Evidence for telomeric fusions as a mechanism for recurring structural aberrations of chromosome 11 in giant cell tumor of bone

Giant cell tumor of bone (GCTB) is a benign but often aggressive tumor with a tendency toward local recurrence. Telomeric associations (tas) or telomeric fusions are common cytogenetic findings that have been implicated in the initiation of chromosome instability and tumorigenesis. We performed cytogenetic studies on 5 cases of GCTB to further characterize chromosome aberrations in these tumors. Four of the 5 cases showed abnormal karyotypes with clonal telomeric fusions involving chromosome 11. In 3 cases, the telomeric fusions of 11pter were apparently the precursor lesions to the progression of sub-clones with structural chromosome aberrations of 11p. Two tumors demonstrated a similar pattern of progression resulting in whole arm losses of 11p, including sub-clones with both whole-arm unbalanced translocations and whole-arm deletions. A third tumor with clonal tas of 11pter showed 2 additional subclones, one with ring chromosome 11 and the other with an extra copy of 1q. To our knowledge, the 2 cases with del(11)(p11) represent the first report of a recurring structural chromosome aberration in GCTB. These findings support the concept that telomeric instability is responsible for a large degree of intratumor heterogeneity and serves as a precursor lesion to subsequent clonal structural aberrations of chromosome 11 in GCTB.     

Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group.

Aneurysmal bone cyst and giant cell tumor of bone are relatively rare bone tumors that sometimes coexist. We examined the karyotypes of 3 aneurysmal bone cysts, 12 giant cell tumors, and 3 combined lesions. All aneurysmal bone cysts showed involvement of chromosome segments 17p11-13 and/or 16q22. In addition, in 1 of the 3 giant cell tumors with secondary aneurysmal bone cyst, both chromosome bands were rearranged as well, albeit not in a balanced translocation. Seven out of 12 giant cell tumors were characterized by telomeric associations. One giant cell tumor showed a dup(16)(q13q22), suggesting the presence of a (minor) secondary aneurysmal bone cyst component, despite the absence of histological proof. Our results, combined with literature data further substantiate that segments 16q22 and 17p11-13 are nonrandomly involved in at least some aneurysmal bone cysts, irrespective of subtype (primary, secondary, intra/extraosseous, solid or classic). These findings strongly suggest that some aneurysmal bone cysts are true neoplasms. In addition, telomeric associations are the most frequent chromosomal aberrations in giant cell tumor of bone, the significance of which remains elusive. In combined giant cell tumor/aneurysmal bone cyst each component seems to retain its own karyotypic abnormality.     

Karyotypic evolution and tumor progression in head and neck squamous cell carcinomas

Cytogenetic analysis was performed on primary tumors, and paired recurrent or metastatic lesions, in 14 patients with head and neck squamous cell carcinomas (HNSCC), in order to identify chromosomal aberrations associated with tumor initiation and progression. Abnormal karyotypes were found in 12 of the 14 patients, with distinctive karyotypic similarities shown in all informative pairs. For individual patients, the degree of karyotypic complexity was similar for the primaries and paired recurrent or metastatic lesions. All 22 samples with clonal chromosomal aberrations displayed complex karyotypes with multiple numerical and unbalanced structural rearrangements, resulting in extensive genomic imbalances. The pathway of clonal evolution could be traced in a few patients, supporting the notion that some aberrations or imbalances, particularly partial or entire loss of 3p, i(8q), and homogeneously staining regions commonly mapping to 11q13, were early genetic events in the initiation of HNSCC.     

Ossifying fibromyxoid tumor of soft parts. Cytogenetic findings

Ossifying fibromyxoid tumor (OFMT) of soft parts is a recently described, rare but morphologically distinctive soft tissue tumor. The histogenesis of this lesion remains uncertain, although several immunohistochemical and ultrastructural features suggest that it is an unusual neural tumor, possibly of Schwann cell origin. We report here a case of a malignant variant of OFMT that occurred in the foot of a 52-year-old man. The karyotype of a pulmonary metastasis exhibited the following complex numeric and structural aberrations:72 approximately 74,XXY,-5,+6,+del(8)(p21),del(9)(p22),+10,der(11)t(3;11)(p21;p15),del(12) (q13),der(13)t(5;13)(q13;q34),+18,+19,+20,-22 [cp10]. A kidney metastasis exhibited the following karyotypic abnormalities: 46,XY,add(3)(p11),+der(3)t(3;?;11)(3qter-->3p11::?::11q13-->11qter), -5,del(8)(p21),add(9)(q22),del(9)(p22),der(11)t(3;11)(p21;p15),del(12)(q13),+der(13)t(5;13) (q13;q34),-22. To our knowledge, this is the first reported case of OFMT in which clonal chromosomal aberrations have been shown.     

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.     

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.     

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.     

Giant cell tumor of bone. Chromosomal analysis of 48 specimens and review of the literature.

Giant cell tumor of bone (GCT) is a distinct clinical, radiographic, and pathologic benign entity that constitutes 5% of all primary bone tumors. For a 5-year period, 47 benign GCTs and 1 malignant GCT from 34 different patients were cytogenetically characterized. Analysis showed clonal karyotypic abnormalities in 16 specimens. Clonal structural abnormalities detected in more than one patient included translocations involving 11p15, fus(14p;21p), and fus(15p;21p). None of the clonal numerical abnormalities observed occurred in more than one patient. Thirty-seven of the 44 successfully analyzed specimens (84%) demonstrated telomeric fusion, with most frequent involvement of chromosomal telomeres 11p, 13p, 15p, 18p, 19p, and 21p. We also compared the presence or absence of random and/or clonal karyotypic abnormalities with clinical behavior to determine if a relationship existed. Most notably, chromosomal abnormalities were detected in all 13 successfully analyzed recurrent lesions, five of which were clonally aberrant. This study summarizes the cytogenetic findings and their relevance in 48 specimens analyzed at our institution and reviews the findings of the 18 other published cases.     

Cytogenetic analysis of pancreatic carcinomas: Intratumor heterogeneity and nonrandom pattern of chromosome aberrations

Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression. Genes Chromosomes Cancer 23:81–99, 1998. © 1998 Wiley-Liss, Inc.     

Cytogenetic abnormalities in 106 oral squamous cell carcinomas

We report karyotypic features of 106 short-term cultured oral squamous cell carcinomas (SCC), 51 new and 55 previously reported cases, with clonal chromosome aberrations. The major cytogenetic findings were as follows: simple karyotypic changes were present in 38 cases (36%) and 68 tumors (64%) displayed complex karyotypes. The most common numerical changes were +7, +8, +9, +16, +18, +20, and -4, -10, -13, -14, -18, -19, -21, -22, and -Y. Structural rearrangements frequently (43% of the breaks) affected the centromeric regions, resulting in the formation of isochromosomes and whole-arm translocations. Among the recurrent structural aberrations identified, the most common were i(1q), i(3q), i(5p), i(8q), del(16)(q22), and hsr. With the exception of chromosomal band 11q13, which was involved in 25 tumors, only centromeric or near-centromeric bands were commonly involved: 3p11 approximately q11 (59 cases), 8p11 approximately q11 (57), 1p11 approximately q11 (48), 13p11 approximately q11 (46), 5p11 approximately q11 (41), 14p11 approximately q11 (41), and 15p11 approximately q11 (37). Losses of genetic material dominated over gains. The most frequent imbalances included loss of 2q33 approximately qter, 3p, 4p, 6q, 8p, 10p, 11q, 13p, 14p, and 15p, and chromosomes 18, 21, 22, and Y, and gain of chromosomes 7 and 20, 8q, and 11q13. No major karyotypic differences could be discerned between the present series of oral SCC and a previously reported series of laryngeal SCC, indicating that common genetic pathways are involved in the initiation and progression of SCC irrespective of site of origin.     

Cytogenetic analysis of 101 giant cell tumors of bone: Nonrandom patterns of telomeric associations and other structural aberrations

Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor with metastatic potential. We performed cytogenetic analysis on 101 GCTB from 92 patients. Karyotypes were obtained from 95 tumors, 47 of which had clonal aberrations. The majority of the cytogenetically abnormal GCTB had multiple, up to 28 per tumor, clones. Clonal telomeric associations (tas) and other structural and numerical changes were found in about 70, 60, and 30%, respectively, of clonally abnormal tumors. Forty‐seven aberrations were recurrent, of which 35 are novel. The vast majority of the recurrent aberrations were tas, confirming the important role of telomeric fusions in the development of GCTB. The frequency of tas in GCTB cultures increased with passaging, suggesting a selective advantage of tas‐positive cells in vitro. The termini most frequently involved in tas were 22p, 13p, 15p, 21p, 14p, 19q, 1q, 12p, 11p, and 20q. The frequency of tas (irrespective of their clonality) was significantly higher in tumors carrying clonal changes, indicating that tas are precursors of other types of aberrations. In line with this assumption, the chromosomes preferentially involved in tas in a given tumor were also the ones most often affected by other rearrangements. We did not find the previously reported amplicon in 20q11.1, assessed by fluorescence in situ hybridization in 10 tumors. Nor did we find any association between cytogenetic features and adverse clinical outcome. Thus, local recurrences probably depend more on the adequacy of surgical treatment than on the intrinsic biology of the tumors. © 2009 Wiley‐Liss, Inc.     

Chromosome aberrations in tenosynovial giant cell tumors and nontumorous synovial tissue

Five tenosynovial giant cell tumors—4 pigmented villonodular synovitis (PVNS) and 1 nodular tenosynovitis (NTS)—were investigated cytogenetically. Clonal chromosome aberrations were detected in 3 of them. One PVNS had t(7;16)(q22;q24) as the sole anomaly, whereas 1 PVNS and the NTS displayed aberrations suggesting clonal evolution: t(1;19)(p11;p12)/t(1;19), + 12 and ins(5;1)(q31;p13p34)/ins(5;1),t(2;4)(p23;q21), respectively. Including our 3 cases, a total of 6 tenosynovial giant cell tumors with karyotypic changes have been reported. Apart from 2 PVNS with trisomies 5 and 7, and 2 NTS with rearrangement of chromosome band 1p13, no recurrent chromosome change has been detected. Although the detection of clonal, acquired chromosome abnormalities has formerly generally been accepted as sufficient to conclude that a lesion is neoplastic, the interpretation of the pathogenetic significance of the karyotypic aberrations in synovial tumors is obscured by the fact that we have also detected comparable aberrations in obviously nonneoplastic synovial tissue. One of 2 lesions from patients with hemorrhagic synovitis carried a clonal del(13)(q12q21), and 2 of 4 synovectomy samples from patients with rheumatoid arthritis displayed –Y and –Y together with +7. The available cytogenetic data therefore cannot be used to resolve the controversy as to whether tenosynovial giant cell tumors are truly neoplastic or only reactive, inflammatory proliferations. © 1993 Wiley-Liss, Inc.     

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.     

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.     

Giant Cell Tumor of Bone: A Neoplasm or a Reactive Condition?

Giant cell tumor of bone (GCTB) is a benign but locally aggressive bone tumor of young adults. It typically presents as a large lytic mass at the end of the epiphysis of long bones. Grossly it is comprised of cystic and hemorrhagic areas with little or no periosteal reaction. Microscopically areas of frank hemorrhage, numerous multinucleated giant cells and spindly stromal cells are present. Telomeric fusions, increased telomerase activity and karyotypic aberrations have been advanced as a proof of its neoplastic nature. However such findings are not universal and can be seen in rapidly proliferating normal cells as well as in several osseous lesions of developmental and/or reactive nature, and the true neoplastic nature of GCTB remains controversial. The ancillary studies have generally not reached to the point where these alone can be taken as sole diagnostic and discriminatory criteria. While giant cells and stromal cells have been extensively studied, little attention has been paid to the overwhelming hemorrhagic component. If examined carefully intact and partially degenerated red blood cells are almost invariably seen in many giant cells as well as in the stroma. While hemorrhage in many patients may be resolved without leaving any trace over time, in some it gives rise to giant cell formation, and in others it may lead to proliferation of fibroblasts and histiocytes. At times one sees xanthomatous cells due to intracytoplasmic cholesterol deposits and sharp cholesterol clefts. Individual genetic makeup, local tissue factors as well as the amount of hemorrhage may play a key role in the final effects and outcome. Malignancy usually does not occur in GCTB and when discover, it usually represents primary bone sarcomas missed at original diagnosis. Embolization therapy to curtail hemorrhage and insertion of cement substance to support matrix are helpful in reducing recurrences. Aneurysmal bone cyst (ABC) shares many features with GCTB. There had been unique karyotypic changes in some aneurysmal bone cysts making it distinct from GCTB. However these changes may be in the endothelial cells which are quite different from stromal or giant cells. It had been concluded that the poor matrix support to the vessels may lead to frequent and profuse intraosseous hemorrhage attracting blood-derived monocytes with active conversion into osteoclasts, resulting in GCTB formation. On the other hand, dilatation of the thin-walled blood vessels results in formation of ABCs. If hemorrhagic foci are replaced by proliferation of fibroblasts and histiocytes, then a picture of fibrous histiocytic lesion is emerged. Enhanced telomerase activity and karyotypic aberrations may be necessary for rapid division of the nuclei of the giant cells in order to be able to deal with significant in situ intraosseous hemorrhage.     

Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group.

The karyotypes of 44 specimens from 35 patients with localized (n = 19) or diffuse (n = 16) tenosynovial giant cell tumors were studied. The majority of cases in both categories (11 of 19 localized; 12 of 16 diffuse) displayed clonal chromosomal aberrations, with a complex karyotype in three cases and a simple chromosomal aberration in the others. No difference in the distribution of karyotypic abnormalities was found between the localized and diffuse form except for trisomies (usually of chromosomes 5 and/or 7), which were more frequent in the diffuse type. The short arm of chromosome 1 (1p11-13) was most frequently rearranged, with 7 of 11 localized and 7 of 12 diffuse lesions affected. These findings indicate that the localized and diffuse forms of tenosynovial giant cell tumor might represent two morphologic manifestations of the same entity. The high frequency of clonal chromosomal abnormalities, with a clustering of structural rearrangements to 1p11-13, suggests that this disease is most likely neoplastic in nature and paves the way to search for gene(s) that might be involved in its development.     

Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group

Leiomyosarcomas (LMS) of soft tissues frequently show complex karyotypic changes, and no specific aberration has been identified. The aim of this study was to search for recurrent chromosome aberrations in soft tissue LMSs and to correlate these, if present, with morphological and clinical parameters. From a series of soft tissue sarcomas thoroughly reexamined cytogenetically and histopathologically, 45 LMSs were retrieved; 35 were classified microscopically as spindle cell, 3 as epithelioid, and 7 as pleomorphic. Clonal chromosome changes were present in 14, 3, and 3 cases, respectively. This series was combined with 11 previously published, karyotypically abnormal pleomorphic LMSs for cytogenetic-clinico-histopathological correlations. The breakpoints were widely scattered, with no predilection of any of the recurrent breakpoints and losses to any of the morphologic subtypes. Combining numerical and unbalanced structural changes, the most frequently lost segments were 3p21-p23 (11 cases), 8p21-pter, 13q12-q13, 13q32-qter (10 cases each), 1q42-qter, 2p15-pter, 18p11 (9 cases each), 1p36, 11q23-qter (8 cases each), and 10q23-qter (7 cases). The most frequent gain was 1q12-q31 (6 cases). There was a greater frequency of losses in 1p and 8p and a lower frequency of losses in 10q and 13q in tumors that had metastasized than in localized tumors. We conclude that LMSs with clonal abnormalities display highly complex karyotypic changes and extensive heterogeneity. No significant correlation exists between these changes and age and sex of the patients, or with depth of tumor, topography, microscopic subtype, or tumor grade. Losses in 1p36 and 8p21-pter may be associated with increased risk of metastases. Comparison of our findings in soft tissue LMS with those previously reported in LMS in other locations suggest that the karyotypic profile is more dependent on site of origin than on microscopic features.     

Multiple cytogenetic abnormalities in a case of osteosarcoma

Cytogenetic analysis of a highly malignant osteosarcoma in a 17-year-old girl revealed extremely complex karyotypic changes with several different clonal numerical and structural chromosome aberrations. The composite karyotype was interpreted as 39–41,X,t(X;9)(q11;p24), −1,der(1),−4,−4,−5,i(7q),−8,del(8)(q21),t(10;19)(p13;q13),del(11)(p11p13),t(12;18)(q24;q12), −13,13q+,−14,14p+,−15,15q+,17p+,19q+,−21,+22,+3–6 mar.     

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.     

Chromosomal abnormalities in giant cell tumors of bone.

Cytogenetic analysis of short-term cultures from ten giant cell tumors of bone revealed clonal and nonclonal chromosome abnormalities in three tumors and nonclonal changes only in seven. None of the clonal aberrations, inv(21)(p11q21) in one tumor, +5 in another, and t(15q22q), dic(4;22)(p16;p1?), double minutes, dicentrics, and ring chromosomes present in three separate clones in the third tumor, were identical to previously reported clonal changes in giant cell tumors. Telomeric associations were found in five tumors. The telomeres of chromosome arms 19q and 15p were particularly frequently involved.