Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas. ALKALCL cases with concurrent MYC translocation are exceedingly rare and are more aggressive and chemoresistent compared with other ALKALCL. We report a patient who presented with ALKALCL possessing coexistent MYC rearrangement, massive tumor dissemination, and early widespread relapse. This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant.

High prevalence of array comparative genomic hybridization abnormalities in adults with unexplained intellectual disability.

PURPOSE: Array comparative genomic hybridization is now a widely used clinical tool for the evaluation of intellectual disability. The current 10% yield of positive findings is based largely on pediatric data. Adults with unexplained intellectual disability have not been systematically studied with array comparative genomic hybridization. Here, we report our initial experience with array comparative genomic hybridization testing on 45 adults with unexplained intellectual disability referred to an adult genetics clinic. METHODS: Beginning in 2006, we applied clinically available array comparative genomic hybridization testing to adults referred with an intellectual disability phenotype. The initial platform used was an early generation targeted or constitutional array, which was replaced by our current platform using more than 5000 bacterial artificial chromosome clones with an average resolution of 500 Kb and targeting 114 disease loci. All patients also underwent high-resolution karyotype analysis and molecular testing for Fragile X syndrome. RESULTS: Our population comprised 45 patients with unexplained intellectual disability (18 men and 27 women) with an average age of 35.1 years. Most patients had not been evaluated by genetics clinics since childhood or had never undergone a genetic evaluation; only two had documentation of prior normal karyotype studies. Three subjects had abnormal high-resolution chromosome studies, which were also confirmed by array comparative genomic hybridization. Seven of the remaining 42 patients (17%) had novel genomic losses identified only by array comparative genomic hybridization. CONCLUSION: Abnormal genomic losses detected by array comparative genomic hybridization are prevalent in adults with unexplained intellectual disability. Our data showing abnormalities in 22% and 17% of overall patients and of cases with normal karyotypes, respectively, suggest that the yield of array comparative genomic hybridization in adults with unexplained intellectual disability may be higher than in pediatric populations.

BCL6 expression correlates with monomorphic histology in children with posttransplantation lymphoproliferative disease.

Posttransplantation lymphoproliferative disease (PTLD) is a complication of organ transplantation with high mortality. Predicting response to first-line therapy, reduction of immune suppression, is difficult because of the heterogeneity of lesions and disease behavior. We sought to determine if BCL6 protein expression in PTLD cells is associated with poor outcome. In a cohort of 25 children with PTLD, 9 of the patients' tumor specimens were positive for BCL6 protein expression. Eight of 13 monomorphic lesions were BCL6 positive, compared with 1 of 11 evaluable polymorphic lesions (P=0.01). Only 1 of the patients with BCL6 expression responded to reduced immune suppression (P=0.19). Recipients of heart transplants who developed PTLD had reduced overall survival rates compared with recipients of other organ transplants who developed PTLD (P=0.04).

Lineage-specific gene duplication and loss in human and great ape evolution.

Given that gene duplication is a major driving force of evolutionary change and the key mechanism underlying the emergence of new genes and biological processes, this study sought to use a novel genome-wide approach to identify genes that have undergone lineage-specific duplications or contractions among several hominoid lineages. Interspecies cDNA array-based comparative genomic hybridization was used to individually compare copy number variation for 39,711 cDNAs, representing 29,619 human genes, across five hominoid species, including human. We identified 1,005 genes, either as isolated genes or in clusters positionally biased toward rearrangement-prone genomic regions, that produced relative hybridization signals unique to one or more of the hominoid lineages. Measured as a function of the evolutionary age of each lineage, genes showing copy number expansions were most pronounced in human (134) and include a number of genes thought to be involved in the structure and function of the brain. This work represents, to our knowledge, the first genome-wide gene-based survey of gene duplication across hominoid species. The genes identified here likely represent a significant majority of the major gene copy number changes that have occurred over the past 15 million years of human and great ape evolution and are likely to underlie some of the key phenotypic characteristics that distinguish these species.

Characterization of glioblastomas in young adults.

Most adult glioblastoma multiformes (GBMs) present in patients 45-70 years old; tumors occurring at the extremes of the adult age spectrum are uncommon, and seldom studied. We hypothesized that young-adult GBMs would differ from elderly-adult and from pediatric GBMs. Cases were identified from years 1997 to 2005. Demographic and histological features, MIB-1 and TP53 immunohistochemical findings and epidermal growth factor receptor (EGFR) amplification status by fluorescence in situ hybridization were compiled and correlated with survival. Twenty-eight (74%) of our 38 young-adult GBM patients had primary de novo tumors, two of which occurred in patients with cancer syndromes. Two additional GBMs were radiation-induced and eight (21%) were secondary GBMs. Seven patients were identified as long-term (>3 years) survivors. Six of 38 cases manifested unusual morphological features, including three epithelioid GBMs, one rhabdoid GBM, one gliosarcoma and one small cell GBM containing abundant, refractile, eosinophilic inclusions. MIB-1 index emerged as the most important prognosticator of survival (P < 0.005). Although there was a trend between extent of necrosis, TP53 immunohistochemical expression, and EGFR amplification status and survival, none reached statistical significance. GBMs in young adults are a more inhomogeneous tumor group than GBMs occurring in older adult patients and show features that overlap with both pediatric and adult GBMs.

Assessment of t(2;5)(p23;q35) translocation and variants in pediatric ALK+ anaplastic large cell lymphoma.

To evaluate t(2;5) and its variants, we studied 21 pediatric cases of anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) by using immunohistochemical staining, fluorescence in situ hybridization, cytogenetics, and reverse transcriptase-polymerase chain reaction. Results showed 7 (33%) cases with t(2;5), 6 (29%) with variant gene rearrangements, 7 (33%) with uncharacterized rearrangements, and 1 with ALK protein expression but no ALK rearrangement. Among 6 variant gene rearrangements, 1 had TPM4-ALK/t(2;19)(p23;p13) and 2 had inv(2) with the breakpoint proximate to ATIC-ALK and an unknown partner gene separately. The genetic features of the remaining 3 cases were as follows: ins(8;2) with an unknown partner gene; conversion from ALK- at diagnosis to ALK+ at recurrence with unspecified gene rearrangement; complex karyotype without involvement of 2p23, suggesting a cryptic translocation. Concordance between different laboratory results varied from 47% to 81%. These data suggest that ALK variants are not uncommon and underscore the necessity of integrating immunohistochemical, cytogenetic, and molecular genetic approaches to detect, characterize, and confirm t(2;5) and its variant translocations.

Nonpositive terminal deoxynucleotidyl transferase in pediatric precursor B-lymphoblastic leukemia.

Terminal deoxynucleotidyl transferase (TdT) is a unique intranuclear DNA polymerase that catalyzes the template-independent addition of deoxynucleotides to the 3'-hydroxyl terminus of oligonucleotide primers. The expression of TdT is restricted to lymphoid precursors. It is a useful marker in distinguishing acute lymphoblastic leukemia (ALL)from mature lymphoid neoplasms. Although TdT- T-cell ALL has been reported in the literature rarely, the frequency and significance of TdT-nonpositive (TdT(np) B-cell ALL have not been examined extensively. We reviewed the immunophenotypes of 186 new cases of pediatric B-cell ALL and found 5 TdT(np) cases (2.7%). They showed significantly higher frequencies of a WBC count of more than 50,000/microL (> 50.0 x 10(9)/L), CD10-, CD34-, and MLL gene rearrangement compared with those in TdT+ cases (3/5 [60%] vs 27/181 [14.9%], P = .03; 3/5 [60%] vs 11/181 [6.1%], P = .003; 4/5 [80%] vs 24/179 [13.4%], P = .002; 3/5 [60%] vs 9/181 [5.0%], P = .0019; respectively). These results indicate that nonpositive TdT does not rule out a diagnosis of ALL and suggest that TdT(np) B-cell ALL might be associated with CD10- and CD34- disease, a high WBC count, and MLL gene rearrangement.

Primary high-grade B-cell lymphoma of the breast with concurrent IGH-BCL2 and MYC-IGL translocations in an adolescent patient.

BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients. As a result of limited clinician experience and the condition's rarity, it poses a great challenge to pediatric pathologists and oncologists in terms of making an accurate diagnosis and choosing better treatment regimens. In this article, we report a case of an adolescent patient who presented with high-grade breast lymphoma with concurrent BCL2-IGH and MYC-IGL translocations, and we review the clinical, pathological, and genetic features; management strategies; and outcomes associated with this unusual neoplasm.

Teratoid Wilms' tumor, an important variant of nephroblastoma.

PURPOSE: The teratoid histologic variant of Wilms' tumor is rare, with only 15 prior reported cases. We review these and report an additional case in which a cytogenetic abnormality was identified that has not previously been reported in a teratoid Wilms' tumor. MATERIALS AND METHODS: A medline search revealed 15 previously reported cases of the teratoid variant of Wilms' tumor. We summarized the characteristics of these cases with attention to radiologic appearance, stage, laterality, histology, response to chemotherapy and outcomes. RESULTS: Characteristic radiologic features suggesting teratoid Wilms' tumor were calcific densities and stippling, or areas of attenuation indicating adipose tissue. The majority of teratoid Wilms' tumor patients had a high tumor stage at presentation (50% stage III or greater). The incidence of bilateral tumors was 38%. Chemotherapy was administered in nine cases and in only one (11%) was there a cytoreductive response. Four deaths (25%) occurred amongst these patients. CONCLUSIONS: Teratoid Wilms' tumors appear to present with a high stage, increased incidence of bilaterality and have a high mortality rate. Treatment strategies should focus on total surgical extirpation, including metastatic sites when feasible, due to this entity's limited response to chemotherapy.

Posttransplant Hodgkin lymphoma preceded by polymorphic posttransplant lymphoproliferative disorder: report of a pediatric case and review of the literature.

Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of immunosuppression in transplant patients and has broad clinical manifestations and pathologic features ranging from reactive lymphoid proliferation to malignant lymphoma. The category of Hodgkin lymphoma and Hodgkin lymphomalike PTLD is an uncommon variant of PTLD. Development of Hodgkin lymphoma subsequent to other subtypes of PTLD in the same patient is even more unusual, especially in pediatric patients. In this report, we describe a pediatric case of Epstein-Barr virus-associated posttransplant Hodgkin lymphoma developing several years after the patient was diagnosed with polymorphic PTLD and review the literature of the previously reported cases in children to further help characterize the clinical features, histopathologic appearances, biology, and treatment strategies of this uncommon entity.

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 >or=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.

Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains.

Extreme gene duplication is a major source of evolutionary novelty. A genome-wide survey of gene copy number variation among human and great ape lineages revealed that the most striking human lineage-specific amplification was due to an unknown gene, MGC8902, which is predicted to encode multiple copies of a protein domain of unknown function (DUF1220). Sequences encoding these domains are virtually all primate-specific, show signs of positive selection, and are increasingly amplified generally as a function of a species' evolutionary proximity to humans, where the greatest number of copies (212) is found. DUF1220 domains are highly expressed in brain regions associated with higher cognitive function, and in brain show neuron-specific expression preferentially in cell bodies and dendrites.

Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.

PURPOSE: High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC. PATIENTS AND METHODS: EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points. RESULTS: Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors. CONCLUSION: High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.

A child with Angelman syndrome and trisomy 13 findings due to associated paternal UPD 15 and segmental UPD 13.

A child with Angelman syndrome, cutis aplasia, cleft palate, and congenital microform cleft lip, born to a father with a Robertsonian translocation 13;15 is described. Molecular studies using polymorphic markers on chromosomes 15 and 13 showed paternal uniparental disomy (UPD) 15 and segmental UPD 13.

Her-2/neu status in breast cancer metastases to the central nervous system.

CONTEXT: Breast cancer is lethal when it metastasizes; one frequent site for spread is the central nervous system (CNS). Approximately 15% to 30% of breast cancers overexpress the protein HER-2/neu at the primary site, but there are few data on whether metastases from these tumors overexpress HER-2/neu and might be responsive to the potentially toxic anti-HER-2/neu immunotherapy (trastuzumab [Herceptin]) used in patients with disseminated disease. OBJECTIVE: To assess CNS breast cancer metastases for HER-2/neu protein overexpression by immunohistochemistry and gene amplification by fluorescence in situ hybridization (FISH) and to compare the status in primary and metastatic sites in the same patient, whenever possible. DESIGN: Central nervous system breast cancer metastases (n = 53) from 33 patients and corresponding primary breast cancer specimens in a subset of these patients (n = 12) were retrospectively identified in surgical pathology and autopsy databases. Fluorescence in situ hybridization analysis using PathVysion probes for HER-2/neu and chromosome enumeration probe 17 (CEP 17) and immunohistochemistry using the c-Erb-B2 antibody (Dako A0485) were compared. Immunohistochemical sections were evaluated by both visual and image analysis techniques. RESULTS: Of 31 cases assessable by FISH, 26% showed gene amplification. One hundred percent concordance for HER-2/neu status was detected between the primary and CNS metastatic lesions in 10 of 10 patients analyzed by FISH; lesser concordance was noted in 12 cases compared by immunohistochemistry. In 9 patients with multiple CNS metastases, FISH showed concordance among different lesions within the same patient. CONCLUSIONS: When FISH is the detection method, CNS metastases accurately reflect the HER-2/neu status of the primary tumor. Central nervous system metastases from breast cancer received as surgical specimens can therefore be used to assess HER-2/neu status in patients in whom the primary tumor is unavailable for analysis.

Acute Philadelphia chromosome-positive leukemia in an adolescent boy after liver transplantation.

Acute leukemia is an untoward event following immunosuppression for solid organ transplantation and is related to the oncogenic effects of Epstein-Barr viral infections. The authors report a case of acute, Philadelphia chromosome-positive, T-cell lymphoblastic leukemia following liver transplantation. Molecular typing demonstrated a minor bcr-abl rearrangement (190 kD), which persisted in remission in 71% of peripheral neutrophils as determined by fluorescence in situ hybridization. The authors conclude that this patient may have presented in a lymphoid blast crisis of chronic myelogenous leukemia with an acute T-cell leukemia/lymphoma syndrome.

Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group.

PURPOSE: This was a retrospective analysis of outcome based on cytogenetics for a Children's Cancer Group phase 3 trial of acute myelogenous leukemia (AML) (CCG-2891). PATIENTS AND METHODS: A retrospective analysis of outcome for newly diagnosed children with AML and myelodysplastic syndrome (MDS) was performed using data collected from CCG-2891. The authors identified 11 patients whose blasts carried t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q among 470 eligible patients entered with acceptable, centrally reviewed cytogenetics. A bone marrow specimen was used for each case of cytogenetic analysis in which 20 banded (either G-banded or Q-banded) metaphases were completed on each subject. All 11 patients had characteristic monocytoid morphology (M4 or M5) and tended to be young (0.1-7.9 years; median 0.9 years). RESULTS: All 11 patients entered remission, but remissions tended to be short; 9 patients relapsed within 12 months (median 4 months). The relapse rate of 82% was significantly higher for this group of patients compared with 46% for the group at large. The relapse rate for this group of patients having t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was also significantly higher compared with subjects with other 11q23 chromosomal abnormalities. The CNS relapse rate of 55% was higher for this group of patients compared with 3% for all other patients in the study. The CNS relapse rate was higher for the subjects who had t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q compared with subjects with all other chromosome 11 abnormalities. Three children survived, two in second remissions (4.7 and 6.3 years after relapse) and one in first remission (7.0 years after diagnosis). Survival and event-free survival for the patients with t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from all other patients with cytogenetics. Similarly, the survival and event-free survival for the patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from the 11q23 group of subjects. CONCLUSIONS: Further research is needed to determine the various changes that are occurring at the molecular level for patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 to gain insight into the mechanisms causing this clinical phenotype associated with a poor prognosis.

Cytogenetics in pediatric low-grade astrocytomas.

BACKGROUND: Cytogenetic analysis in certain tumors is a vital part of classification and assignment of prognosis. Few studies have examined the value of cytogenetic analysis in pediatric brain tumors. This is especially true of low-grade astrocytomas (LGA) of childhood. This study examines the correlation between cytogenetic abnormalities and survival in children with low-grade astrocytomas. The literature on adults with LGA suggest better survival for those whose tumors have normal cytogenetics compared to those with abnormal. We hypothesized this would also be true of children with low-grade astrocytomas. PROCEDURE: A retrospective study was performed of children presenting between 1980 and 1998 to The Children's Hospital, Denver, who had LGA and on whose tumors informative cytogenetics had obtained. RESULTS: One hundred and forty-nine children were diagnosed with histologically proven LGA. Twenty-nine had successful cytogenetic analysis. One or more chromosomal abnormalities were observed in eight tumors while normal karyotypes were observed in 21 tumors. Actuarial progression-free survival at 5 years was 87.5% for the eight children with abnormal cytogenetics and 43% for those with normal (P=0.56). Overall survival at 5 years was 83% for those with abnormal cytogenetics and 78% for those with normal (P=0.8). The differences in progression-free survival and overall survival between these two groups were not significant. Those children with WHO Grade I tumors had significantly superior progression-free and overall survival than those with Grade II tumors. CONCLUSIONS: It appears unlikely that, for children with LGA, those with normal cytogenetics have a better prognosis than those with abnormal. Histologic grade is a better predictor of outcome than cytogenetics.

Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood.

BACKGROUND: Renal cell carcinoma (RCC) is rare in children and comprises only 1-3% of all pediatric primary renal tumors. Recently, several case reports have described RCC developing in patients previously treated for advanced stage neuroblastoma (NB). METHODS AND RESULTS: Our experience with four patients treated for advanced stage NB during early childhood who developed RCC later in life are added to 14 others in the literature. CONCLUSION: These patients and our review of the literature suggest an association between RCC and NB that warrants further study.