303, 1999.     

Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors

Chromosome studies of lipomas have revealed an extensive cytogenetic heterogeneity. To investigate the frequencies of previously recognized cytogenetic subgroups and to find out if more recurrent rearrangements can be identified, we have analyzed cytogenetically short-term tissue cultures of 237 samples from 188 adipose tissue tumors obtained from 142 patients. Only one of 58 tumors from 18 patients with multiple lipomas (more than two tumors) had karyotypic changes. Among the sporadic lipomas, 20 tumors had supernumerary ring chromosomes of unknown origin, 55 had different aberrations involving chromosome segment 12q13-15, 11 had changes of 6p or chromosome 13, but no rings or 12q13-15 changes, and 14 had various other aberrations. Ring chromosomes were found in all cytogenetically abnormal lipomas histologically classified as atypical and in nine tumors classified as typical lipoma or spindle cell lipoma. Recombinations between 12q 13-15 and a few other bands or segments were seen more than once: 3q27-28 (15 tumors), 2p22-24 and 2q35 (four tumors), 1 p32-34 and 13q 12-14 (three tumors), and 5q33 (two tumors). Recombinations of 12q 13-15 with 2q35 and 13q 12-14 have not been described before. Of eight tumors with chromosome 13 aberrations, five had loss of 13q material. Aberrations of 12q 13-15, 6p, and/or chromosome 13 were found simultaneously in nine tumors. Two to four samples from the same tumor were investigated in 29 tumors with clonal aberrations. Thirteen of these tumors displayed clonal evolution, also noted in another 17 tumors in which only one sample had been investigated. Thus clonal evolution occurred in 30% of the tumors and was particularly frequent in atypical lipomas. Genes Chrom Cancer 9:207-215 (1994). © 1994 Wiley-Liss, Inc.     

Trisomy 7 in nonneoplastic cells

The somatic mutation theory of tumorigenesis states that mutations are necessary for tumor development. On the other hand, acquired, clonal chromosomal alterations are occasionally detected in otherwise normal, nonneoplastic cells—for example, loss of sex chromosomes occurs in bone marrow cells and lymphocytes in elderly individuals—and it is therefore evident that not all mutations are by themselves sufficient for neoplasia to occur. Thus, the finding of an acquired, clonal chromosomal abnormality does not constitute proof that a lesion is neoplastic. Trisomy 7 has, as the sole clonal chromosomal aberration, been reported in a wide variety of epithelial tumor types but also in some mesenchymal and neurogenic neoplasms. It has been suggested to be a primary, i.e., tumor-initiating, abnormality in tumors of the bladder, brain, colon, kidney, lung, ovary, prostate, and thyroid. But data from cytogenetic studies of solid tumors, macroscopically normal tissue in the proximity of solid tumors, and nonneoplastic lesions now question the importance of a solitary +7 as a neoplasia-associated change. Most solid tumors in which trisomy 7 has been found as the sole change in one clone have also displayed other, cytogenetically unrelated, clones with complex karyotypic abnormalities. Such karyotypic differences among coexisting clones could indicate that the neoplasm is polyclonal, that the cytogenetically disparate clones have emerged during tumor progression from one original clone carrying submicroscopic genomic changes only, or that the clone with +7 does not represent the tumor parenchyma. The latter interpretation is supported by the finding of cells with trisomy 7 in macroscopically normal tissue outside tumors of the brain, kidney, and lung. A seemingly decisive argument against the belief that the finding of an acquired, clonal +7 proves that a neoplasm exists is the detection of clones with an extra copy of chromosome 7 in several nonneoplastic lesions and tissues, such as atherosclerotic plaques, chorionic villi, chronic pyelonephritis, Dupuytren's contracture, focal steatosis of the liver, Peyronie's disease, and rheumatoid synovitis. That the abnormality arises in vivo has been shown by in situ hybridization with chromosome 7 specific probes; +7 is no in vitro artifact. It is unknown in which cell type the trisomy occurs; some data from colon adenomas favor epithelial cells, whereas data from kidney tumors and colon carcinomas suggest that the +7 arises in cells of the immune system. This question may possibly be resolved by obtaining a pure cell line with trisomy 7 cells only, to be characterized further by immunologic and morphologic methods. Another line of investigation might be to search for clonal chromosomal abnormalities in nonneoplastic tissues in other species. Finally, it remains to be elucidated whether +7 is a neutral genome mutation or whether it confers a selective advantage upon the cell. © 1993 Wiley-Liss, Inc.     

Cytogenetic evolution in primary tumors,local recurrences,and pulmonary metastases of two soft tissue sarcomas

The karyotypic pattern at different stages of tumor development may provide information on tumor progression but few data are available regarding human solid tumors. Cytogenetic analysis was performed on the primary tumor and four lung metastases of a synovial sarcoma, and the primary tumor, two consecutive local recurrences, and six pulmonary metastases, obtained at two different occasions, of a malignant fibrous histiocytoma (MFH). Simultaneous existence of more than one cytogenetically aberrant clone was also assessed through analysis of more than one sample from the same surgical specimen. Clonal chromosome aberrations were detected in all samples from the synovial sarcoma, and in both local recurrences and five of the metastases from the MFH. All clones in both tumors were cytogenetically related. The primary synovial sarcoma tumor contained two clones, one of which was also found in the lung metastases, together with a third clone that had acquired additional aberrations. Four clones with a near-tetraploid chromosome number and complex aberrations were identified in the MFH. Likely evolutionary pathways could be deduced in both cases. In the patient with synovial sarcoma one of the pulmonary metastases, rather than the primary tumor, might well have been the source of another of the pulmonary metastases. In the MFH the cytogenetic findings indicated the presence of two co-existing lineages in the primary tumor, one giving rise to the local recurrences and one to the pulmonary metastases. Our findings show that cytogenetic analysis can be used to establish the chronologic relationships between different clones in primary tumors, local recurrences and distant metastases, to determine what genetic changes are of importance for the metastatic capability of tumor cells, and to help establish the origin of the metastatic lesions.