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Meningiomas are usually benign tumors; however, they can recur after surgical resection and occasionally show histologic progression to a higher grade II and III malignancy. The second most frequently reported genetic abnormality after 22q loss is deletion of 1p, although alterations in 9q, 10q, and 14q are also implicated in meningioma progression. Fourteen tumors comprising six benign, four atypical, and four malignant meningiomas were examined by means of cytogenetic and fluorescence in situ hybridization analysis. All tumors showed losses in different regions of 1p, with 1p11, 1p13, 1p21, 1p22, 1p32, and 1q21 breakpoints; eight tumors also presented alterations of chromosome 14. Five of the six cases with deletions on 1p and normal chromosome 14 were grade I, and two were recurrent. All but one of the eight cases with simultaneous 1p deletion and alterations of chromosome 14 were grade II (3 cases) and grade III (4 cases); all the grade III cases were recurrent. These results support the possible association between changes in 1p and chromosome 14 with the evolution of aggressive meningiomas through tumor progression.

Deletion of 1p is associated with histological progression to meningiomas. Detection of this alteration may be a predicting factor for recurrences in this tumor. We present 8 meningiomas from four patients: the original tumor and the first recurrence in one patient, and the first and second recurrences in the other three were studied. We compared results of monosomy 22 and deletion of chromosome 1p with cytogenetic methods and fluorescence in situ hybridization (FISH) analysis obtained from slides of direct preparations, of cultured cells and slides of touch preparations. The cytogenetic study showed normal chromosome 22 and deletion on 1p32 in both samples of one patient; only monosomy 22 in both recurrences in another patient, and normal karyotypes with different non-clonal anomalies in the other tumors. However, with FISH analysis, monosomy 22 in both recurrences of three patients was demonstrated, as well as the loss of 1p in all tumors. These results were more evident in the analysis of direct and touch preparations than in those of cultured cells.

Cytogenetic analysis of a malignant sacrococcygeal teratoma in an adult patient revealed near-haploid (77%), near-diploid (19%), and polyploid (4%) cells. The near-haploid cells had a karyotype of 25,XX,der(5)t(5;7)(p15;p13),+7,der(9)t(6;9)(p21;q34),r(17)(p13q25) . In the near-diploid and polyploid cells identical copies of the structural chromosomal changes were found. Although some of the anomalies observed appear unique to this case, a common breakpoint in chromosome 6 was previously reported as specific in a subgroup of extragonadal germ cell tumors of adults.

Cytogenetic analyses of 10 cases of recurrent meningiomas growing in culture between 1–10 days are reported, of which seven showed benign morphology, one atypical, and two, malignant features. Normal karyotypes with nonclonal alterations were found in three cases, one case with only monosomy 22, and complex karyotypes in the remaining six. Four cases were hypodiploid, one pseudodiploid, and one hyperdiploid. The chromosomes most often involved in structural rearrangements were 1, 7, and 14 and the losses were chromosomes 7, 10, 14, 15, 18, and 22. Ring chromosome, dicentrics, double minutes, and association between satellites were found in one case. These complex karyotypes with hypodiploidy, structural rearrangements, and other markers in recurrent meningiomas may indicate aggressive tumor characteristics.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Histologically, it is subdivided histologically into two main subtypes: alveolar (ARMS) and embryonal (ERMS). ARMS is characterized by t(2;13)(q35;q14) or its variant t(1;13)(p36;q14), which fuse PAX3 and PAX7, respectively, with FKHR to produce chimeric genes. ERMS is frequently associated with loss of heterozygosity of 11p15.5. We investigated seven RMS (three ARMS and four ERMS) by means of cytogenetic, fluorescence in situ hybridization, and molecular analyses, including the study of the main genes implicated in the G1- to S-phase cell cycle transition, and correlated these studies with pathologic findings and clinical outcome. All tumors showed clonal, numerical, and structural chromosomal abnormalities. Two ARMS had the t(2;13)(q35;q14) and the third a PAX7/FKHR fusion, a cryptic t(1;13)(p36;q14), undetected by cytogenetic techniques, but revealed by reverse transcriptase polymerase chain reaction. One ERMS showed a der(11)t(3;11)(p21;p15) as a sole structural anomaly. Gene amplification was seen in four tumors, as double minutes or in the form of homogeneously staining regions. Overexpression of MYCN oncogene was found in two ARMS; N-myc DNA probe detected oncogene amplification located on the double minutes of these cases. Analysis of the regulatory genes responsible for G1- to S-phase transition showed a homozygous deletion of the 9p21 locus genes in a spindle-cell ERMS.

Stage 4S neuroblastoma is a disease associated with spontaneous regression and good survival. We present a patient whose evolution has shown the variety and complexity of this disease in infants. Biologic factors, such as ploidy, MYCN copy number, loss of 1p36, and other chromosomal gains and losses were determined. A complex pattern of genetic abnormalities, such as near-diploidy, MYCN gain (2–4 copies per haploid genome) and imbalance/deletion of 1p36 was seen in the diagnostic sample. An extensive disseminated disease after a latent period of 26 months was associated with a special genetic evolution, such as tetraploidy, MYCN amplification (2:100–500 copies), 1p36 deletion, and gain of 17q. Our results provide evidence that either the primary tumor was heterogeneous in terms of gene amplification or that amplification was acquired later on as a transition from MYCN gain. We suggest that near–di-/tetraploid 4S tumors with MYCN gain and/or deletion 1p could be progressing 4S tumors.

We studied a case of adenoid cystic carcinoma. Cytogenetic analysis was performed on short-term culture, and the karyotype revealed only an abnormal cell line with the following changes: partial trisomy 5q, 6q deletion, monosomy of chromosome 9,der(10)t(10;15), a possible ring chromosome 22, and loss of the Y chromosome. The implication of chromosomes 6 and 9 is considered in relation to the karyotypic evolution of this type of tumor.

We studied a case of typical syncytial meningioma. Cytogenetic analysis of the tumor cells showed a karyotype with normal chromosomes 22 and only one anomaly, del(1)(p32). Cases of meningiomas with normal chromosomes 22 and other anomalies are rare, and it is difficult to correlate their histologic characteristics and biologic behavior.

Deletion of 1p is associated with histological progression to meningiomas. Detection of this alteration may be a predicting factor for recurrences in this tumor. We present 8 meningiomas from four patients: the original tumor and the first recurrence in one patient, and the first and second recurrences in the other three were studied. We compared results of monosomy 22 and deletion of chromosome 1p with cytogenetic methods and fluorescence in situ hybridization (FISH) analysis obtained from slides of direct preparations, of cultured cells and slides of touch preparations. The cytogenetic study showed normal chromosome 22 and deletion on 1p32 in both samples of one patient; only monosomy 22 in both recurrences in another patient, and normal karyotypes with different non-clonal anomalies in the other tumors. However, with FISH analysis, monosomy 22 in both recurrences of three patients was demonstrated, as well as the loss of 1p in all tumors. These results were more evident in the analysis of direct and touch preparations than in those of cultured cells.

Atypical teratoid/rhabdoid tumor of the central nervous system is a rare childhood tumor with a distinct histologic appearance and an aggressive clinical course. Few tumors have been analyzed cytogenetically. The only consistent chromosomal abnormality identified in some of these tumors has been monosomy or deletions of chromosome 22; in others, a normal chromosome 22 was present. The authors report an atypical teratoid/rhabdoid neoplasm of the central nervous system with a novel complex rearrangement affecting chromosomes 6 and 11 as the sole anomaly. The involvement of region 11p15 could be important in the pathogenesis of this entity.

The cytogenetic analysis of a spindle-cell rhabdomyosarcoma of the parotid gland in a 6-year-old boy is reported. The tumor cells showed an abnormal karyotype with a hypotriploid modal chromosome number and clonal structural rearrangements affecting chromosomes 1, 8, 12, 21, and 22. The tumor karyotype was: 59, XY, -1, -3, -4, -5, -6, +8, +8, +del(8)(q22q24), -9, -10, del(12)(q13), -15, -16, -17, -18, der(21)t(12;21)(p11;p11), -22, der(22)t(1;22)(q12;p11).

Cytogenetic analyses of four malignant mixed mesodermal tumors (MMMT) of the uterus are reported, of which one was of the homologous type and three of the heterologous type. Karyotypic analyses were obtained in two cases from original tumors and in two cases from tumors xenotransplanted into nude mice. The karyotype of the homologous MMMT was normal in three different passages of a nude mice xenograft line established from the primary tumor. The heterologous tumors showed normal karyotype in one case and hyperdiploid and near triploid range with extensive numerical and structural rearrangements in two cases. Deletion of chromosome 1 at p32, and deletion of chromosome 11 at q13 were common markers in anomalous cases. The chromosomes most often involved in structural rearrangements were chromosomes 1, 9, 11, 12, 17, and 19. Double minutes, homogeneously staining regions, and telomeric association were also seen.

Medulloblastoma is the most common primitive neuroectodermal tumor (PNET) in children, but is very rare in adults. An isochromosome for the long arms of 17, i(17q), is found in about 30% of pediatric cases. Cytogenetic studies in adults are very scarce; only six cases have been described cytogenetically: three cases had normal karyotype, two were studied partially, and another presented only two clonal structural anomalies: del(9)(q12) and del(11)(q22). We studied the chromosomes from medulloblastoma in a 27-year-old woman and found one hypotetraploid stemline with clonal alterations. In the structural anomalies, chromosomes 3, 9, 12, and i(17q) were involved. Chromosome 9 presented a deletion in the long arm, del(9)(ql3), with consequent loss of the 9q13→qter region. This anomaly was similar to one found in a previous case. We suggest that the partial loss of the long arm of chromosome 9 may be a characteristic change of adult medulloblastoma.

Cytogenetic analysis of a human renal oncocytoma revealed a near-haploid chromosome number of 36 with the loss of chromosomes 1, 2, 3, 6, 8, 9, 15, 17, 21, and 22. Review of the literature disclosed that this cytogenetic configuration is extremely rare in solid human tumors and that no renal oncocytomas with near-haploid stemline karyotype have been described. These results are compared with the other published cases of oncocytoma.

Cytogenetic analysis of 8 cases of xenografted human osteosarcomas are reported, including six newly diagnosed and two recurrent tumors. Histologically five were osteoblastic, two were chondroblastic, and one was the microcellular type. All tumors were studied in short-term primary cultures between two and six days. Clonal and nonclonal abnormalities were present in the eight cases; four had a chromosome number in the hypotriploid range, two in the hyperdiploid, one in the hypodiploid, and one in the hypertetraploid range. All cases had complex karyotypes and the recognizable structural rearrangements clustered to chromosome arms 1p, 1q, 3p, 5p, 6q, 11p, 13p, 14p, 15q, 16p, 16q, 20q, 21p, and 22q. Seven cases presented double monosomy 17 and six tumors showed double minutes (dmin) or a homogeneously staining region (hsr). This fact has been described recently and its relation with the amplification of the MDM2 gene observed in osteosarcomas is as yet unknown.

Cytogenetic analyses of 10 cases of recurrent meningiomas growing in culture between 1-10 days are reported, of which seven showed benign morphology, one atypical, and two, malignant features. Normal karyotypes with nonclonal alterations were found in three cases, one case with only monosomy 22, and complex karyotypes in the remaining six. Four cases were hypodiploid, one pseudodiploid, and one hyperdiploid. The chromosomes most often involved in structural rearrangements were 1, 7, and 14 and the losses were chromosomes 7, 10, 14, 15, 18, and 22. Ring chromosome, dicentrics, double minutes, and association between satellites were found in one case. These complex karyotypes with hypodiploidy, structural rearrangements, and other markers in recurrent meningiomas may indicate aggressive tumor characteristics.

Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the gastrointestinal tract. Gain of function mutations of tyrosine kinase receptors, c-KIT, and PDGFRa have been identified in most GIST; c-KIT exon 11 mutations are the most common. The type of c-KIT or PDGFRa mutation indicates tumor responsiveness to imatinib treatment or progression, although GIST with homozygous mutation has been poorly studied. We analyzed 145 GIST at the immunohistopathologic and genetic levels. Formalin-fixed, paraffin-embedded sections were used for our studies. The histological variables included: mitotic count per 50 HPF, necrosis, pleomorphism, and cell type. The immunophenotype was defined using a battery of antibodies. Furthermore, DNA was extracted and intronic PCR primers were used to amplify exons 9, 11, 13, and 17 of c-KIT and 12 and 18 of PDGFRa. Bidirectional sequencing with specific primers was performed on an ABI 310 sequencer using the BigDye Terminator v1.1 kit. A total of 96 mutations was observed, and from them five cases showed homozygous mutations in exon 11 of c-KIT. No homozygous mutations were observed in other exons of c-KIT or PDGFRa. The five homozygous mutations were: two deletions of codons 557e558, the same deletion plus V559D, deletion of codons 559e573, and deletion of codons 554e559; all mutations were located in the part 50 of the exon 11. Four cases were male, the median age being 59 years (range, 38e78 years). The median tumor size was 15 cm (range, 8e16 cm); four were gastric tumors, and one was derived from the small bowel. The mitotic count was 20 mitoses per 50 HPF (range, 7e32 cm); spindle cell type was present in four cases, and one case showed an epithelioid phenotype. All cases were classified as high risk and expressed c-KIT. Moreover all tumors progressed, and two patients died from the disease. Homozygous mutations in c-KIT define a subgroup of GIST of high risk and poor prognosis. However, more studies with more cases are needed to confirm the aggressiveness of the homozygous mutations in GISTs and the clinical implications. Supported by the following grants: AECC and FIVO, Valencia, Spain. COMPARISON OF CYTOGENETIC AND MOLECULAR GENETIC TOOLS TO ASCERTAIN PROGNOSTIC CHROMOSOMAL ABERRATIONS IN UVEAL MELANOMA

A direct cytogenetic analysis was performed on tumor samples obtained from two patients with clinical and histopathologic diagnosis of primary peripheral neuroepithelioma. Both tumors presented the translocation t(11;22)(q24;q12). These results confirm those previously obtained by other authors and suggest a common histogenetic origin for this tumor with Ewing's sarcoma and Askin's tumor, in which the same translocation has been described.