Nancy R. Schneider

Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide.

PURPOSE To describe the occurrence of secondary acute myeloid leukemia (AML) in children with acute lymphoblastic leukemia (ALL) treated with etoposide (VP-16). PATIENTS AND METHODS Two hundred five consecutive children with early B-lineage ALL were treated according to the Dallas/Fort Worth (DFW) protocol between January 1986 and July 1, 1991. Therapy included a four-drug induction followed by consolidation and continuation phases of nightly oral mercaptopurine (6-MP) and repetitive courses of divided-dose oral methotrexate (dMTX) and asparaginase (L-asp). Three doses of VP-16 and cytarabine (Ara-C) were given during consolidation and later, during continuation, two doses were given 3 to 4 days apart, every 9 weeks. Intrathecal (IT) chemotherapy was given throughout the treatment period. RESULTS Two hundred three of the 205 patients entered remission. Only eight of these 203 children have had a bone marrow relapse (ALL). However, 10 other children have developed secondary AML 23 to 68 months following the diagnosis of ALL. Overall event-free survival (EFS) at 4 years is 79.3% +/- 5.1%, with a risk of secondary AML at 4 years of 5.9% +/- 3.2%. CONCLUSION This experience provides strong evidence for a link between epipodophyllotoxin therapy and secondary AML since none of these children received alkylating agent therapy or irradiation. This serious complication raises concern as to the appropriate use of epipodophyllotoxins in the treatment of childhood ALL.

Precursor B-cell lymphoblastic lymphoma: A study of nine cases lacking blood and bone marrow involvement and review of the literature

We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

Cytogenetics of a renal cell carcinoma in a 17-month-old child: Evidence for Xp11.2 as a recurring breakpoint☆

A renal cell carcinoma from a 17-month-old boy with a history of maternal hydrocarbon exposure was found to have a 46,Y,t(X;17)(p11.2;q25) karyotype. Although this translocation has not previously been reported, other translocations involving Xp11.2 have been described, suggesting that this may represent a non-random breakpoint involved in the pathogenesis of childhood renal cell carcinoma. Both chromosomes 3 in the tumor were normal by both karyotype and RFLP analysis.

Cytogenetic evaluation of a large series of hepatoblastomas: Numerical abnormalities with recurring aberrations involving 1q12-q21

Hepatoblastoma is a malignant embryonal liver tumor that occurs almost exclusively in infants and very young children. Previous cytogenetic studies of hepatoblastoma have investigated small series or individual cases. This report is on the cytogenetics of a large series of 111 hepatoblastoma specimens, with cytogenetic results consecutively karyotyped over a 12‐year period. Abnormal karyotypes were observed in 55 cases (∼50% of the total). Numerical aberrations were observed in 41 cases (36% of the total), particularly trisomies of chromosomes 2, 8, and 20. Chromosome losses were less common than chromosome gains. Structural abnormalities were observed in 43 cases (39% of the total). Unbalanced translocations resulting in trisomy 1q and involving breakpoints at 1q12–21 were the most common structural abnormality, observed in 20 tumors (18% of total cases); the corresponding translocated chromosome was highly varied. The previously reported t(1;4) was observed in seven cases. Most tumors with translocations involving 1q12–21 also displayed numerical chromosome aberrations, the most common of which were chromosomal trisomies, whereas tumors with other structural rearrangements had fewer numerical abnormalities. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat/index.html.

Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near‐triploid and near‐tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51–54; chromosomes 8, 5, 11, and 12 at MN 57–60; chromosomes 2, 3, 9,16, and 22 at MN 63–67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68–79, and Y only at MN ≥≥80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near‐trisomy, and near‐tetrasomy.

The first recurring chromosome translocation in hepatoblastoma: Der(4)t(1;4)(q12;q34)

We report four cases of hepatoblastoma with a derivative chromosome 4 from an unbalanced translocation between the long arms of chromosomes 1 and 4, an aberration reported only rarely in isolated cases of other types of neoplasms. The abnormality in three hepatoblastomas was der(4)t(1;4)(q12;q34), whereas the fourth case appeared to have a der(4)t (q25;q32). All had hyperdiploid tumor karyotypes; however, in the case with t(q25;q32), the der(4) was the only abnormality in the stemline. We speculate that the oncogenetic event in our cases may be the loss of a gene or genes on distal 4q or their alteration by juxtaposition to 1q12 heterochromatin. Genes Chromosom. Cancer 19:291–294, 1997.

Renal cell carcinoma with translocation (X;1) Further evidence for a cytogenetically defined subtype

A renal cell carcinoma from a 15-year-old male had a 49,Y,t(X;1)(p11.2;q21), +der(X)t(X;1) (p11.2;q21), +5, -16, +17, +18 karyotype. This is the third report of a translocation involving a breakpoint at Xp11.2 in a renal cell carcinoma in a child. A total of nine cases of renal cell carcinoma involving Xp11, including this case, have been reported. Of the eight cases for which there are genetics reports, all are male. Patients with renal cell carcinoma with abnormalities at Xp11 appear to be younger than renal cell carcinoma patients overall.

Primary effusion lymphomas exhibit complex and recurrent cytogenetic abnormalities

Summary. Cytogenetic findings in a few primary effusion lymphoma (PEL) cell lines have been reported, but only three complete karyotypes of primary specimens from patients with this neoplasm have been published. In this study, cytogenetic analysis was performed on 11 effusion specimens from 10 patients with PEL. We corroborate data obtained from the cell line studies that trisomy 7, trisomy 12 and aberrations in the proximal long arm of chromosome 1 (1q) are recurring cytogenetic aberrations in PEL and also identify breakpoints at 3q23, 7p22, 7q22, 10q24, 12q24, 13q22, 14q24, 14q32, 15p11.2 and Xq22 as well as +8, +15, +19, +X and –Y as recurring chromosome abnormalities. The identification of recurring cytogenetic aberrations may lead to delineation of the genetic events in PEL.

Report of a complex karyotype in recurrent metastatic fibrolamellar hepatocellular carcinoma and a review of hepatocellular carcinoma cytogenetics.

Metastatic fibrolamellar hepatocellular carcinoma (HCC) was detected in the abdominal lymph nodes of an adolescent male after resection of the primary tumor. No dividing cells were isolated from attempted cytogenetic studies of the primary tumor. However, cytogenetic analysis of lymph node metastases detected 9 and 12 months after partial hepatectomy revealed abnormal hypertriploid karyotypes, with a suggestion of clonal evolution: 62-92 < 3n >,XX, -Y, +3, +6, +6, +7, +7, +8, +10, +13, +15, +16, +20, -21, -22, +mar1 x 2, +mar[cp6]/46,XY[8] and 78 < 3n >,XX, -Y,der(1)t(1;1)(p36.1;q21), +4, +6, +6, +7, +7,i(8)(q10), +10, +15, +20, -21, -22, +mar1 x 2, +mar2[3]/46, XY[17], respectively. Karyotypes of this variant of HCC have not been reported previously. The cytogenetics of HCC are reviewed.

Cytogenetics as an adjunct in establishing a definitive diagnosis of synovial sarcoma by fine-needle aspiration†

Synovial sarcomas account for up to 10% of all soft tissue sarcomas and are characterized by a specific chromosomal abnormality, t(X;18)(p11.2;q11.2), that is observed in both monophasic and biphasic variants.