Karl Gaal

Sinonasal NK/T-cell lymphomas in the United States.

Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized. Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-&ggr;) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR-&ggr; gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma. Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.

Immune monitoring with iTAg MHC Tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant recipients despite the introduction of posttransplantation viral monitoring and preemptive antiviral therapy. We evaluated the use of HLA class I tetramers in monitoring CMV-specific T-cell recovery to predict patients at risk for CMV-related complications. This prospective multicenter clinical trial obtained nearly 1400 tetramer/allele results in more than 800 biweekly blood samples from 83 patients monitored for 1 year after transplantation. Major HLA types were included (A*0101, A*0201, B*0702, B*0801, B*3501). iTAg MHC Tetramers (Beckman Coulter) were used to enumerate CMV-specific CD8(+) T cells by flow cytometry using a single-platform absolute counting method. Assay variability was 8% or less and results were available within 3 hours. Delayed recovery of CMV-specific T cells (< 7 cells/μL in all blood samples during the first 65 days after transplantation) was found to be a significant risk factor for CMV-related complications; these patients were more likely to develop recurrent or persistent CMV infection (relative risk 2.6, CI 1.2-5.8, P = .01) than patients showing rapid recovery, which was associated with protection from CMV-related complications (P = .004). CMV tetramer-based immune monitoring, in conjunction with virologic monitoring, can be an important new tool to assess risk of CMV-related complications and to guide preemptive therapeutic choices.

Primary effusion lymphoma with subsequent development of a small bowel mass in an HIV-seropositive patient: a case report and literature review.

Primary effusion lymphoma is a distinct clinicopathologic entity usually characterized by presentation as a lymphomatous body cavity effusion in the absence of a solid tumor mass or dissemination during its clinical course. This lymphoma is typically present in human immunodeficiency virus (HIV)-infected patients and frequently associated with Kaposis sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8) viral sequences. Here we report a rare case of KSHV/HHV8-associated primary effusion lymphoma with secondary involvement of the small bowel as an obstructive tumor mass in an HIV-infected man. The solid small bowel lymphoma demonstrated essentially identical morphology, immunophenotype, KSHV/HHV8 viral status, and immunoglobulin light chain rearrangements to the pleural cavity-based primary effusion lymphoma in the same patient.

Impact of Graft Cell Dose on Transplant Outcomes following Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation: Higher CD34+ Cell Doses Are Associated with Decreased Relapse Rates

Peripheral blood stem cells (PBSC) have been increasingly used in the matched unrelated donor (MUD) transplant setting, but the impact of CD34(+) cell dose on outcomes in this setting have not been well characterized. We analyzed 181 consecutive patients who underwent MUD-PBSC transplantation at the City of Hope between August 2000 to December 2004. Patients were conditioned with either full-intensity regimen or reduced-intensity regimen. There was a significant inverse relationship between higher CD34(+) cell dose and faster neutrophil engraftment (r = -0.16, P = .035). By univariate analysis, a CD34(+) cell dose > or =4.2 x 10(6)/kg (above the lowest quartile) was associated with significantly lower relapse risk (hazard ratio [HR] = 0.67, P = .0126), with a trend for corresponding improvement for disease-free survival (HR = 0.84, P = .12) but not overall survival (HR = 0.91, P = .46). The impact of the CD34(+) cell dose remained significant in multivariate analysis. The higher CD34(+) cell dose was significantly associated with faster recovery of absolute lymphocyte counts on day +30 posttransplant. Subset analysis demonstrated that the higher CD34(+) cell dose was associated with (1) greater reduction in relapse in myeloid malignancies than that in lymphoid malignancies, (2) greater reduction in reduced-intensity conditioning than in full-intensity conditioning, (3) greater reduction in relapse when there is a inhibitory killer-cell immunoglobulin-like receptor ligand (iKIRL)-mismatch in the gravft-versus-host (GVH) direction, and (4) greater reduction in relapse when there is a lack of iKIRL, suggesting that the protective effect of CD34(+) cell dose against relapse may be immune-mediated, possibly through NK cell recovery.

A rapid, one step assay for simultaneous detection of FLT3/ITD and NPM1 mutations in AML with normal cytogenetics

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KSHV/HHV8-associated lymphoma simulating anaplastic large cell lymphoma.

We report a unique, previously undescribed case of KSHV/HHV8-associated lymphoma in a 49-year-old HIV-seropositive patient. The cervical lymph node-based lymphoma displayed distinctive characteristic features of preferential sinusoidal infiltrate and anaplastic cellular morphology, closely resembling classic anaplastic large cell lymphoma of the WHO classification both histologically and immunophenotypically. Paraffin immunohistochemical study showed that the lymphoma cells were strongly positive for KSHV/HHV8 latency-associated nuclear antigen, and PCR analysis confirmed the presence of KSHV/HHV8 infection. Epstein-Barr virus in situ hybridization was negative. Molecular study clearly demonstrated B-cell lineage with immunoglobulin heavy and kappa light chain gene rearrangements. This case may add to the spectrum of the heterogeneous category of KSHV/HHV8-associated B-cell lymphomas.

Therapy-related acute lymphoblastic leukemia without 11q23 abnormality: report of six cases and a literature review.

Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare secondary leukemia following chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormality, frequently detected in therapy-related acute myeloid leukemia, is the most common cytogenetic alteration in t-ALL. However, t-ALL cases without 11q23 abnormality have been rarely described. We describe 6 adults with secondary t-ALL without 11q23 abnormalities following various treatment regimens for primary malignancies. We also reviewed 48 t-ALL cases, with complete chromosomal karyotyping, reported in the literature from 1992 to 2007. In the 48 cases, an 11q23 abnormality involving the MLL gene locus was the predominant chromosomal aberration (32 [67%]), followed by t(9;22) (6 [13%]) and a normal karyotype (4 [8%]). Compared with t-ALL cases with an 11q23 abnormality, cases without an 11q23 abnormality had a relatively longer latency period (median, 36 vs 19 months) and a different primary malignancy spectrum. No major difference was observed between groups in regard to age, sex, or receipt of a topoisomerase II inhibitor. The t(8;14)(q11.2;q32), a rare, nonrandom, balanced chromosomal translocation differing from the more common translocation involving c-MYC on chromosome 8q24, was seen in 1 adult t-ALL case, which may suggest another possible pathogenesis of this disease.

High Dose Therapy and Autologous Hematopoietic Cell Transplantation in Peripheral T-Cell Lymphoma (PTCL): Analysis of Prognostic Factors

Patients with peripheral T cell lymphoma (PTCL) have a poor prognosis with current treatment approaches. We examined the outcomes of high-dose therapy (HDT) and autologous hematopoietic cell transplant (AHCT) on the treatment of PTCL and the impact of patient/disease features on long-term outcome. Sixty-seven patients with PTCL-not otherwise specified (n = 30), anaplastic large cell lymphoma (n = 30), and angioimmunoblastic T cell lymphoma (n = 7) underwent HDT/AHCT at the City of Hope. The median age was 48 years (range: 5-78). Twelve were transplanted in first complete remission (1CR)/partial remission (PR) and 55 with relapsed or induction failure disease (RL/IF). With a median follow-up for surviving patients of 65.8 months (range: 24.5-216.0) the 5-year overall survival (OS) and progression-free survival (PFS) were 54% and 40%, respectively. The 5-year PFS was 75% for 1CR/PR compared to 32% for RL/IF patients (P = .01). When the Prognostic Index for PTCL unspecified (PIT) was applied at the time of transplant, patients in the PIT 3-4 group had 5-year PFS of only 8%. These results show that HDT/AHCT can improve long-term disease control in relapsed/refractory PTCL and that HDT/AHCT should ideally be applied either during 1CR/PR, or as part of upfront treatment. More effective and novel therapies are needed for patients with high-risk disease (PIT 3-4 factors) and allogeneic HCT should be explored in these patients.

Aberrant Expression of CD7 in Myeloblasts Is Highly Associated With De Novo Acute Myeloid Leukemias With FLT3/ITD Mutation

Acute myeloid leukemia (AML) with normal cytogenetics represents approximately 40% to 50% of de novo AML. This heterogeneous AML subgroup constitutes the single largest cytogenetic group with an intermediate prognosis. Previous studies have suggested that the Fms-like tyrosine kinase-3 internal tandem duplication (FLT3/ITD) mutation-positive de novo AML may represent a distinctive subgroup of AML. We analyzed the clinical and pathologic features of 15 cases of de novo AML with normal cytogenetics and with the FLT3/ITD mutation. In comparison with patients with AML without the FLT3/ITD mutation, patients with FLT3/ITD+ AML are relatively younger, more often have marked peripheral leukocytosis with a higher number of circulating blasts at initial examination, more often have minimal differentiation morphologic features, more frequently have abnormal CD7 coexpression, and have poorer outcome. Close association of aberrant CD7 expression and FLT3/ITD mutation in the myeloblasts of FLT3/ITD+ AML suggests that FLT3/ITD- mediated leukemic transformation occurs in the more early stage of myeloid progenitor cells.

Assessing karyotype precision by microarray-based comparative genomic hybridization in the myelodysplastic/myeloproliferative syndromes

BackgroundRecent genome-wide microarray-based research investigations have revealed a high frequency of submicroscopic copy number alterations (CNAs) in the myelodysplastic syndromes (MDS), suggesting microarray-based comparative genomic hybridization (aCGH) has the potential to detect new clinically relevant genomic markers in a diagnostic laboratory.ResultsWe performed an exploratory study on 30 cases of MDS, myeloproliferative neoplasia (MPN) or evolving acute myeloid leukemia (AML) (% bone marrow blasts ≤ 30%, range 0-30%, median, 8%) by aCGH, using a genome-wide bacterial artificial chromosome (BAC) microarray. The sample data were compared to corresponding cytogenetics, fluorescence in situ hybridization (FISH), and clinical-pathological findings. Previously unidentified imbalances, in particular those considered submicroscopic aberrations (< 10 Mb), were confirmed by FISH analysis. CNAs identified by aCGH were concordant with the cytogenetic/FISH results in 25/30 (83%) of the samples tested. aCGH revealed new CNAs in 14/30 (47%) patients, including 28 submicroscopic or hidden aberrations verified by FISH studies. Cryptic 344-kb RUNX1 deletions were found in three patients at time of AML transformation. Other hidden CNAs involved 3q26.2/EVI1, 5q22/APC, 5q32/TCERG1,12p13.1/EMP1, 12q21.3/KITLG, and 17q11.2/NF1. Gains of CCND2/12p13.32 were detected in two patients. aCGH failed to detect a balanced translocation (n = 1) and low-level clonality (n = 4) in five karyotypically aberrant samples, revealing clinically important assay limitations.ConclusionsThe detection of previously known and unknown genomic alterations suggests that aCGH has considerable promise for identification of both recurring microscopic and submicroscopic genomic imbalances that contribute to myeloid disease pathogenesis and progression. These findings suggest that development of higher-resolution microarray platforms could improve karyotyping in clinical practice.