Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706.

B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.

Clonal rearrangement of 15p11.2, 16p11.2, and 16p13.3 in a case of nodular fasciitis: additional evidence favoring nodular fasciitis as a benign neoplasm and not a reactive tumefaction.

This article describes a case of nodular fasciitis with the karyotype 47,XY,+4/46,XY,add(15)(p11.2), t(16;16)(p13.3;p11.2). The presence of clonal chromosomal abnormalities in this case, as well as in three previously reported cases, indicates that nodular fasciitis is a benign neoplasm and not a reactive lesion.

Isochromosome (17)(q10) as the sole structural chromosomal rearrangement in a case of botryoid rhabdomyosarcoma.

We describe a case of botryoid rhabdomyosarcoma with the karyotype 53,XX,+2,+5,+8,+12,+13, i(17)(q10),+19,+20. Only two cytogenetically analyzed cases of this tumor were previously reported and structural chromosomal abnormalities in each tumor were different.

Translocation (2;15)(p23;q21.2) and interstitial deletion of 7q in a case of low-grade myxofibrosarcoma.

We describe a case of low-grade myxofibrosarcoma with the karyotype 46,XX,t(2;15)(p23;q21.2), del(7)(q?11.2q?22). Only six of these tumors have been previously studied and all were cytogenetically different.

Trisomy 15 is frequently observed as a minor clone in patients with Anemia/MDS/NHL and as a major clone in patients with AML.

Trisomy 15 as the sole karyotypic aberration is an uncommon clonal cytogenetic aberration in hematological malignancies, making its significance unclear. Previous studies have reported relations of trisomy 15 with low-grade myelodysplasia or a benign age-related phenomenon associated with loss of the Y chromosome. To define the significance of trisomy 15, we conducted a retrospective study of all examples of trisomy 15 accessed in our laboratories. Trisomy 15 was observed as a clonal abnormality (> or =2 cells) in 17 cases and nonclonal (single cell) in 9 cases. The majority of cases (14/17 clonal cases) had a minor clone (5-35% of metaphase cells) of trisomy 15. The minority of cases (3/17) had a major clone (80-95% of metaphase cells) of trisomy 15. Two of these 3 cases were diagnosed as having acute myelocytic leukemia. Fluorescence in-situ hybridization (FISH) with the use of a chromosome 15-specific alpha-satellite probe was performed on 3 of 17 clonal cases and on 3 of 9 nonclonal cases. FISH results revealed the presence of a minor clone (from 3 to 5 of 700 interphase cells) in 5 of them, 2 of which had trisomy 15 in 20% of metaphase cells. These results may indicate that the 20% of trisomy 15 are very likely an overrepresentation of a very minor clone that could be transitory. In summary, the analysis of our cytogenetic and FISH results revealed the presence of two types of trisomy 15 clones: a minor clone that could be transitory or indolent and a major clone that could be of a neoplastic nature.

Sclerosing epithelioid fibrosarcoma: a cytogenetic, immunohistochemical, and ultrastructural study of an unusual histological variant.

A case of sclerosing epithelioid fibrosarcoma was studied. The tumor cells expressed vimentin, focally epithelial membrane antigen and CD34, contained cisternae of rough endoplasmic reticulum, large Golgi apparatus, many pinocytotic vesicles, and were devoid of basal lamina. Their composite karyotype was 45,Y,t(X;6)(q13;q15), t(6;13)(p11.2;q13),-22¿2/46,Y,t(X;6)(q13;q15),add(13)(p12), add(22)(q13)¿3/44 approximately 46,der(X)t(X;6)(q13;q21),-Y, t(13;14)(q10;q10),-22,add(22)(q13)¿7/46,XY¿8.

Translocation (8;13)(q24.2;q33) in a malignant rhabdoid tumor of the liver.

A case of malignant rhabdoid tumor of the liver associated with hypercalcemia of malignancy was studied. The karyotype of the liver primary was 46,XY,t(8;13)(q24.2;q33)[7]/46,XY[13], and of the brain metastasis 46,XY,t(8;13)(q24;q33)[5]/46,XY,t(7;13)(p14;q22) [3]/46,XY,t(1;2;3)(q25;q21;p21) [2]/46,XY[13], respectively. Band 8q24 was previously reported to be rearranged in two malignant rhabdoid tumors, one renal and one hepatic.

Solitary fibrous tumor of the pleura: a cytogenetic study.

A solitary fibrous tumor of the pleura was studied. Its karyotype was 46,XY,t(6;17) (p11.2;q23),ins(9;12)(q22;q15q24.1),inv(16)(p13.1q24). The rearrangement of 12q13-15 was also described in a subset of hemangiopericytomas of soft tissue and meninges. Because both types of tumors are morphologically and immunophenotypically quite similar, and because some of them share rearrangement of 12q13-15, the possibility of their histogenetical relatedness should be considered.

Trisomy 6 as a primary karyotypic aberration in hematologic disorders.

We identified seven patients with hematologic disorders and trisomy 6 as the sole karyotypic aberration in bone marrow aspirates or unstimulated peripheral blood. Five patients were male and two were female; all were adults with ages ranging from 22 to 74 years. Three of the seven patients presented with manifestations of peripheral cytopenia. Their bone marrows were hypocellular with slight or no dysplastic changes and without an increase in blasts. One of these patients subsequently developed acute myeloid leukemia (AML-M1). The four remaining patients were initially diagnosed with AML--three consistent with French-American-British classification of M1 and M4 in the fourth patient. These results suggest that trisomy 6 is a nonrandom primary numerical anomaly of myeloid disorders. The association of cytopenia and hypoplastic bone marrow with trisomy 6 may constitute a new, distinctive variant among myelodysplastic syndromes.

Clear cell sarcoma of the ileum: the crucial role of cytogenetics for the diagnosis.

We report a case of clear cell sarcoma that arose in the ileum and metastasized to the liver. The tumor cells did not contain melanin or glycogen; expressed S-100 protein, but not HMB45; and contained possible atypical melanosomes when examined by electron microscopy. They carried a clonal chromosomal rearrangement: 50,XY,t(2;7)(q37;q22),+8,+8,+9,+11, t(12;22)(q13;q12). The diagnosis was greatly facilitated by the cytogenetic analysis. The translocation t(12;22)(q13;q12-13) has been reported as specific for clear cell sarcomas.

Pigmented choroid plexus carcinoma: a cytogenetic and ultrastructural study.

A pigmented choroid plexus carcinoma was studied. The pigment was Fontana-positive, and the neoplastic cells focally expressed melanosomal marker HMB45 and contained probable aberrant melanosomes. The tumor was composed of two pseudodiploid clones, having the karyotypes 46,XY,inv(4)(q12q35),t(6;15)(q21;q22),inv(7)(p11.2q22),t(19; 22) (q13.4;q11.2)[15]/46,XY,t(4;14)(q31.1; p11.2),t(12;13)(p11.1;q34)[6]. The available data seem to indicate that rearrangements of 7p11-12, 9q11-12, 15q22, and 19q13.4 may play a role in the development of choroid plexus carcinomas.

Evaluating sex chromosome content of sorted human sperm samples with use of dual-color fluorescence in situ hybridization.

OBJECTIVE: Although most methods for selecting the sex of offspring by sorting spermatozoa are ineffective at shifting the ratio of Y- to X-containing cells, some commercial sources continue to offer such services. Our objective was to evaluate commercially "sorted" samples with use of dual-color fluorescence in situ hybridization and to identify variations in assessment by comparing motile and total sperm populations, donors, observers, and fluorescence in situ hybridization probes. STUDY DESIGN: Cryopreserved sperm from seven anonymous donors were processed as for insemination. Sperm cells from each total sample or motile subfraction were prepared for fluorescence in situ hybridization by incubation with disulfide-reducing agents to expand sperm nuclei. Two sets of X and Y chromosome-specific, fluorophore-labeled deoxyribonucleic acid probes were used. At least 400 nuclei from each preparation were classified independently by three blinded observers. Hybridization efficiency, aneuploidy, and sex chromosome content were evaluated in subsets of five unsorted, five female-oriented, and five male-oriented samples. Total and motile subfractions were compared with eight samples. Fluorescence in situ hybridization probes were compared in five paired unsorted samples. RESULTS: No differences were detected between washed samples and paired motile subfractions. No differences in hybridization and aneuploidy were detected between groups of sorted samples. The Y/X ratio was significantly different between the sorted groups. However, male-oriented samples had a lower Y/X ratio than female-oriented samples did. Observer and probe choice accounted for small but significant variations that did not alter conclusions about the X/Y ratio for sorted samples. CONCLUSION: In a series of 10 sorted samples from one commercial source, dual-color fluorescence in situ hybridization demonstrated a small but significant shift in the sex chromosome ratios among samples. However, this shift was opposite to that expected by the orientation of the sorted samples.

Chromosome 11 abnormalities in Bowen disease of the vulva.

Chromosomal cytogenetic abnormalities are common in tumor cells and are often the basis for more detailed chromosomal mapping of tumor suppressor and oncogenes. Chromosome 11 abnormalities are frequently recognized in various neoplasms. We report a case of Bowen disease (squamous cell carcinoma in situ) of the vulva with an isolated 11p cytogenetic abnormality. A chromosome 11 paint confirmed two copies of chromosome 11 in all analyzed metaphases. An 11p subtelomeric probe confirmed an abnormality of 11p15-->pter indicative of a deletion. Previous studies of invasive vulvar cancers also frequently show 11p cytogenetic abnormalities, but never as an isolated finding. The patient suffered from other diseases that may also be related to this locus. Breakage and p53 studies were normal. It is possible that an 11p abnormality in Bowen's disease is a precursor in the evolution of invasive vulva cancer.

Mesenchymal chondrosarcoma. A cytogenetic, immunohistochemical and ultrastructural study.

A case of mesenchymal chondrosarcoma was studied. The tumor was near-tetraploid and the clonal structural chromosomal abnormalities included add(7)(p13), add(22)(q13), markers, and double minutes. The ultrastructural and immunohistochemical findings were consistent with the diagnosis. Strong immunoreactivity for desmin was an unusual, not previously reported, feature of the neoplasm.

Cytogenetic abnormalities in renal oncocytic neoplasms.

We have performed cytogenetic studies on five renal oncocytic neoplasms (three grade 2 tumors and two grade 1 tumors) identified histologically by light microscopy. One grade 1 tumor failed to produce mitotic cells. The other four tumors exhibited both normal and abnormal cell lines. Numerical abnormalities were found in both the single grade 1 and two of the grade 2 tumors whereas structural abnormalities were limited to grade 2 tumors. Aneuploidy of chromosome 12 was observed in both grade 1 and 2 tumors. Grade 2 tumors showed more extensive numerical change than the grade 1 tumors. Abnormalities of chromosome 3 characteristic of renal cell carcinoma were not found in any tumor in this series. A combination of C-banding and HaeIII endonuclease banding was used to identify an ambiguous marker. In our four cases and in the cases previously reported, loss of a sex chromosome, abnormalities of chromosomes 1 and 22, and trisomy 12 are findings most often observed in renal oncocytoma.

Angiocentric immunoproliferative lesion (lymphomatoid granulomatosis). A cytogenetic, immunophenotypic, and genotypic study.

We report the occurrence of a cytogenetically abnormal clone 46,XX,t(1;6)(p35;q23),t(1;9;19)(q23;p24;q13) in the spleen of a 23-year-old woman with a three-year history of angiocentric immunoproliferative lesion (AIL) (lymphomatoid granulomatosis). The skin, lungs, spleen, liver and, focally, bone marrow were involved by atypical lymphohistiocytic infiltrates. Immunophenotypic study of the spleen showed that 46% of the cells displayed a helper/inducer T-cell phenotype. However, analysis of DNA isolated from the spleen failed to show clonal T-cell receptor beta-chain gene, T-cell receptor gamma-chain gene, or immunoglobulin heavy chain gene and light chain gene rearrangements. The finding of a cytogenetically abnormal clone supports the concept that angiocentric immunoproliferative lesion is a neoplastic process.