Academic Appointments

Administrative Appointments

  • Associate Chair for Hematopathology, Department of Pathology (2005 - 2013)
  • Associate Chair for Clinical Services, Department of Pathology (2008 - 2011)
  • Vice Chair of Pathology for Clinical Services, Department of Pathology (2011 - 2015)
  • Medical Director, Anatomic Pathology and Clinical Laboratory Services, Stanford Hospital & Clinics (2008 - 2016)
  • Interim Vice Chair for Clinical Pathology, Department of Pathology (2015 - 2016)
  • Senior Associate Chair for Hematopathology, Department of Pathology (2013 - 2016)

Research & Scholarship

Current Research and Scholarly Interests

I study molecular genetic and immunophenotypic changes in human hematopoietic neoplasms. These include acute and chronic leukemias, lymphoma, and splenic tumors.


2016-17 Courses


All Publications

  • Significance of myelodysplastic syndrome-associated somatic variants in the evaluation of patients with pancytopenia and idiopathic cytopenias of undetermined significance. Modern pathology Fernandez-Pol, S., Ma, L., Ohgami, R. S., Arber, D. A. 2016; 29 (9): 996-1003


    In this study, we set out to evaluate the frequency of mutations in 20 myelodysplastic syndrome-associated genes in 53 individuals with pancytopenia in which bone marrow evaluation failed to meet standard criteria for a diagnosis of myelodysplastic syndrome. These idiopathic pancytopenia cases were associated with no specific cause for their pancytopenia (n=28), aplastic anemia (n=13), pancytopenia attributable to liver disease (n=4), pancytopenia associated with autoimmune disease (n=4), and pancytopenia attributed to drug effect (n=4). We also selected 38 bone marrow aspirates from patients presenting with pancytopenia and meeting criteria for a diagnosis of myelodysplastic syndrome (n=21) or acute myeloid leukemia (n=17) as malignant comparison cases. Targeted sequencing of the 20 genes was performed on all cases. The idiopathic pancytopenia group had a lower average age (46 vs 66 years, P<0.0001) and a lower number of mutations per case that were statistically significant (0.81 vs 1.18, P=0.045). The frequency of cases with at least one mutation was higher for cases with a diagnosable myeloid neoplasm (68 vs 38%, P=0.012). Except for mutations in U2AF1, which was mutated in 5 of the 38 malignant cases (13.2%) and in none of the idiopathic pancytopenia cases (P=0.011), the frequency of mutations in the genes evaluated was not significantly different between idiopathic pancytopenia and malignant cases. Median and mean clinical follow-up for the idiopathic pancytopenia group was available for 444 and 739 days, respectively. Over this time frame, none of the idiopathic pancytopenia patients was diagnosed with a myelodysplastic syndrome or an acute myeloid leukemia. These findings provide further evidence that identification of mutations in several genes associated with myelodysplastic syndromes should not be used alone to support a diagnosis of a myelodysplastic syndrome.Modern Pathology advance online publication, 3 June 2016; doi:10.1038/modpathol.2016.100.

    View details for DOI 10.1038/modpathol.2016.100

    View details for PubMedID 27255165

  • Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Modern pathology Wang, S. A., Tam, W., Tsai, A. G., Arber, D. A., Hasserjian, R. P., Geyer, J. T., George, T. I., Czuchlewski, D. R., Foucar, K., Rogers, H. J., Hsi, E. D., Bryan Rea, B., Bagg, A., Dal Cin, P., Zhao, C., Kelley, T. W., Verstovsek, S., Bueso-Ramos, C., Orazi, A. 2016; 29 (8): 854-864


    The distinction between chronic eosinophilic leukemia, not otherwise specified and idiopathic hypereosinophilic syndrome largely relies on clonality assessment. Prior to the advent of next-generation sequencing, clonality was usually determined by cytogenetic analysis. We applied targeted next-generation sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of idiopathic hypereosinophilic syndrome patients (n=51), and assessed the significance of mutations in conjunction with clinicopathological features. The findings were further compared with those of 17 chronic eosinophilic leukemia, not otherwise specified patients defined by their abnormal cytogenetics and/or increased blasts. Mutations were detected in 14/51 idiopathic hypereosinophilic syndrome patients (idiopathic hypereosinophilic syndrome/next-generation sequencing-positive) (28%), involving single gene in 7 and ?2 in 7 patients. The more frequently mutated genes included ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%). Idiopathic hypereosinophilic syndrome/next-generation sequencing-positive patients showed a number of clinical features and bone marrow findings resembling chronic eosinophilic leukemia, not otherwise specified. Chronic eosinophilic leukemia, not otherwise specified patients showed a disease-specific survival of 14.4 months, markedly inferior to idiopathic hypereosinophilic syndrome/next-generation sequencing-negative (P<0.001), but not significantly different from idiopathic hypereosinophilic syndrome/next-generation sequencing-positive (P=0.117). These data suggest that targeted next-generation sequencing helps to establish clonality in a subset of patients with hypereosinophilia that would otherwise be classified as idiopathic hypereosinophilic syndrome. In conjunction with other diagnostic features, mutation data can be used to establish a diagnosis of chronic eosinophilic leukemia, not otherwise specified in patients presenting with hypereosinophilia.Modern Pathology advance online publication, 13 May 2016; doi:10.1038/modpathol.2016.75.

    View details for DOI 10.1038/modpathol.2016.75

    View details for PubMedID 27174585

  • The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia BLOOD Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M. J., Le Beau, M. M., Bloomfield, C. D., Cazzola, M., Vardiman, J. W. 2016; 127 (20): 2391-2405


    The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.

    View details for DOI 10.1182/blood-2016-03-643544

    View details for Web of Science ID 000378333900009

    View details for PubMedID 27069254

  • Reclassifying myelodysplastic syndromes: what's where in the new WHO and why. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program Arber, D. A., Hasserjian, R. P. 2015; 2015 (1): 294-298


    A revision to the 4th edition of the WHO Classification of myelodysplastic syndromes (MDSs), originally published in 2008, is expected in mid-2016. Based on recommendations of a Clinical Advisory Committee, the revision will aim to incorporate new discoveries in MDS that impact existing disease categories. Although the basic diagnostic principles of the WHO classification remain unchanged, several changes to the classification are proposed. All revisions are considered preliminary until the actual publication of the monograph and online document. Proposals for change include abandoning the routine use of "refractory anemia/cytopenia" in the various disease names, including the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying most cases of the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. This review will provide details of the major proposed changes as well as rationale for the revisions.

    View details for DOI 10.1182/asheducation-2015.1.294

    View details for PubMedID 26637736

  • Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations MODERN PATHOLOGY Ohgami, R. S., Ma, L., Merker, J. D., Gotlib, J. R., Schrijver, I., Zehnder, J. L., Arber, D. A. 2015; 28 (5): 706-714


    We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms, RUNX1, ASXL1, TET2, CEBPA, IDH1, IDH2, DNMT3A, FLT3, NPM1, TP53, NRAS, EZH2, CBL, U2AF1, SF3B1, SRSF2, JAK2, CSF3R, and SETBP1, across 93 cases of acute myeloid leukemia (AML) using capture target enrichment and next-generation sequencing. Of these cases, 79% showed at least one nonsynonymous mutation, and cases of AML with recurrent genetic abnormalities showed a lower frequency of mutations versus AML with myelodysplasia-related changes (P<0.001). Mutational analysis further demonstrated that TP53 mutations are associated with complex karyotype AML, whereas ASXL1 and U2AF1 mutations are associated with AML with myelodysplasia-related changes. Furthermore, U2AF1 mutations were specifically associated with trilineage morphologic dysplasia. Univariate analysis demonstrated that U2AF1 and TP53 mutations are associated with absence of clinical remission, poor overall survival (OS), and poor disease-free survival (DFS; P<0.0001), whereas TET2 and ASXL1 mutations are associated with poor OS (P<0.03). In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance in OS and DFS, respectively. Our results demonstrate unique relationships between mutations in AML, clinicopathologic prognosis, subtype categorization, and morphologic dysplasia.Modern Pathology advance online publication, 21 November 2014; doi:10.1038/modpathol.2014.160.

    View details for DOI 10.1038/modpathol.2014.160

    View details for Web of Science ID 000353774200010

  • Mixed Phenotype Acute Leukemia A Study of 61 Cases Using World Health Organization and European Group for the Immunological Classification of Leukaemias Criteria AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weinberg, O. K., Seetharam, M., Ren, L., Alizadeh, A., Arber, D. A. 2014; 142 (6): 803-808


    The 2008 World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias together under a new heading of mixed phenotype acute leukemia (MPAL). The lineage-specific marker criteria have also changed for a diagnosis of MPAL. The goal of this study was to characterize clinical significance of this new group.Sixty-one patients diagnosed with MPAL using either European Group for the Immunological Classification of Leukaemias (EGIL) criteria or 2008 WHO criteria were included in this study.Sixteen patients (26%) diagnosed with acute biphenotypic leukemia using EGIL criteria did not fulfill 2008 WHO criteria for MPAL. Cytogenetic data were available for 32 patients, and the most common abnormality was t(9;22) (five of 32 cases). Clinical outcome data suggested that younger patients with MPAL (?21 years) had better overall survival (OS) in both the EGIL and WHO groups (EGIL, P = .0403; WHO, P = .0601). Compared with 177 patients with acute myeloid leukemia (AML), MPAL patients had better OS (P = .0003) and progression-free survival (P = .0001). However, no difference in OS between MPAL and 387 patients with acute lymphoblastic leukemia was present (P = .599).As defined by the 2008 WHO classification, fewer patients are now classified as having MPAL than with the EGIL criteria. In this study, patients with MPAL have a better clinical outcome compared with patients with AML.

    View details for DOI 10.1309/AJCPPVUPOTUVOIB5

    View details for Web of Science ID 000345053900012

  • De novo acute myeloid leukemia with 20-29% blasts is less aggressive than acute myeloid leukemia with >= 30% blasts in older adults: a Bone Marrow Pathology Group study AMERICAN JOURNAL OF HEMATOLOGY Hasserjian, R. P., Campigotto, F., Klepeis, V., Fu, B., Wang, S. A., Bueso-Ramos, C., Cascio, M. J., Rogers, H. J., Hsi, E. D., Soderquist, C., Bagg, A., Yan, J., Ochs, R., Orazi, A., Moore, F., Mahmoud, A., George, T. I., Foucar, K., Odem, J., Booth, C., Morice, W., DeAngelo, D. J., Steensma, D., Stone, R. M., Neuberg, D., Arber, D. A. 2014; 89 (11): E193-E199


    It is controversial whether acute myeloid leukemia (AML) patients with 20-29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged >50 years, including 142 RAEBT and 429 with ?30% blasts (AML30), as well as 151 patients with 10-19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4-year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P?=?0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P?

    View details for DOI 10.1002/ajh.23808

    View details for Web of Science ID 000344010100001

    View details for PubMedID 25042343

  • STAT3 mutations are frequent in CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia. Leukemia Ohgami, R. S., Ma, L., Merker, J. D., Martinez, B., Zehnder, J. L., Arber, D. A. 2013; 27 (11): 2244-2247

    View details for DOI 10.1038/leu.2013.104

    View details for PubMedID 23563237

  • Clonal Identity and Differences in Primary Cutaneous B-Cell Lymphoma Occurring at Different Sites or Time Points in the Same Patient AMERICAN JOURNAL OF DERMATOPATHOLOGY Fujiwara, M., Morales, A. V., Seo, K., Kim, Y. H., Arber, D. A., Sundram, U. N. 2013; 35 (1): 11-18


    Primary cutaneous B-cell lymphomas (PCBCL) are rare. Marginal zone lymphomas and follicle center lymphomas (FCL) represent a majority of these cases, and a significant number of cases present with multiple lesions. It is unclear whether multiple lesions in PCBCL represent dissemination of a single clone or multiple new primary lymphomas. In the current study, we analyzed paired samples from 20 PCBCL patients at more than 1 site (16) or at the same site at different time points (4) and 12 patients with benign lymphoid infiltrates to investigate for the presence or absence of a clone, and if present, whether the clones were identical. Both IGH@ and IGK@ rearrangements were tested using the BIOMED-2 protocol. We identified a clone (IGH@ and/or IGK@) in 19 of 20 (95%) PCBCL patients and 2 of 12 (17%) benign lymphoid infiltrate patients. The B-cell clones were proven to be identical in 11 of 20 (55%) PCBCL patients, including 7 of 16(44%) biopsies from patients with 2 different sites and 4 of 4 biopsies (100%) from patients at the same site but different time points. In 4 cases (3 FCL and 1 marginal zone lymphoma), different clones were detected at different sites, suggesting the possibility of a second simultaneous primary lymphoma. Our results indicate that the presence of identical clones is highly suggestive of lymphoma. To our knowledge, this is the first report to investigate the detection of identical clones in 2 distinct biopsies in PCBCL patients. Although the study is small and the results need to be confirmed in a larger study, these findings suggest that a subset of PCBCL at different sites may represent different primary tumors rather than occurrence of a single disease.

    View details for DOI 10.1097/DAD.0b013e318255dbae

    View details for Web of Science ID 000314103600006

    View details for PubMedID 22588547

  • The Differential Diagnosis and Bone Marrow Evaluation of New-Onset Pancytopenia AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weinzierl, E. P., Arber, D. A. 2013; 139 (1): 9-29


    New-onset pancytopenia can be caused by a wide variety of etiologies, leading to a diagnostic dilemma. These etiologies range from congenital bone marrow failure to marrow space-occupying lesions, infection, and peripheral destruction, to name a few. Bone marrow examination, in addition to a detailed clinical history, is often required for an accurate diagnosis. The purpose of this review is to provide a brief overview of many of the causes of new-onset pancytopenia in adults and children, with emphasis on bone marrow findings and recommendations of additional testing and clinical evaluation when needed, with the overall aim of aiding the pathologist's role as a consultant to the patient's treating physician.

    View details for DOI 10.1309/AJCP50AEEYGREWUZ

    View details for Web of Science ID 000312678900003

    View details for PubMedID 23270895

  • DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups BRITISH JOURNAL OF HAEMATOLOGY Ohgami, R. S., Ma, L., Ren, L., Weinberg, O. K., Seetharam, M., Gotlib, J. R., Arber, D. A. 2012; 159 (2): 182-190


    To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P=00439) and specifically with megakaryocytic dysplasia (P=00003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P=00469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 257 and 186, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P=0000411) as well as within AML NOS (DFS; P=00023), AML with intermediate cytogenetic risk (OS; P=00104) and normal karyotype AML (OS; P=000636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases.

    View details for DOI 10.1111/bjh.12029

    View details for Web of Science ID 000309242000009

    View details for PubMedID 22924777

  • BRAF-mutated, Microsatellite-stable Adenocarcinoma of the Proximal Colon: An Aggressive Adenocarcinoma With Poor Survival, Mucinous Differentiation, and Adverse Morphologic Features AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Jayachandran, P., Koong, A. C., Chang, D. T., Kwok, S., Ma, L., Arber, D. A., Balise, R. R., Tubbs, R. R., Shadrach, B., Pai, R. K. 2012; 36 (5): 744-752


    The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

    View details for DOI 10.1097/PAS.0b013e31824430d7

    View details for Web of Science ID 000302814000013

    View details for PubMedID 22314188

  • Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies LEUKEMIA Ohgami, R. S., Ohgami, J. K., Pereira, I. T., Gitana, G., Zehnder, J. L., Arber, D. A. 2011; 25 (9): 1439-1443


    T-cell large granular lymphocytic (LGL) leukemia is a complex diagnosis, requiring persistent clonal expansions of LGLs, and cytopenias. Often the diagnosis is unclear as non-clonal expansions of LGLs commonly occur in reactive conditions. To better understand T-LGL leukemia, we performed a comprehensive clinicopathologic analysis of 85 patients with LGL expansions. Interestingly, distinct CD8+(dim)/CD57+ populations, seen by flow cytometry, were significantly associated with clonal T-LGL leukemia (P < 0.001) as well as neutropenia (median absolute neutrophil count (ANC) 1.45 vs 3.19 10(9)/l; P = 0.0017). Furthermore, cases with distinct CD8+(dim)/CD57+ populations and monoclonal T cells had even lower ANCs (median ANC 1.41 10(9)/l; P = 0.001) compared with cases without these dual criteria. Additionally, complete or partial loss of CD5 expression was independently associated with clonal T-LGL leukemia (P<0.001) and neutropenia (median ANC 1.41 vs 2.70 10(9)/l; P = 0.002). This study describes specific immunophenotypic parameters to better define clonal cases of T-LGL leukemia associated with significant neutropenia.

    View details for DOI 10.1038/leu.2011.107

    View details for Web of Science ID 000294665400008

    View details for PubMedID 21617700

  • Mixed-phenotype acute leukemia: historical overview and a new definition LEUKEMIA Weinberg, O. K., Arber, D. A. 2010; 24 (11): 1844-1851


    Acute leukemia with a mixed phenotype is a rare disease and comprises 2-5% of all acute leukemias. These disorders have been known historically by a variety of names, such as mixed lineage leukemia, bilineal leukemia and biphenotypic leukemia, and the criteria for diagnosis have often been arbitrary. The scoring criteria proposed by the European Group for the Immunological Characterization of Leukemias represented a major attempt to define this disorder. However, the relative weight given to some markers and the lack of lineage specificity of most markers have raised questions regarding the significance of this approach. In 2008, the World Health Organization classification of hematopoietic and lymphoid tumors proposed a simpler diagnostic algorithm, which relies on fewer and more lineage-specific markers to define mixed-phenotype acute leukemia (MPAL). MPAL with t(9;22) and MLL rearrangement have been separated. Several studies have suggested that patients with acute leukemia of mixed phenotype have a worse clinical outcome when compared with matched controls with acute myeloid leukemia or acute lymphoblastic leukemia. Further studies are needed to confirm the significance of MPAL as currently defined, to determine a standardized treatment approach and to better understand the biological and clinical aspects of this disease.

    View details for DOI 10.1038/leu.2010.202

    View details for Web of Science ID 000284057400003

    View details for PubMedID 20844566

  • Acute Myeloid Leukemia HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Heerema-McKenney, A., Arber, D. A. 2009; 23 (4): 633-?


    The evolution of acute myeloid leukemia (AML) classification reflects greater understanding of the AML pathogenesis. The 2008 World Health Organization classification incorporated cytogenetic and molecular genetic findings and introduced important prognostic correlations. In this article, the authors discuss the different types of AML and their diagnoses.

    View details for DOI 10.1016/j.hoc.2009.04.003

    View details for Web of Science ID 000269004500002

    View details for PubMedID 19577162

  • The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes BLOOD Vardiman, J. W., Thiele, J., Arber, D. A., Brunning, R. D., Borowitz, M. J., Porwit, A., Harris, N. L., Le Beau, M. M., Hellstrom-Lindberg, E., Tefferi, A., Bloomfield, C. D. 2009; 114 (5): 937-951


    Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

    View details for DOI 10.1182/blood-2009-03-209262

    View details for Web of Science ID 000268491100007

    View details for PubMedID 19357394

  • Low Stage Follicular Lymphoma: Biologic and Clinical Characterization According to Nodal or Extranodal Primary Origin AMERICAN JOURNAL OF SURGICAL PATHOLOGY Weinberg, O. K., Ma, L., Seo, K., Beck, A. H., Pai, R. K., Morales, A., Kim, Y., Sundram, U., Tan, D., Horning, S. J., Hoppe, R. T., Natkunam, Y., Arber, D. A. 2009; 33 (4): 591-598


    Studies suggest that primary extranodal follicular lymphoma (FL) is not infrequent but it remains poorly characterized with variable histologic, molecular, and clinical outcome findings. We compared 27 extranodal FL to 44 nodal FL using morphologic, immunohistochemical, and molecular genetic techniques and evaluated the clinical outcome of these 2 similarly staged groups. Eight cases of primary cutaneous follicle center lymphoma were also studied. In comparison to nodal FL, a greater number of extranodal FL contained a diffuse growth pattern (P=0.004) and lacked CD10 expression (P=0.014). Fifty-four percent of extranodal and 42% of nodal FL cases showed evidence of t(14;18), with minor breakpoints (icr, 3'BCL2, 5'mcr) more commonly found in extranodal cases (P=0.003). Outcome data showed no significant differences in overall survival (P=0.565) and progression-free survival (P=0.627) among extranodal, nodal, and primary cutaneous follicle center lymphoma cases. Analysis of all cases by t(14;18) status indicate that the translocation-negative group is characterized by a diffuse growth pattern (P=0.043) and lower BCL2 expression (P=0.018). The t(14;18)-positive group showed significantly better overall survival (P=0.019) and disease-specific survival (P=0.006) in comparison with the t(14;18)-negative group. In low stage FL, the status of t(14;18) seems to be more predictive of outcome than origin from an extranodal versus nodal site.

    View details for Web of Science ID 000264818800014

    View details for PubMedID 19065102

  • Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system BLOOD Weinberg, O. K., Seetharam, M., Ren, L., Seo, K., Ma, L., Merker, J. D., Gotlib, J., Zehnder, J. L., Arber, D. A. 2009; 113 (9): 1906-1908


    Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into "AML with myelodysplasia-related changes" (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P= .014), presented with a lower hemoglobin (P= .044), more frequently expressed CD14 (P= .048), and exhibited a decreased frequency of CEBPA mutations (P= .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P< .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

    View details for DOI 10.1182/blood-2008-10-182782

    View details for Web of Science ID 000263723700007

    View details for PubMedID 19131546

  • Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone BLOOD Feldman, A. L., Arber, D. A., Pittaluga, S., Martinez, A., Burke, J. S., Raffeld, M., Camos, M., Warnke, R., Jaffe, E. S. 2008; 111 (12): 5433-5439


    Rare cases of histiocytic and dendritic cell (H/DC) neoplasms have been reported in patients with follicular lymphoma (FL), but the biologic relationship between the 2 neoplasms is unknown. We studied 8 patients with both FL and H/DC neoplasms using immunohistochemistry, fluorescence in situ hybridization (FISH) for t(14;18), and polymerase chain reaction (PCR)/sequencing of BCL2 and IGH rearrangements. There were 5 men and 3 women (median age, 59 years). All cases of FL were positive for t(14;18). The H/DC tumors included 7 histiocytic sarcomas, 5 of which showed evidence of dendritic differentiation, and 1 interdigitating cell sarcoma. Five H/DC tumors were metachronous, following FL by 2 months to 12 years; tumors were synchronous in 3. All 8 H/DC tumors showed presence of the t(14;18) either by FISH, or in 2 cases by PCR with the major breakpoint region (MBR) probe. PCR and sequencing identified identical IGH gene rearrangements or BCL2 gene breakpoints in all patients tested. All H/DC tumors lacked PAX5, and up-regulation of CEBPbeta and PU.1 was seen in all cases tested. These results provide evidence for a common clonal origin of FL and H/DC neoplasms when occurring in the same patient, and suggest that lineage plasticity may occur in mature lymphoid neoplasms.

    View details for DOI 10.1182/blood-2007-11-124792

    View details for Web of Science ID 000256786500012

    View details for PubMedID 18272816

  • "Minor" BCL2 breakpoints in follicular lymphoma - Frequency and correlation with grade and disease presentation in 236 cases JOURNAL OF MOLECULAR DIAGNOSTICS Weinberg, O. K., Ai, W. Z., Mariappan, M. R., Shum, C., Levy, R., Arber, D. A. 2007; 9 (4): 530-537


    Follicular lymphomas are frequently associated with the t(14;18)(q32;q21). This translocation can be detected by karyotype, polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). In addition to the breakpoints currently used for diagnosis located in the major breakpoint region (MBR) and the minor cluster region (mcr), recent studies have reported the existence of other breakpoints (3' BCL2, 5'mcr, and icr). In this study, we examined the frequency of all five breakpoints in 236 cases of follicular lymphomas by real-time PCR analysis. The distribution of breakpoint sites consisted of MBR in 118 cases (50%), mcr in 11 (5%), icr in 32 (13%), 3' BCL2 in 13 (6%), and 5' mcr in three cases (1%). These findings illustrate significantly higher frequency of the icr breakpoint as compared with the more frequently studied mcr. Correlation of breakpoints with histology showed that MBR breakpoints occur more frequently in grade 2 lymphomas (P = 0.042). A majority of the PCR-negative cases (75%) contained an IGH/BCL2 translocation with FISH methods, suggesting the presence of other BCL2 breakpoints. Correlation of breakpoints with survival did not reveal significant differences. Diagnostic laboratories should consider expanding their PCR methods to include other BCL2 breakpoints and correlating with FISH methods when appropriate.

    View details for DOI 10.2353/jmoldx.2007.070038

    View details for Web of Science ID 000249471400014

    View details for PubMedID 17652637

  • Identification of novel RUNXI (AMLI) translocation partner genes SH3D19, YTHDF2, and ZNF687 in acute myeloid leukemia GENES CHROMOSOMES & CANCER Nguyen, T. T., Ma, L. N., Slovak, M. L., Bangs, C. D., Cherry, A. M., Arber, D. A. 2006; 45 (10): 918-932


    Three patients diagnosed with acute myeloid leukemia (AML) with reciprocal 21q22/RUNX1(AML1) translocations involving chromosomes 1 and 4 were studied. Three novel RUNX1 translocation partner genes on 1q21.2 (ZNF687), 1p35 (YTHDF2), and 4q31.3 (SH3D19) were identified using a panhandle polymerase chain reaction and the 3' rapid amplification of cDNA ends method. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the region in the partner gene with the highest Alu density, suggesting that Alus may contribute to the recombination events. Two out of three of the cases retained RUNX1's entire RUNT domain in the translocation, and RUNX1 mutations were absent in the fusion transcripts, confirmed by reverse transcription-polymerase chain reaction and sequencing analysis. SH3D19 encodes a cytoplasmic protein EBP known to suppress RAS-induced cellular transformation, which can be inhibited by nuclear recruitment. The t(4;21) created a hybrid RUNX1-EBP protein retaining RUNX1's DNA binding domain, which may result in nuclear localization of the chimeric protein and inhibition of EBP's RAS-suppressive functions. Future studies would be useful to further characterize these novel fusion protein products.

    View details for DOI 10.1002/gcc.20355

    View details for Web of Science ID 000240036200004

    View details for PubMedID 16858696

  • The frequency of B- and T-cell gene Rearrangements and Epstein-Barr virus in T-cell lymphomas - A comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations JOURNAL OF MOLECULAR DIAGNOSTICS Tan, B. T., Warnke, R. A., Arber, D. A. 2006; 8 (4): 466-475


    We report on a series of 58 cases of angioimmunoblastic T-cell lymphoma (AILT) and 59 cases of peripheral T-cell lymphoma, unspecified (PTCL-NOS). Subsets of cases from both diagnostic groups were complicated by associated B-cell proliferations, and we performed B- and T-cell clonality studies and in situ hybridization for Epstein-Barr virus (EBV) to investigate the relationship between B-cell proliferation, B-cell clonality, and EBV. Using multiplex polymerase chain reaction assays based on the BIOMED-2 collaborative study, we detected TCRgamma T-cell clones in 78 and 81% of AILT and PTCL-NOS cases, respectively, and IGH B-cell clones in 34 and 35% of AILT and PTCL-NOS cases, respectively. The majority of cases contained EBV-positive cells, including 50% of AILT and 57% of PTCL-NOS cases, and cases with B-cell proliferations were more often EBV-positive. Although a relatively high rate of B-cell clonality has been shown for AILT, our findings for PTCL-NOS differ from previous reports in that B-cell clonality was relatively frequent. Overall, a positive B-cell clone correlated, in part, with the presence of a B-cell proliferation but not with EBV. Our findings demonstrate that B-cell clonality is a common finding in AILT and PTCL-NOS, and its presence should not negate the diagnosis established by morphologic, immunophenotypic, and clinical findings.

    View details for DOI 10.2353/jmoldx.2006.060016

    View details for Web of Science ID 000240256600010

    View details for PubMedID 16931587

  • Bone marrow biopsy involvement by non-Hodgkin's lymphoma - Frequency of lymphoma types, patterns, blood involvement, and discordance with other sites in 450 specimens AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., George, T. I. 2005; 29 (12): 1549-1557


    To evaluate the features of bone trephine biopsy involvement by non-Hodgkin lymphoma, 450 specimens were evaluated for percentage of marrow involvement, pattern of involvement, presence of germinal centers or follicular structures, and discordance with other involved sites. A subset of 197 cases was evaluated for evidence of concurrent peripheral blood involvement. Follicular grade 1 lymphoma (30.4%) was the most common type to involve the marrow, followed by diffuse large B-cell lymphoma (16.0%), mantle cell lymphoma (9.3%), low-grade B-cell lymphoma, not otherwise specified (8.7%), lymphoplasmacytic lymphoma (8.4%), follicular grade 2 lymphoma (7.1%), and mature T- and NK-cell lymphomas (6.4%). A mixed pattern of infiltration was most common, followed by paratrabecular, nodular, diffuse, and interstitial patterns. Greater than 90% of follicular lymphomas had at least a focal paratrabecular infiltration pattern, but this pattern was also seen with other lymphoma types. Interstitial disease infiltration tended to correlate with lymphoplasmacytic lymphoma but was also not specific. The presence of germinal centers or follicular structures was associated with follicular lymphoma in 88% of cases. Discordance between the bone marrow morphology and other tissue sites was observed in 24.9% of cases and was most often seen with follicular or diffuse large B-cell lymphoma. Peripheral blood involvement by lymphoma was observed in 29% of cases, found in all disease groups except for follicular grade 3 lymphoma. This study highlights the frequency of different lymphoma patterns in the marrow, limitations of primary lymphoma classification on biopsy material alone, and the relative frequency of marrow discordance and peripheral blood involvement by marrow lymphoma.

    View details for Web of Science ID 000233539500001

    View details for PubMedID 16327427

  • Telomerase activity and proliferation index in aggressive mature B-cell lymphoma: Comparison to germinal center phenotypic markers HUMAN PATHOLOGY Chiu, K. C., Fine, M., Ikle, D., Slovak, M. L., Arber, D. A. 2003; 34 (12): 1259-1264


    Cell proliferation may be evaluated by various methods, including Ki-67 immunohistochemistry and measures of telomerase activity. Both methods would theoretically show comparable increases in a given case. To evaluate the relationship between these 2 markers of proliferation in aggressive mature B-cell lymphomas, 48 cases were studied. The study group included 5 cases of mantle cell lymphoma (MCL); 6 cases of Burkitt's/Burkitt's-like lymphoma (BL); 9 cases of follicular lymphoma, grade 3 (FLC); and 28 cases of diffuse large B-cell lymphoma (DLC). Telomerase activity was measured as total product generated (TPG) units, and TPG results for the aforementioned cases were compared to the TPG results for 10 cases of reactive follicular hyperplasia. An overlap in TPG scores between reactive cases and lymphoma cases was found. Significant differences in both log TPG (P = 0.0443) and Ki-67 (P = 0.0006) were seen in the different lymphoma types. A positive correlation between Ki-67 percentage and TPG score was identified in FLC (r = 0.9281; P = 0.0003), but a poor correlation between these 2 indicators was seen in the other lymphoma types. Cluster analysis identified distinct patterns for MCL, FLC, and BL, but heterogeneous patterns for DLC. Because increases in both Ki-67 proliferation and telomerase activity are reported in normal germinal centers (GCs), these tests were also evaluated for usefulness as markers of a GC cell phenotype. Among the FLC and DLC cases, features of a GC phenotype significantly correlated with increased Ki-67 percentage (P = 0.0152), but not with increased log TPG. An elevated log TPG correlated with CD10 expression, and elevated Ki-67 percentage correlated with both CD10 and BCL-6 expression. TPG level and Ki-67 percentage did not correlate with the presence of t(14;18) or BCL-2 protein expression. Although the proliferation patterns were fairly distinctive for MCL, FLC, and BL, these studies show that markers of cell proliferation do not by themselves,identify distinct subtypes of large cell lymphomas. With the exception of FLC, the tumors exhibited poor correlation between telomerase activity and Ki-67 proliferation index. These tests did show some correlation with expression of GC cell phenotypic markers, however.

    View details for DOI 10.1016/j.humpath.2003.07.009

    View details for Web of Science ID 000187749300007

    View details for PubMedID 14691911

  • Detection of NPM/MLF1 fusion in t(3;5)-positive acute myeloid leukemia and myelodysplasia HUMAN PATHOLOGY Arber, D. A., Chang, K. L., Lyda, M. H., Bedell, V., Spielberger, R., Slovak, M. L. 2003; 34 (8): 809-813


    Balanced translocations are rare in myelodysplasia (MDS) and acute myeloid leukemia (AML) with multilineage dysplasia; however, the t(3;5)(q25;q35) and insertion variant occur in a subset of patients. To evaluate the possible genes involved in this translocation, we studied 6 cases with a t(3;5) by fluorescence in situ hybridization with probes directed against the nucleophosmin (NPM), EVI1, and Ribophorin genes, as well as a newly developed myeloid leukemia factor 1 (MLF1) BAC clone. The histologic spectrum of the cases was variable, ranging from refractory cytopenia with multilineage dysplasia to AML with multilineage dysplasia in the World Health Organization classification. An NPM/MLF1 fusion was identified in 5 of 6 cases, whereas the EVI1 and Ribophorin genes were not involved in any of the cases. The NPM/MLF1-positive cases were predominantly young adult males (median age, 33 years) who responded well to hematopoietic stem cell transplantation. These findings suggest that an NPM/MLF1 fusion is the primary molecular abnormality in t(3;5) MDS and AML with multilineage dysplasia, and also that cases with NPM/MLF1 may be clinically distinct from other MDS-associated disease.

    View details for DOI 10.1016/S0046-8177(03)00251-X

    View details for Web of Science ID 000184992200014

    View details for PubMedID 14506644

  • High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities LEUKEMIA Ishizawa, S., Slovak, M. L., Popplewell, L., Bedell, V., Wrede, J. E., Carter, N. H., Snyder, D. S., Arber, D. A. 2003; 17 (6): 1091-1095


    To evaluate the frequency and cytogenetic and immunophenotypic features of therapy-related, precursor B-cell acute lymphoblastic leukemia (ALL), 152 cases of immature B-cell ALL were reviewed. These were compared to the frequency of therapy-related acute myeloid leukemia (t-AML) during the same time period. Eight ALL cases with a prior diagnosis of malignancy were identified, including six (4.0%) with prior therapy considered to be therapy-related ALL (t-ALL). The t-ALL cases followed treatment for breast carcinoma (two cases), lung carcinoma (two cases), lymphocyte predominance Hodgkin's disease and follicular lymphoma with a latency period of 13 months to 8 years. All t-ALL cases had a pro-B (CD10-negative) immunophenotype with significantly higher expression of CD15 and CD65, compared to the de novo CD10-positive ALL cases. All six t-ALL cases had MLL abnormalities by fluorescence in situ hybridization, and four showed t(4;11)(q21;q23). These represented half of all 11q23-positive adult ALL cases. During the same time period, 4.9% of all AML cases were considered t-AML. There was a 16.7% frequency of 11q23 abnormalities in the t-AML group. Despite the similar frequency in therapy-related disease among ALL and AML cases, there were differences in the frequency of the diseases and t-ALL represented 12% of all therapy-related leukemias. However, t-ALL represented 46% of all 11q23-positive therapy-related leukemias. The immunogenetic features of t-ALL appear distinct and may aid in identifying more cases of this disease type in the future.

    View details for DOI 10.1038/sj.leu.2402918

    View details for Web of Science ID 000183300400013

    View details for PubMedID 12764373

  • Value of combined morphologic, cytochemical, and immunophenotypic features in predicting recurrent cytogenetic abnormalities in acute myeloid leukemia HUMAN PATHOLOGY Arber, D. A., Carter, N. H., Ikle, D., Slovak, M. L. 2003; 34 (5): 479-483


    To evaluate the reliability of previously described morphologic, cytochemical and immunophenotypic criteria for the identification of acute myeloid leukemias (AMLs) with t(8;21), inv(16)/t(16;16) and t(15;17), 300 cases were reviewed retrospectively. Eighteen AMLs with features of t(8;21), 31 with features of inv(16)/t(16;16), and 22 with features of t(15;17) were identified. Cytogenetic studies were available for 228 cases and identified 15 cases of t(8;21), 30 cases of inv(16)/t(16;16), 18 cases of t(15;17) and 11 cases 11q23 AML. The true positive rate for pre-cytogenetic evaluation was 95% for t(15;17), 88% for inv(16)/t(16;16) and 87.5% for t(8;21). No difference in 5-year survival was identified in the precytogenetic and corresponding cytogenetic disease groups. No specific features to predict 11q23 abnormalities were identified. This study confirms the reliability of a combined morphologic, cytochemical and immunophenotypic approach to the initial classification of AML. Cytogenetic studies are still needed on all cases to identify the small proportion of cases that will be missed by these methods and to identify other significant cytogenetic abnormalities in AML.

    View details for DOI 10.1016/S0046-8177(03)00085-6

    View details for Web of Science ID 000183190200011

    View details for PubMedID 12792922

  • Prognostic impact of acute myeloid leukemia classification - Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A., Stein, A. S., Carter, N. H., Ikle, D., Forman, S. J., Slovak, M. L. 2003; 119 (5): 672-680


    To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme. Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts. Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences. These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.

    View details for DOI 10.1309/EM7KCOR4GLMHRCX4

    View details for Web of Science ID 000182494800007

    View details for PubMedID 12760285

  • Epstein-Barr virus nuclear antigen (EBNA)-1 carboxy-terminal and EBNA-4 sequence polymorphisms in nasal natural killer/T-cell lymphoma in the United States LABORATORY INVESTIGATION Gaal, K., Weiss, L. M., Chen, W. G., Chen, Y. Y., Arber, D. A. 2002; 82 (7): 957-962


    Epstein-Barr virus (EBV) polymorphisms were examined in 12 cases of nasal natural killer (NK)/T-cell lymphoma diagnosed in the United States (U.S.-NL) with respect to the EBV-associated nuclear antigen (EBNA)-1 carboxy (C)-terminal region and the EBNA-4 region. A single dominant EBV strain was found in all cases. EBNA-1 sequences were remarkably homogeneous, showing either a P-ala (2/12) or P-ala variant (9/12) sequence. Other EBNA-1 subtypes known to be common in U.S.-reactive samples, such as P-thr or V-leu, were not identified. The final case had a base deletion with frame shift and premature stop codon. EBNA-1 C-terminal amino acid substitutions were common at codons 499 (10/12 cases), 502 (7/12), 524 (9/12), and 528 (6/12), all previously reported "hot spots." However, unlike previous reports of other EBV-associated neoplastic and reactive tissues, mutations were absent at residues 487 and 492. Mutations within HLA-A11-restricted immunogenic EBNA-4 epitopes 399-408 and 416-424 occurred in 3 of 12 cases but were not associated with HLA-A11 status. In summary, the exclusive finding of P-ala variant or P-ala EBNA-1 sequences in U.S.-NL cases differs from that reported in U.S.-reactive and non-U.S.-NL cases. Although the significance of this difference is not known for certain, it may be related to geographic and/or site-specific variations, rather than oncogenicity per se.

    View details for DOI 10.1097/01.LAB.0000020416.66825.A0

    View details for Web of Science ID 000176831200016

    View details for PubMedID 12118098

  • Diagnostic utility of bilateral bone marrow examination - Significance of morphologic and ancillary technique study in malignancy CANCER Wang, J., Weiss, L. M., Chang, K. L., Slovak, M. L., Gaal, K., Forman, S. J., Arber, D. A. 2002; 94 (5): 1522-1531


    To retrospectively evaluate the significance of morphologic examination and ancillary studies performed on bilateral bone marrow biopsy specimens, 1864 bone marrow samples were studied.Bilateral bone marrow biopsy specimens included 883 specimens that were evaluated for involvement by non-Hodgkin lymphoma (NHL); 381 specimens that were evaluated for involvement by carcinoma (CA); 362 specimens that were evaluated for involvement by Hodgkin disease (HD); 94 specimens that were evaluated for involvement by sarcoma (SA); 56 specimens that were evaluated for involvement by multiple myeloma (MM); 53 specimens that were evaluated for involvement by acute and chronic leukemia, myelodysplasia, and/or myeloproliferative disorders (LEUK); and 35 specimens that were evaluated for other reasons.Of all 1864 specimens, 410 samples (22.0%) were positive for disease, including 77% of MM samples, 58% of LEUK samples, 29.6% of NHL samples, 14% of SA samples, 9.9% of HD samples, and 6.8% of CA samples. A discrepancy between the left and right sides was identified in 48 specimens (11.7% of positive samples). The discrepancy rate was 39% for HD samples, 29% for SA samples, 23% for CA samples, and 9.2% for NHL samples. No morphologic discrepancies between bilateral samples were found in MM samples or LEUK samples. Bilateral flow cytometric studies (n = 113 samples) were positive in 11 samples (9.7%; all morphologically positive), with two discrepancies detected between bilateral samples. Bilateral cytogenetic studies (n = 74 samples) were positive in 5 samples (7%), and there were no discrepancies. Bilateral molecular studies (n = 16 samples) were positive in 7 samples (44%), and there were 3 discrepancies.Bilateral morphologic evaluation is useful in the evaluation of patients with NHL, HD, CA, and SA and is not indicated for patients with acute or chronic leukemia, myelodysplasia, MM, and other diseases. Bilateral flow cytometric or cytogenetic studies of bone marrow did not provide additional information in this population to justify bilateral samples. The role of bilateral molecular analysis needs to be defined further, but pooled samples for molecular studies may be adequate.

    View details for DOI 10.1002/cncr.10364

    View details for Web of Science ID 000174221600019

    View details for PubMedID 11920510

  • Therapy-related acute myeloid leukemia/myelodysplasia with balanced 21q22 translocations AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A., Slovak, M. L., Popplewell, L., Bedell, V., Ikle, D., Rowley, J. D. 2002; 117 (2): 306-313


    The morphologic and immunophenotypic findings of 36 cases of 21q22 acute myeloid leukemia (AML) and myelodysplasia (MDS) were compared, including 14 de novo t(8;21) AMLs, 11 t(8;21) therapy-related AML/MDS cases, and 11 therapy-related AML/MDS cases with other 21q22 balanced translocations [t(n;21)]. Cases were evaluated for the presence of Auer rods, distinct chunky cytoplasmic blast cell granules, promyelocyte increase, cytoplasmic perinuclear clearing (hofs) of blast cells, eosinophil increase, andfeatures of associated trilineage dysplasia. Results of immunophenotyping studies for CD19, CD34, and CD56 expression were compared. Cases of de novo and therapy-related t(8;21) disease shared common morphologic features of chunky cytoplasmic granules, perinuclear hofs, and promyelocyte increases that were not seen consistently in the t(n;21) group of t-AML/MDS cases. Immunophenotypic similarities also were observed between the 2 t(8;21) groups. De novo and therapy-related t(8;21) disease, however, differed by the frequent presence of associated dysplasia in both t-AML/MDS groups, which was infrequent in the de novo t(8;21) group. Therapy-related AMI/MDS with t(8;21) shares characteristic morphologic and immunophenotypic features with de novo t(8;21) AML, but frequently also occurs with associated myelodysplastic changes, similar to other therapy-related acute leukemias.

    View details for Web of Science ID 000173661600018

    View details for PubMedID 11863228

  • Evaluation of T cell receptor testing in lymphoid neoplasms - Results of a multicenter study of 29 extracted DNA and paraffin-embedded samples JOURNAL OF MOLECULAR DIAGNOSTICS Arber, D. A., Braziel, R. M., Bagg, A., Bijwaard, K. E. 2001; 3 (4): 133-140


    To evaluate current diagnostic methods used for the evaluation of T cell receptor (TCR) gene rearrangements, 24 different laboratories analyzed 29 lymphoid neoplasm samples of extracted DNA and paraffin-embedded tissue and were asked to complete a technical questionnaire related to the testing. Participating laboratories performed Southern blot and polymerase chain reaction (PCR) testing for rearrangements of the TCRbeta chain gene and PCR for the TCRgamma chain gene rearrangements. Of 14 laboratories performing TCRbeta Southern blot analysis, there was complete agreement in 10 of 14 cases, with some false negative results obtained in 4 cases. No false positive results were obtained by Southern blot analysis. TCRbeta PCR analysis was only performed by two laboratories, and only 47.1% of positive samples were detected. Twenty-one laboratory results were obtained for TCRgamma PCR. This method showed an overall detection rate of 77.9% for T cell gene rearrangements with a 4.1% false positive rate, as compared to both TCRgamma Southern blot analysis results and immunophenotyping. The detection rate for TCRgamma PCR, however, significantly differed when extracted DNA samples from frozen tissue were compared to paraffin-embedded tissue (85.4% versus 65.9%; P = 0.0005). Significant differences in true positive results were obtained when laboratories using primers directed against multiple TCRgamma variable regions (V1-8 plus one to three other primer sets) were compared to laboratories that used only a single set of TCR primers directed against the V1-8 (P < 0.0001). Other technical factors significantly affecting results were also identified. These findings provide useful data on the current state of diagnostic TCR testing, highlight the risk of false negative results for TCR testing directed against only portions of the TCRgamma gene, and identify limitations of testing of paraffin-embedded tissues in some laboratories.

    View details for Web of Science ID 000171989200002

    View details for PubMedID 11687596

  • Realistic pathologic classification of acute myeloid leukemias AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A. 2001; 115 (4): 552-560


    Most classification systems of acute myeloid leukemia (AML) rely largely on the criteria proposed by the French-American-British (FAB) Cooperative Group. The recently proposed World Health Organization (WHO) classification of neoplastic diseases of the hematopoietic and lymphoid tissues includes a classification of AMLs. The proposed WHO classification of AMLs includes traditional FAB-type categories of disease, as well as additional disease types that correlate with specific cytogenetic findings and AML associated with myelodysplasia. This system includes a large number of disease categories, many of which are of unknown clinical significance, and there seems to be substantial overlap between disease groups in the WHO proposal. Some disease types in the WHO proposal cannot be diagnosed without detailed clinical information, or they are diagnosed only by the cytogenetic findings. In this report, a realistic pathologic classification for AML is proposed that includes disease types that correlate with specific cytogenetic translocations and can be recognized reliably by morphologic evaluation and immunophenotyping and that incorporates the importance of associated myelodysplastic changes. This system would be supported by cytogenetic or molecular genetic studies and could be expanded as new recognizable clinicopathologic entities are described.

    View details for Web of Science ID 000167794000010

    View details for PubMedID 11293903

  • Keratin immunohistochemistry detects clinically significant metastases in bone marrow biopsy specimens in women with lobular breast carcinoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Lyda, M. H., Tetef, M., Carter, N. H., Ikle, D., Weiss, L. M., Arber, D. A. 2000; 24 (12): 1593-1599


    Some patients with breast cancer currently undergo bone marrow biopsy to make clinical decisions regarding therapy; however, lobular carcinoma can be difficult to detect in routine histologic sections. The authors reviewed retrospectively all available bone marrow biopsies from patients with lobular carcinoma diagnosed between January, 1, 1989, and September, 25, 1997, at the City of Hope National Medical Center to identify useful morphologic features and to determine the utility of pan-keratin immunohistochemical (IHC) staining. A total of 65 biopsies from 54 patients were reviewed. Thirteen of the 65 biopsies were classified initially as containing metastatic tumor based on histologic features alone. With the addition of keratin IHC, seven additional cases of metastatic disease were detected. Forty of the 54 patients received stem cell replacement or autologous bone marrow transplantation. Disease-free survival after high-dose chemotherapy with stem cell replacement or autologous bone marrow transplantation was stratified into three groups based on hematoxylin and eosin (H&E) staining and IHC results. Two-year disease-free survival was 33% for the H&E-/IHC+ group versus 90% for the H&E-/IHC- group (p = 0.005) among patients clinically free of disease at the time of stem cell replacement or autologous bone marrow transplantation. Two-year disease-free survival was 0% in the H&E+/IHC+ group (p = 0.04, compared with the H&E-/ IHC+ group). The authors conclude that routine morphologic examination without the aid of keratin IHC is unreliable in detecting clinically relevant metastatic lobular carcinoma in bone marrow biopsies. These findings suggest that pan-keratin immunostaining may be indicated on bone marrow biopsy specimens from lobular carcinoma patients if the biopsy appears histologically negative for metastatic tumor on H&E sections.

    View details for Web of Science ID 000165590400002

    View details for PubMedID 11117779

  • Molecular diagnostic approach to non-Hodgkin's lymphoma JOURNAL OF MOLECULAR DIAGNOSTICS Arber, D. A. 2000; 2 (4): 178-190

    View details for Web of Science ID 000165235700003

    View details for PubMedID 11232108

  • Sinonasal NK/T-cell lymphomas in the United States AMERICAN JOURNAL OF SURGICAL PATHOLOGY Gaal, K., Sun, N. C., Hernandez, A. M., Arber, D. A. 2000; 24 (11): 1511-1517


    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-gamma) 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-gamma 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.

    View details for Web of Science ID 000165136500006

    View details for PubMedID 11075852

  • Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms - Frequent expression in renal cell carcinoma and endometrial stromal sarcoma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chu, P. G., Arber, D. A. 2000; 113 (3): 374-382


    We tested 505 cases of nonhematopoietic neoplasms by immunohistochemistry using a newly characterized monoclonal antibody (clone 56C6) against the CD10 antigen. CD10 was expressed widely in neoplasms of the genitourinary tract, including 41 (89%) of 46 cases of renal cell carcinoma, 13 (54%) of 24 cases of transitional cell carcinoma, and 11 (61%) of 18 cases of prostatic adenocarcinoma. In addition, 5 (100%) of 5 endometrial stromal sarcomas, 3 (60%) of 5 rhabdomyosarcomas, 7 (50%) of 14 pancreatic adenocarcinomas, 5 (45%) of 11 cases of schwannoma, and 12 (40%) of 30 cases of malignant melanoma also were positive for CD10. Similar to normal tissue, CD10 positivity was restricted to the apical surface of malignant glandular cells of well-differentiated colonic, pancreatic, and prostatic adenocarcinoma, whereas in poorly differentiated adenocarcinoma and other tumors, such as melanoma, transitional cell carcinoma, renal cell carcinoma, and endometrial stromal sarcoma, the CD10 positivity showed diffuse cytoplasmic or membranous/Golgi patterns. The monoclonal antibody clone 56C6 is a reliable marker for CD10 in paraffin immunohistochemistry after heat-induced epitope retrieval. CD10 expression in renal cell carcinoma and endometrial stromal sarcoma may be a useful marker in the differential diagnoses of these tumors because both tumors otherwise lack specific markers.

    View details for Web of Science ID 000085475000008

    View details for PubMedID 10705818

  • Paraffin section detection of the c-kit gene product (CD117) in human tissues: Value in the diagnosis of mast cell disorders HUMAN PATHOLOGY Arber, D. A., Tamayo, R., Weiss, L. M. 1998; 29 (5): 498-504


    The c-kit gene product (CD117) is known to be expressed by a variety of normal human tissue cell types, including breast epithelium, germ cells, melanocytes, immature myeloid cells, and mast cells. To further characterize the expression of this antigen, 117 normal human tissues and 576 human tumors were studied by paraffin section immunohistochemistry. Varying degrees of CD117 expression were identified in various normal cells and in 53% of all tumors studied. In most cases (42% of total), CD117 expression was weak. Expression was most common in mast cell disease (100%), testicular germ cell tumors (100%), endometrial carcinomas (100%), papillary and follicular thyroid carcinomas (100%), small cell carcinomas (91%), malignant melanomas (90%), and ovarian epithelial carcinomas (87%). Strong immunoreactivity was only identified in cases of mast cell disease (11 of 11 cases), serous ovarian carcinoma (3 of 16), malignant melanoma (2 of 40), small cell lung carcinoma (one of seven), and adenoid cystic carcinoma (one of one). Although the pattern of reactivity was primarily cytoplasmic, a membrane staining pattern was seen in a subset of cases, and strong membrane staining was identified in normal mast cells and all cases of mast cell disease. The lack of tumor specificity of weak expression of this antigen limits its diagnostic utility in most cases. However, the strong membrane reactivity for CD117 identified in mast cells may be useful in the diagnosis of mast cell disorders.

    View details for Web of Science ID 000073550600011

    View details for PubMedID 9596274

  • Splenic vascular tumors: A histologic, immunophenotypic, and virologic study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Strickler, J. G., Chen, Y. Y., Weiss, L. M. 1997; 21 (7): 827-835


    Vascular tumors of the spleen include several different entities, some of which are unique to that organ. Twenty-two such proliferations were studied, including 10 hemangiomas, six littoral cell angiomas, four angiosarcomas, and two hamartomas. The hemangiomas included seven with localized tumors and three with diffuse angiomatosis of the spleen. All cases were studied by paraffin section immunohistochemistry with a large panel of antibodies. In addition, all cases were studied for the presence of the Kaposi's sarcoma-associated herpesvirus (KSHV) using the polymerase chain reaction. The morphologic findings were similar to those previously reported. All proliferations were vimentin positive, and one angiosarcoma was focally keratin positive. All cases reacted for CD31, whereas 20 of 22 were positive for von Willebrand's factor and 19 of 22 were positive for Ulex europeaus. CD34 expression in lining cells was identified in 10 of 10 hemangiomas, two of four angiosarcomas, and one of two hamartomas, whereas all six cases of littoral cell angioma were negative. CD68 was expressed in all cases of littoral cell angioma but was also positive in all three diffuse hemangiomas, two of seven localized hemangiomas, and two of four angiosarcomas. CD21 expression was restricted to the lining cells of littoral cell angioma, and CD8 expression was only identified in two of two hamartomas and two of four angiosarcomas. KSHV was not detected in any of the cases. These findings suggest that there are distinct immunophenotypic as well as morphologic features of splenic vascular tumors. Littoral cell angiomas have a characteristic CD34-/CD68+/CD21+/CD8- immunophenotype and hamartomas have a characteristic CD68-/CD21-/CD8+ phenotype. The frequent CD68 expression in diffuse hemangioma suggests an immunophenotypic difference from localized hemangioma of the spleen.

    View details for Web of Science ID A1997XW92300011

    View details for PubMedID 9236839

  • Acute myeloid leukemia with t(6;9) (p23;q34) - Association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype AMERICAN JOURNAL OF CLINICAL PATHOLOGY Alsabeh, R., Brynes, R. K., Slovak, M. L., Arber, D. A. 1997; 107 (4): 430-437


    The translocation (6;9)(p23;q34) is a rare cytogenetic aberration found in patients with acute myeloid leukemia (AML). The clinical, morphologic, and immunophenotypic findings of eight t(6;9) acute leukemias are described. The patients included six men and two women with a mean age of 38.5 years. The leukemias were classified in the French-American-British (FAB) system as AML FAB M2 in four cases and as FAB M4 in four cases. Underlying myelodysplasia was evident in six cases. Bone marrow basophilia was found at presentation in six of the seven cases studied. In two cases with basophilia, darkly stained granules were also present in many eosinophils. In one case, initial basophilia was absent, but was present at relapse, as were eosinophils containing darkly stained granules. Iron stains were available in five cases; four showed increased incorporation and three had ringed sideroblasts. All cases studied by flow cytometry (six at presentation and three at relapse) expressed CD13, CD33, and human leukocyte antigen-DR. At presentation, five cases were CD34 negative. In one case at presentation, a subset of blasts (18%) weakly expressed CD34. Three cases studied at relapse were positive for CD34. Two of seven cases studied were terminal deoxynucleotidyl transferase positive. The t(6;9)(p23;q34) was the only cytogenetic abnormality in five cases. Trisomy 8 was found in two cases, and ring 12 was present in one case. Three patients are living with refractory leukemia 6 weeks to 6 months after initial diagnosis, and three patients died of complications of allogeneic bone marrow transplantation. Only one patient is alive without evidence of disease 3 years after bone marrow transplantation. t(6;9) leukemia is an unusual type of AML that is associated with poor prognosis, early age of onset, basophilia, myelodysplasia with frequent ringed sideroblasts, and a CD34-negative initial phenotype.

    View details for Web of Science ID A1997WP86600008

    View details for PubMedID 9124211

  • Non-Hodgkin's lymphoproliferative disorders involving the spleen MODERN PATHOLOGY Arber, D. A., Rappaport, H., Weiss, L. M. 1997; 10 (1): 18-32


    One hundred eight splenectomy specimens involved by lymphoid neoplasms were studied to assess the frequency and pattern of involvement of the various disease groups. Cases were classified by the Working Formulation as well as by the Revised European-American classification of lymphoid neoplasms. Including the more recently described disease entities, large cell/immunoblastic lymphomas were the most common neoplasm, both primarily and secondarily, to involve the spleen (33.3% of all cases). The next most common lymphoid neoplasm to involve the spleen was chronic lymphocytic leukemia/ small lymphocytic lymphoma, found in 19.4% of cases, followed by follicular center cell lymphoma (13.0%), lymphoplasmacytoid lymphoma (9.3%), splenic marginal zone lymphoma (8.3%), mantle cell lymphoma (6.5%), and hairy cell leukemia (6.5%). The remaining 3.7% of cases included T-cell proliferations and one difficult-to-classify mixed cell lymphoma. More than 95% of the cases could be placed into one of three morphologic patterns of splenic involvement, i.e., 57.4% of spleens were involved by predominantly white pulp disease, 20.4% by predominantly nodular disease, without a predilection for white or red pulp, and 17.6% by predominantly red pulp disease. Although the white pulp and nodular patterns were primarily, but not exclusively, B-cell disorders, specimens with predominantly red pulp disease included all of the cases of hairy cell leukemia, as well as cases of both B- and T-cell lymphomas.

    View details for Web of Science ID A1997WD75200004

    View details for PubMedID 9021723

  • Paraffin section immunophenotyping of acute leukemias in bone marrow specimens AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A., Jenkins, K. A. 1996; 106 (4): 462-468


    The immunohistochemical evaluation of acute leukemia specimens has been limited in the past due of the inability to detect many lineage-related antigens in paraffin sections. With the improvement in immunohistochemical methods as well as the introduction of new antibodies, these limitations are now reduced. To evaluate the diagnostic utility of paraffin section immunohistochemistry in the lineage determination of acute leukemias, 77 previously immunophenotyped acute leukemias were studied with a panel of antibodies that included antibodies directed against CD3, CD20, CD34, CD43, CD68, CD79a, HLA-DR, myeloperoxidase (MPX), and terminal deoxynucleotidyl transferase (TdT). The cases included 48 acute myeloid leukemias, 18 precursor B-cell acute lymphoblastic leukemias, 6 T-cell acute lymphoblastic leukemias, and 5 mixed precursor B/myeloid leukemias. This immunohistochemical panel correctly identified the lineage of 96% of both acute myeloid leukemias and acute lymphoblastic leukemias and identified evidence of mixed lineage in 60% of mixed lineage leukemias. Antibodies directed against CD3, CD79a, MPX, and TdT were found to be the most useful, although the latter three alone were not entirely lineage specific. These findings suggest a role for paraffin section immunohistochemistry in the lineage determination of some cases of acute leukemia.

    View details for Web of Science ID A1996VL41700005

    View details for PubMedID 8853033

  • FREQUENT PRESENCE OF THE EPSTEIN-BARR-VIRUS IN INFLAMMATORY PSEUDOTUMOR HUMAN PATHOLOGY Arber, D. A., Kamel, O. W., VANDERIJN, M., Davis, R. E., Medeiros, L. J., Jaffe, E. S., Weiss, L. M. 1995; 26 (10): 1093-1098


    Inflammatory pseudotumor is a presumably nonneoplastic, hematopoietic, and spindled fibrous proliferation that may occur at a variety of anatomic sites. The origin of these proliferations is generally unknown. To evaluate the role of the Epstein-Barr virus (EBV) in inflammatory pseudotumor, 18 specimens from 17 patients were studied by in situ hybridization for EBV ribonucleic acid (RNA), and the morphological and immunologic characteristics of the infected cells were evaluated. These specimens included 10 lymph nodes, six splenic masses, and two hepatic masses. Overall, EBV RNA was detected in 41.2% (seven of 18) of the cases. These included two of 10 (20%) lymph nodes, four of six (66.7%) splenic pseudotumors, and one of two (50%) hepatic lesions. The degree of EBV infection was significantly greater within the tumors in comparison with the surrounding, uninvolved tissue. Two morphologically different EBV-positive cell types, spindled and round cells, were evident, and the infected cell type differed significantly when the nodal and extranodal cases were compared. All of the positive extranodal cases shown, numerous EBV-positive spindled cells, whereas no positive spindle cells (only positive round cells, morphologically consistent with lymphocytes) were noted in the two EBV-positive lymph node pseudotumors. Double-labeling immunohistochemical and in situ hybridization studies in some cases identified rare EBV-positive B cells and rare EBV positive T cells in four and three cases, respectively. Most EBV-positive cells in all cases failed to immunoreact with any B- or T-cell markers. Three of five cases studied, however, did show a subpopulation of smooth muscle actin/EBV-positive spindled cells, five of seven cases showed vimentin/EBV-positive spindled cells, and one of four cases had EBV-positive spindled cells that immunoreacted as follicular dendritic cells. These results suggest that EBV plays a role in a significant number of cases of inflammatory pseudotumor with differences in the incidence of EBV infection and the cell type (spindled vs round cell) infected when extranodal and nodal cases are compared, suggesting a difference in pathogenesis. The cell type infected in extranodal cases seemed to be of mesenchymal origin but could not be clearly defined.

    View details for Web of Science ID A1995RZ22000007

    View details for PubMedID 7557942



    The incidence of non-Hodgkin's lymphoma of the nasal region is much higher in Peru than in the United States and is similar to the incidence of sinonasal lymphomas in Asian countries. To characterize these lymphomas, we evaluated the clinical, morphologic, and immunohistochemical features of 14 cases and also analyzed the cases for Epstein-Barr virus (EBV) RNA using a sensitive and specific in situ hybridization method. Morphologically, the cases consisted of nine large cell immunoblastic lymphomas, one diffuse mixed cell lymphoma, one diffuse small cleaved lymphoma, one small noncleaved lymphoma, and two cases unclassifiable in the Working Formulation. Eleven cases demonstrated evidence of T lineage, two were of B lineage and one of indeterminate immunophenotype. In 13 of the lymphoma cases including all of the T-cell lymphomas, EBV RNA was detected in a high percentage of cells. Double-labeling immunohistochemical and in situ hybridization studies identified CD43 positivity in the cells labeling for EBV RNA. Much smaller amounts of EBV RNA were detectable in six of eight control benign nasopharyngeal biopsy specimens, and two were completely negative. These findings are similar to the prevalence of EBV-positive T-cell lymphomas in Asian countries and differ from the findings of the more common EBV-negative B-cell nasal lymphomas in the United States. These findings suggest that EBV plays a role in the development of nasal T-cell lymphomas and that the incidence of EBV infection may explain the reported "East-West" difference in the incidence of nasal T-cell lymphomas.

    View details for Web of Science ID A1993KT99100010

    View details for PubMedID 8388175



    A highly sensitive in situ hybridization methodology for Epstein-Barr virus (EBV) RNA was used to determine the topography of EBV infection in 16 cases of human immunodeficiency virus-associated lymphoid tissues. Four lymphomas, 11 persistent generalized lymphadenopathy (PGL) lymph nodes, and one lymphoepithelial cyst were studied. The pattern of EBV infection was diffuse in all lymphoma cases and predominantly interfollicular in PGL nodes. No discernable pattern of infection was present in the lymphoepithelial cyst. Germinal center cells were also infected in seven of the PGL cases, and this pattern predominated in one case. Double labeling immunohistochemistry/in situ hybridization studies on four cases of PGL indicated that the EBV infection was primarily involving B-lymphocytes, but rare infected T-lymphocytes were also identified. These studies further clarify the pattern and cellular site of EBV infection in human immunodeficiency virus-related lymphoid disease.

    View details for Web of Science ID A1992JP04900017

    View details for PubMedID 1344820

  • A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. Modern pathology Ozawa, M. G., Bhaduri, A., Chisholm, K. M., Baker, S. A., Ma, L., Zehnder, J. L., Luna-Fineman, S., Link, M. P., Merker, J. D., Arber, D. A., Ohgami, R. S. 2016; 29 (10): 1212-1220


    Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.Modern Pathology advance online publication, 24 June 2016; doi:10.1038/modpathol.2016.102.

    View details for DOI 10.1038/modpathol.2016.102

    View details for PubMedID 27338637

  • Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma. Human pathology Fernandez-Pol, S., Bangs, C. D., Cherry, A., Arber, D. A., Gratzinger, D. 2016; 55: 39-43


    Histiocytic sarcoma is rare and difficult to distinguish from histologic mimics such as myeloid sarcoma due to its relatively nonspecific immunoprofile. A subset of histiocytic sarcomas are clonally related to synchronous or metachronous follicular lymphomas. Interestingly, the histiocytic tumor component has been shown to harbor BCL2 gene translocations that are identical to those found in the lymphoma. We present one case of histiocytic sarcoma and initially occult follicular lymphoma in which detection of a BCL2 gene translocation helped support the diagnosis. We also provide follow up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma. Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis. Testing for an IGH/BCL2 translocation should be considered in the diagnostic workup of difficult to characterize neoplasms with histiocytic/monocytic morphology and immunoprofile.

    View details for DOI 10.1016/j.humpath.2016.04.004

    View details for PubMedID 27134111

  • Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia Khodadoust, M. S., Luo, B., Medeiros, B. C., Johnson, R. C., Ewalt, M. D., Schalkwyk, A. S., Bangs, C. D., Cherry, A. M., Arai, S., Arber, D. A., Zehnder, J. L., Gotlib, J. 2016; 30 (4): 947-950

    View details for DOI 10.1038/leu.2015.136

    View details for PubMedID 26055304

  • An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified HUMAN PATHOLOGY Hoffmann, J. C., Chisholm, K. M., Cherry, A., Chen, J., Arber, D. A., Natkunam, Y., Warnke, R. A., Ohgami, R. S. 2016; 48: 9-17
  • Primary Gastric Hodgkin's Lymphoma: An Extremely Rare Entity and A Diagnostic Challenge DIGESTIVE DISEASES AND SCIENCES Sethi, S., Higgins, J. P., Arber, D. A., Visser, B., Banerjee, S. 2015; 60 (10): 2923-2926
  • Surface Light Chain Expression in Primary Mediastinal Large B-Cell Lymphomas by Multiparameter Flow Cytometry AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weinberg, O. K., Rodig, S. J., Pozdnyakova, O., Ren, L., Arber, D. A., Ohgami, R. S. 2015; 144 (4): 635-641


    Primary mediastinal large B-cell lymphoma (PMLBL) is an aggressive B-cell lymphoma typically localized to the mediastinum. To date, no study has undertaken a comprehensive analysis of this entity by multiparameter flow cytometry.Cases of PMLBL with diagnostic flow cytometry were identified from pathology databases of Boston Children's Hospital, Brigham and Women's Hospital, and Stanford Hospital.Most of these patients with PMLBL were women with a median age of 30 years who had stage 1 disease that lacked bone marrow involvement. By flow cytometry, 50% of all PMLBLs showed restricted surface immunoglobulin expression. When comparing patients with PMLBL by the absence or presence of surface light chain immunoglobulins, no differences were seen in the morphologic appearance; expression of CD23, CD30, or CD10; age at presentation; or clinical stage (P > .5 for all). In addition, both groups showed similarly good survival outcomes and were alive at last follow-up (11/14 [79%]; P = .542).This multi-institutional study demonstrates that 50% of PMLBLs can present with clonal surface light chain expression and that PMLBL is more immunophenotypically diverse than previously described. Furthermore, our findings suggest that the absence or presence of surface light chains should not be used as criteria for diagnosis in this disease.

    View details for DOI 10.1309/AJCP3Q1DHWKCQRWY

    View details for Web of Science ID 000361565000013

  • Cytogenetic Variation of B-Lymphoblastic Leukemia With Infrachromosomal Amplification of Chromosome 21 (iAMP21) A Multi-Institutional Series Review AMERICAN JOURNAL OF CLINICAL PATHOLOGY Johnson, R. C., Weinberg, O. K., Cascio, M. J., Dahl, G. V., Mitton, B. A., Silverman, L. B., Cherry, A. M., Arber, D. A., Ohgami, R. S. 2015; 144 (1): 103-112


    B-lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21) is a relatively uncommon manifestation of acute leukemia and limited predominantly to the pediatric population. Case-specific information regarding flow cytometric, morphologic, and laboratory findings of this subtype of leukemia is currently lacking.We searched the databases of three large institutions for lymphoblastic leukemia with iAMP21 from 2005 through 2012 and analyzed the clinicopathologic features.We identified 17 cases with five or more RUNX1 signals on interphase nuclei, 14 of which were consistent with the Children's Oncology Group (COG) definition for iAMP21?namely, the presence of three or more RUNX1 signals on one marker chromosome. These cases showed a statistically significant lower peripheral WBC count and older age at diagnosis compared with all pediatric cases of B-ALL. We also identified three cases with increased RUNX1 signals scattered on multiple marker chromosomes that did not meet the COG definition of iAMP21 but showed similar 21q instability and older age at presentation.Our findings not only demonstrate that B-ALL with iAMP21 is truly a distinct clinicopathologic entity but also suggest that a subset of cases of B-ALL with iAMP21 can show variable cytogenetic features.

    View details for DOI 10.1309/AJCPLUYF11HQBYRB

    View details for Web of Science ID 000356753300012

  • The diagnostic and clinical impact of genetics and epigenetics in acute myeloid leukemia INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Ohgami, R. S., Arber, D. A. 2015; 37: 122-132


    Acute myeloid leukemia (AML) is a complex disease, for which our understanding of the role of genetic and epigenetic changes has undergone significant advancements. Newer diagnostic and prognostic classifications have increasingly incorporated such information, and novel therapies have been developed to target specific genes, processes, and pathways based on this growing understanding. Given the rapid evolution of this field, it is critical for physicians and translational researchers to have a more in-depth understanding of this evolving landscape. Here, we review both genetics and epigenetics in acute myeloid leukemia from a practical standpoint.

    View details for DOI 10.1111/ijlh.12367

    View details for Web of Science ID 000354561000019

  • Mast Cells in Systemic Mastocytosis Have Distinctly Brighter CD45 Expression by Flow Cytometry AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chisholm, K. M., Merker, J. D., Gotlib, J. R., Gitana, G., Lefterova, M., Zehnder, J. L., George, T. I., Arber, D. A., Ohgami, R. S. 2015; 143 (4): 527-534


    We sought to determine the significance of bright CD45 expression on mast cells in cases of systemic mastocytosis vs mast cells in bone marrows uninvolved by systemic mastocytosis and compare this CD45 expression with CD25 and CD2 expression on mast cells.Multiparameter flow cytometry was performed on 31 cases of systemic mastocytosis and 70 bone marrow cases that were not involved by systemic mastocytosis. Bright expression of CD45 was defined as more than 20% of CD117+ mast cells showing brighter CD45 expression than the average expression level of lymphocytes.Mast cells with bright CD45 expression were seen in 26 systemic mastocytosis cases and three bone marrows uninvolved by systemic mastocytosis (sensitivity, 84%; specificity, 96%). CD25 alone had a greater sensitivity (100%) but lower specificity (93%) compared with bright CD45 for identifying abnormal mast cells, while CD2 alone had lower sensitivity but higher specificity. To reach a specificity of 100%, CD25 together with bright CD45 on mast cells was the optimal combination to detect cases of systemic mastocytosis.A combination of bright CD45 and CD25 appears to specifically identify abnormal mast cells in cases of systemic mastocytosis. Further studies will be necessary to confirm these results.

    View details for DOI 10.1309/AJCPZ3J4GEEYIRRA

    View details for Web of Science ID 000351331200009

  • The utility of IgM, CD21, HGAL and LMO2 in the diagnosis of pediatric follicular lymphoma HUMAN PATHOLOGY Karnik, T., Ozawa, M. G., Lefterova, M., Luna-Fineman, S., Alvarez, E., Link, M., Zehnder, J. L., Arber, D. A., Ohgami, R. S. 2015; 46 (4): 629-633


    Pediatric follicular lymphoma (pFL) is a rare neoplasm with features differing from follicular lymphoma arising in adults. Here, we describe a rare case of pFL that showed morphologic features partially overlapping with progressive transformation of germinal centers and reactive follicular hyperplasia. As typical of pFL, neoplastic B cells within follicles did not express B-cell leukemia/lymphoma 2 (BCL2). However, this case showed additional distinctive abnormal findings, which contributed to the diagnosis: (1) diffuse and uniform staining of immunoglobulin M (IgM) on cells within and outside of follicles, (2) abnormally dim expression of CD21 on follicular dendritic cells, and (3) expression of human germinal center-associated lymphoma (HGAL) and LIM domain only 2 (LMO2) on B cells in interfollicular and follicular areas. This case demonstrates the utility of these abnormal features, which can be seen in adult- or usual-type follicular lymphoma, in the diagnosis of pFL. Further studies are necessary to evaluate the significance of these findings in other cases of pFL.

    View details for DOI 10.1016/j.humpath.2014.12.016

    View details for Web of Science ID 000352117000020

  • Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proceedings of the National Academy of Sciences of the United States of America Green, M. R., Kihira, S., Liu, C. L., Nair, R. V., Salari, R., Gentles, A. J., Irish, J., Stehr, H., Vicente-Dueas, C., Romero-Camarero, I., Sanchez-Garcia, I., Plevritis, S. K., Arber, D. A., Batzoglou, S., Levy, R., Alizadeh, A. A. 2015; 112 (10): E1116-25


    Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.

    View details for DOI 10.1073/pnas.1501199112

    View details for PubMedID 25713363

  • Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Green, M. R., Kihira, S., Liu, C. L., Nair, R. V., Salari, R., Gentles, A. J., Irish, J., Stehr, H., Vicente-Duenas, C., Romero-Camarero, I., Sanchez-Garcia, I., Plevritis, S. K., Arber, D. A., Batzoglou, S., Levy, R., Alizadeh, A. A. 2015; 112 (10): E1116-E1125
  • Best Practices in Diagnostic Immunohistochemistry Workup of Cutaneous Lymphoid Lesions in the Diagnosis of Primary Cutaneous Lymphoma ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Dewar, R., Andea, A. A., Guitart, J., Arber, D. A., Weiss, L. M. 2015; 139 (3): 338-350


    Primary cutaneous lymphoma is a common extranodal non-Hodgkin lymphoma. These lesions share common features with their nodal counterparts, but also have differences in morphology, unique clinical presentations, and immunohistochemical features.To review the 2008 World Health Organization (WHO) and 2005 consensus WHO-EORTC (European Organisation for Research and Treatment of Cancer) classifications, and address the immunohistochemical findings in the most common primary cutaneous T- and B-cell lymphomas. Since clonality testing is commonly used as an ancillary test in the evaluation of cutaneous lymphoma, a brief section in the use and pitfalls of clonality testing is included.The WHO and EORTC classification publications and the relevant recent literature were used to compile appropriate and practical guidelines in this review.The practice of dermatopathology and hematopathology varies widely. Thus, while this review provides an overview and guideline for the workup of lymphoid lesions of the skin, the practitioner should understand the importance of clinical correlation as well as appropriate utility of available resources (such as clonality testing) in arriving at a diagnosis in cutaneous lymphoid lesions.

    View details for DOI 10.5858/arpa.2014-0018-CP

    View details for Web of Science ID 000352223200009

    View details for PubMedID 25724031

  • Reactive lymphoid hyperplasia of the terminal ileum: a benign (lymphoma-like) condition that may harbor aberrant immunohistochemical patterns or clonal immunoglobulin heavy chain gene rearrangements. Applied immunohistochemistry & molecular morphology Mojtahed, A., Pai, R. K., Anderson, M. W., Arber, D. A., Longacre, T. A. 2014; 22 (8): 585-592


    Small endoscopic biopsies of the terminal ileum may be difficult to assess for early involvement by lymphoma. Immunophenotypic and genotypic analyses are often utilized, but the performance of these studies in this setting is not well defined. Terminal ileal biopsies from 66 patients with prominent lymphoid hyperplasia and abnormal "lymphoma-like" morphology were evaluated by immunohistochemistry (IHC) for CD3, CD5, CD43, CD20, CD21, and CD10 expression and for IGH@ gene rearrangement by polymerase chain reaction using BIOMED-2 primers. Patients ranged in age from 3 to 80 years. Indications for endoscopy included inflammatory bowel disease (29), diarrhea and/or abdominal pain (28), history of lymphoma (13), and others (4). Four biopsies with abnormal morphology had abnormal IHC and a clonal IGH@ peak; all were obtained from patients with a history of lymphoma and determined to be recurrent lymphoma. Three biopsies with abnormal morphology and abnormal IHC but no clonal IGH@ peak were obtained from patients with a history of lymphoma (2) and chronic diarrhea (1); all showed symptom resolution or remission of disease (mean follow-up, 37 mo). Eight biopsies with abnormal morphology but no abnormal IHC expression also had abnormal IGH@ results (4 clonal and 4 borderline). IGH@ evaluation of follow-up biopsies for these cases were nonclonal (7) or clonal, but with a different clone from the prior biopsy (1); follow-up of the 8 patients showed no evidence of lymphoma (mean, 37.8 mo). Abnormal IHC expression pattern or clonal IGH@ rearrangement in endoscopic biopsies of the lymphoid-rich terminal ileum do not necessarily warrant a diagnosis of lymphoma. To prevent misdiagnosis, B-cell clonality studies should only be performed when there is strong clinical suspicion for lymphoma and compelling IHC data; the absence of a reproducible clone in repeat biopsy specimens may be useful in patients that do not have other clinical evidence of lymphoma.

    View details for DOI 10.1097/01.pai.0000446497.93867.98

    View details for PubMedID 24897069

  • Reactive Lymphoid Hyperplasia of the Terminal Ileum: A Benign (Lymphoma-like) Condition That May Harbor Aberrant Immunohistochemical Patterns or Clonal Immunoglobulin Heavy Chain Gene Rearrangements APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Mojtahed, A., Pai, R. K., Anderson, M. W., Arber, D. A., Longacre, T. A. 2014; 22 (8): 585-592
  • Acute Myeloid Leukemia With Monosomal Karyotype Morphologic, Immunophenotypic, and Molecular Findings AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weinberg, O. K., Ohgami, R. S., Ma, L., Seo, K., Ren, L., Gotlib, J. R., Seetharam, M., Cherry, A., Arber, D. A. 2014; 142 (2): 190-195


    Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype.In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al.Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML-MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK.Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group.

    View details for DOI 10.1309/AJCPMLO84JDNVLNK

    View details for Web of Science ID 000339415400009

  • STAT3 mutations are present in aggressive B-cell lymphomas including a subset of diffuse large B-cell lymphomas with CD30 expression. Haematologica Ohgami, R. S., Ma, L., Monabati, A., Zehnder, J. L., Arber, D. A. 2014; 99 (7): e105-7



    View details for DOI 10.3324/haematol.2013.101543

    View details for PubMedID 24837465

  • New-onset pancytopenia: a diagnostic approach-reply. Human pathology Weinzierl, E., Arber, D. A. 2014; 45 (7): 1552-1553

    View details for DOI 10.1016/j.humpath.2013.10.041

    View details for PubMedID 24796507

  • E-Cadherin Is a Specific Marker for Erythroid Differentiation and Has Utility, in Combination With CD117 and CD34, for Enumerating Myeloblasts in Hematopoietic Neoplasms AMERICAN JOURNAL OF CLINICAL PATHOLOGY Ohgami, R. S., Chisholm, K. M., Ma, L., Arber, D. A. 2014; 141 (5): 656-664


    Objectives E-cadherin, epithelial calcium-dependent cell adhesion protein, has been identified as a marker of immature erythroid precursors in recent years. However, the specificity of E-cadherin in bone marrow specimens for erythroblasts vs myeloblasts or other early hematopoietic precursors in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has not been fully elucidated. Methods We analyzed 105 cases of AML and MDS to evaluate the specificity of E-cadherin. Results Of 84 cases of AML, including cases with megakaryocytic, erythroid, monocytic, and granulocytic differentiation, all five acute erythroleukemia cases were positive, as well as one case of megakaryoblastic leukemia that showed coexpression of glycophorin A. In addition, we demonstrate that a panel of three markers, E-cadherin, CD117, and CD34, is effective in identifying lineage-specific myeloblasts in cases of MDS where left-shifted erythroid hyperplasia may complicate morphologic assessment of myeloblasts. Conclusions In marrow specimens, E-cadherin is a useful marker for erythroid differentation.

    View details for DOI 10.1309/AJCP8M4QQTAZPGRP

    View details for Web of Science ID 000335200400007

  • Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study HAEMATOLOGICA Rogers, H. J., Vardiman, J. W., Anastasi, J., Raca, G., Savage, N. M., Cherry, A. M., Arber, D., Moore, E., Morrissette, J. J., Bagg, A., Liu, Y., Mathew, S., Orazi, A., Lin, P., Wang, S. A., Bueso-Ramos, C. E., Foucar, K., Hasserjian, R. P., Tiu, R. V., Karafa, M., Hsi, E. D. 2014; 99 (5): 821-829


    Acute myeloid leukemia and myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) have a poor prognosis. Indeed, the inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has been recognized as a poor risk karyotype in the revised International Prognostic Scoring System. However, inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is not among the cytogenetic abnormalities pathognomonic for diagnosis of acute myeloid leukemia irrespective of blast percentage in the 2008 WHO classification. This multicenter study evaluated the clinico-pathological features of acute myeloid leukemia/myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and applied the revised International Prognostic Scoring System to myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2). A total of 103 inv(3)(q21q26.2)/t(3;3)(q21;q26.2) patients were reviewed and had a median bone marrow blast count of 4% in myelodysplastic syndrome (n=40) and 52% in acute myeloid leukemia (n=63) (P<0.001). Ninety-one percent of patients showed characteristic dysmegakaryopoiesis. There was no difference in overall survival between acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) (12.9 vs. 7.9 months; P=0.16). Eighty-three percent of patients died (median follow up 7.9 months). Complex karyotype, monosomal karyotype and dysgranulopoiesis (but not blast percentage) were independent poor prognostic factors in the entire cohort on multivariable analysis. The revised International Prognostic Scoring System better reflected overall survival of inv(3)(q21q26.2)/t(3;3)(q21;q26.2) than the International Prognostic Scoring System but did not fully reflect the generally dismal prognosis. Our data support consideration of myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) as an acute myeloid leukemia with recurrent genetic abnormalities, irrespective of blast percentage.

    View details for DOI 10.3324/haematol.2013.096420

    View details for Web of Science ID 000336257500009

  • Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms BLOOD Wang, S. A., Hasserjian, R. P., Fox, P. S., Rogers, H. J., Geyer, J. T., Chabot-Richards, D., Weinzierl, E., Hatem, J., Jaso, J., Kanagal-Shamanna, R., Stingo, F. C., Patel, K. P., Mehrotra, M., Bueso-Ramos, C., Young, K. H., DiNardo, C. D., Verstovsek, S., Tiu, R. V., Bagg, A., Hsi, E. D., Arber, D. A., Foucar, K., Luthra, R., Orazi, A. 2014; 123 (17): 2645-2651


    Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN-U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters.

    View details for DOI 10.1182/blood-2014-02-553800

    View details for Web of Science ID 000335895800016

    View details for PubMedID 24627528

  • Challenges in Consolidated Reporting of Hematopoietic Neoplasms. Surgical pathology clinics Ohgami, R. S., Arber, D. A. 2013; 6 (4): 795-806


    This article focuses on the challenges of generating comprehensive diagnostic reports in hematopathology. In particular, two main challenges that diagnosticians face are (1) interpreting and understanding the rapid advances in molecular and genetic pathology, which have gained increasing importance in classifications of hematopoietic neoplasms, and (2) managing the logistics of reporting ancillary studies and incorporating them effectively into a final synthesized report. This article summarizes many important genetic findings in hematopoietic neoplasms, which are required for accurate diagnoses, and discusses practical issues to generating accurate and complete hematopathology reports.

    View details for DOI 10.1016/j.path.2013.08.001

    View details for PubMedID 26839198

  • Hidden Mastocytosis in Acute Myeloid Leukemia With t(8;21)(q22;q22) AMERICAN JOURNAL OF CLINICAL PATHOLOGY Johnson, R. C., Savage, N. M., Chiang, T., Gotlib, J. R., Cherry, A. M., Arber, D. A., George, T. I. 2013; 140 (4): 525-535


    Objectives: To assess the frequency of systemic mastocytosis (SM) in a large series of acute myeloid leukemia (AML) with t(8;21)(q22;q22). Methods: We retrospectively characterized 40 bone marrow aspirate smears and biopsy specimens from patients with AML with t(8;21) for the presence of SM. Cases were assessed for mast cell morphology and immunohistochemistry, as well as KIT exon 8 and 17 mutational assessment by reverse transcription polymerase chain reaction. Results: Four patients met criteria for SM, 1 met criteria for myelomastocytic leukemia, and 8 demonstrated the benign finding of mast cell hyperplasia. Conclusions: We recommend examining all cases of AML with t(8;21) for the presence of SM via morphology, immunophenotyping, and KIT mutational analysis studies.

    View details for DOI 10.1309/AJCP1Q0YSXEAHNKK

    View details for Web of Science ID 000330099800010

    View details for PubMedID 24045550

  • B-Cell Transcription Factor Expression and Immunoglobulin Gene Rearrangement Frequency in Acute Myeloid Leukemia With t(8;21)(q22;q22) AMERICAN JOURNAL OF CLINICAL PATHOLOGY Johnson, R. C., Ma, L., Cherry, A. M., Arber, D. A., George, T. I. 2013; 140 (3): 355-362


    Objectives: To assess a large series of patients with acute myeloid leukemia (AML) with t(8;21) for both IGH@ and IGK@ B-cell gene rearrangements and for expression of PAX5, OCT2, and Bob.1 by immunohistochemistry and expression of CD19, CD79a, CD20, and CD22 by flow cytometry immunophenotyping. Methods: A total of 48 cases of AML with t(8;21)(q22;q22) were evaluated by immunohistochemistry and/or heavy chain and light chain immunoglobulin rearrangement studies where paraffin-embedded and/or fresh frozen material was available for study; previously performed flow cytometry studies were also reviewed in available cases. Results: Our study yielded 1 of 19 cases of AML with t(8;21) with an IGH@ gene rearrangement; blasts were associated with weak PAX5 expression. In addition, expression of antigens CD79a by flow cytometry and OCT2 by immunohistochemistry were highly associated with PAX5 expression, and CD19 was expressed in most cases assessed. Conclusions: Although B-cell antigen and B-cell transcription factor expression is seen in the majority of AMLs with t(8;21)(q22;q22) and correlates with PAX5 expression, immunoglobulin gene rearrangements are an uncommon event in this group of leukemias.

    View details for DOI 10.1309/AJCPFBCFXP94AKWJ

    View details for Web of Science ID 000323359800011

    View details for PubMedID 23955454

  • Acute myeloid leukemia, version 2.2013. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Tallman, M. S., Abboud, C. N., Altman, J. K., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Lancet, J., Maness, L. J., Marcucci, G., Martin, M. G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Wang, E. S., Gregory, K. M., Naganuma, M. 2013; 11 (9): 1047-1055


    These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.

    View details for PubMedID 24029121

  • Acute Myeloid Leukemia, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Tallman, M. S., Abboud, C. N., Altman, J. K., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Lancet, J., Maness, L. J., Marcucci, G., Martin, M. G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Wang, E. S., Gregory, K. M., Naganuma, M. 2013; 11 (9): 1047-1055
  • Pediatric Acute Myeloid Leukemia as Classified Using 2008 WHO Criteria A Single-Center Experience AMERICAN JOURNAL OF CLINICAL PATHOLOGY Davis, K. L., Marina, N., Arber, D. A., Ma, L., Cherry, A., Dahl, G. V., Heerema-McKenney, A. 2013; 139 (6): 818-825


    The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

    View details for DOI 10.1309/AJCP59WKRZVNHETN

    View details for Web of Science ID 000319302200017

    View details for PubMedID 23690127

  • Bone marrow evaluation in new-onset pancytopenia. Human pathology Weinzierl, E. P., Arber, D. A. 2013; 44 (6): 1154-1164


    The new onset of pancytopenia often creates a diagnostic dilemma to the treating physician and leads to bone marrow biopsy and aspiration. To determine the distribution of bone marrow findings in such cases of new-onset pancytopenia in a tertiary academic medical center, we evaluated 250 recent bone marrow aspirates and biopsies performed in the setting of new-onset pancytopenia in patients without previously diagnosed hematologic neoplastic disease. Of the 250 bone marrow studies, 193 were performed in adults and 57 were performed in children. In children, the most prevalent bone marrow finding was B-lymphoblastic leukemia, followed by nonspecific changes attributed clinically to a variety of factors including multifactorial, autoimmune, inflammatory, and infectious etiologies. In adults, hematologic neoplastic causes of pancytopenia were the most prevalent diagnoses, with the cases divided mostly between acute myeloid leukemia and myelodysplastic syndrome, with fewer numbers of cases of acute lymphoblastic leukemia, myeloproliferative neoplasms, and lymphomas. Many bone marrow findings demonstrated nonspecific changes that were attributed clinically to a variety of etiologies such as myelodysplastic syndrome, multifactorial causes, hypersplenism, drugs, and systemic disease. Overall, in both the pediatric and the adult population, new-onset pancytopenia was most commonly associated with neoplasia, although the neoplasm differed by age group. Although in most cases, a definitive diagnosis could be made based solely on bone marrow aspirate and biopsy interpretation, a significant fraction of cases in both children and adults demonstrated nonspecific marrow findings that required clinical follow-up and/or repeat biopsy for definitive diagnosis.

    View details for DOI 10.1016/j.humpath.2012.10.006

    View details for PubMedID 23332933

  • Indolent T-Lymphoblastic Proliferation (iT-LBP): A Review of Clinical and Pathologic Features and Distinction from Malignant T-Lymphoblastic Lymphoma ADVANCES IN ANATOMIC PATHOLOGY Ohgami, R. S., Arber, D. A., Zehnder, J. L., Natkunam, Y., Warnke, R. A. 2013; 20 (3): 137-140


    In recent years, a new pathologic entity has emerged: indolent T-lymphoblastic proliferation (iT-LBP). iT-LBPs share immunophenotypic similarities with T-lymphoblastic lymphoma; however, T-lymphoblastic proliferations are clinically indolent, and unlike the malignant counterpart, these expansions of nonclonal terminal deoxynucleotidyl transferase (TdT)+ T cells do not require treatment. Here we review the clinical and pathologic features, which are required for an accurate diagnosis of an iT-LBP. We demonstrate specific criteria can be used to accurately diagnose iT-LBP, notably: (1) confluent groups of TdT+ T cells in a biopsy specimen, (2) relative preservation of surrounding normal lymphoid architecture, (3) TdT+ T cells without morphologic atypia, (4) absence of thymic epithelium, (5) nonclonal TdT+ T cells, (6) immunophenotype of developmentally normal immature thymic T cells, and (7) clinical evidence of indolence (follow-up >6 mo without progression).

    View details for DOI 10.1097/PAP.0b013e31828d17ec

    View details for Web of Science ID 000317588700001

  • Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Pang, W. W., Pluvinage, J. V., Price, E. A., Sridhar, K., Arber, D. A., Greenberg, P. L., Schrier, S. L., Park, C. Y., Weissman, I. L. 2013; 110 (8): 3011-3016


    Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.

    View details for DOI 10.1073/pnas.1222861110

    View details for Web of Science ID 000315954400082

  • A Detailed Flow Cytometry Analysis of the Immune System in Non-Leukemic Cells of Acute Myeloid Leukemia Demonstrates the Prognostic Significance of Lymphocyte Subsets Ohgami, R. S., Alcasid, M., Ren, L., Gotlib, J. R., Arber, D. A. NATURE PUBLISHING GROUP. 2013: 353A-354A
  • Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival in Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2); a Bone Marrow Pathology Group Study Rogers, H. J., Vardiman, J. W., Anastasi, J., Raca, G., Savage, N. M., Cherry, A. M., Arber, D., Moore, E., Morrissette, J. J., Bagg, A., Liu, Y., Mathew, S., Orazi, A., Lin, P., Wang, S. A., Bueso-Ramos, C. E., FOUCAR, K., Hasserjian, R. P., Hsi, E. D. NATURE PUBLISHING GROUP. 2013: 358A-358A
  • The Pathologist's Approach to T-Cell Large Granular Lymphocytic Leukemia Diagnosis: A Multicenter Comparative Study by the Bone Marrow Pathology Group Neff, J. L., Fan, X., Ohgami, R., Wu, Y., Choi, S. M., King, R. L., Tagliente, D. J., Bagg, A., Orazi, A., Arber, D. A., Wang, S. A., Morice, W. G. NATURE PUBLISHING GROUP. 2013: 351A-351A
  • A Detailed Clinicopathologic Review of Castleman Disease Demonstrates That Atypical/Dysplastic Follicular Dendritic Cells Positive for SOX11, S-100, CXCL13, or D2-40 Are a Frequent Finding in Hyaline Vascular and Plasma Cell Variants Ohgami, R. S., Alcasid, M., Warnke, R. A., Arber, D. A. NATURE PUBLISHING GROUP. 2013: 353A-353A
  • The Prognostic Value of CXCR4 in Acute Myeloid Leukemia APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Ahn, J. Y., Seo, K., Weinberg, O. K., Arber, D. A. 2013; 21 (1): 79-84


    CXC chemokine receptor (CXCR4) has been shown to be expressed in a subset of acute myeloid leukemia (AML) patients and is correlated with a poor prognosis. CXCR4 expression appears to be an independent prognostic factor for survival in a heterogeneous group of AML patients. To better assess its significance, we analyzed CXCR4 expression in a group of AML patients.The prognostic value of CXCR4 expression in 53 patients with AML presenting between 2003 and 2008 was analyzed. Formalin-fixed, paraffin-embedded bone marrow biopsy or clot sections were stained using immunohistochemical methods.CXCR4 was expressed in 26 patients (49.1%). A patient age of less than 60 years (P=0.023), achievement of complete remission after induction therapy (P<0.001), and no CXCR4 expression (P=0.010) were all associated with better progression-free survival (PFS). Among mutations of NPM1, CEBPA, FLT3 ITD, and FLT3 D835 and expression of CXCR4, only CXCR4 expression was associated with PFS (P=0.010; by log-rank test). By multivariate analysis, CXCR4 expression was an independent prognostic factor (P=0.001 for PFS and P=0.001 for overall survival). CXCR4 expression in patients with a normal karyotype was detected in 15 of 22 patients (68.2%, relative ratio 4.46, P=0.035). Expression of CXCR4 in normal-karyotype AML showed inferior PFS (median 2.0 vs. 10.7 mo, P=0.026) and had a trend toward inferior overall survival (median 10.8 vs. 14.0 mo, P=0.058).These results suggest that CXCR4 expression is associated with poor prognosis in patients with AML. Specifically, CXCR4 expression is common in normal-karyotype AML and is a marker of more aggressive disease in this population. CXCR4 expression could be incorporated into the risk assessment of patients with AML.

    View details for Web of Science ID 000313153100010

    View details for PubMedID 22914607

  • TdT(+) T-lymphoblastic Populations Are Increased in Castleman Disease, in Castleman Disease in Association With Follicular Dendritic Cell Tumors, and in Angioimmunoblastic T-cell Lymphoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ohgami, R. S., Zhao, S., Ohgami, J. K., Leavitt, M. O., Zehnder, J. L., West, R. B., Arber, D. A., Natkunam, Y., Warnke, R. A. 2012; 36 (11): 1619-1628


    T-lymphoblastic lymphoma is an aggressive neoplasm requiring prompt clinical treatment. Conversely, indolent T-lymphoblastic proliferation mimics T-lymphoblastic lymphoma but consists of a proliferation of non-neoplastic TdT+ T cells, requiring no treatment. Recently, we identified several cases of indolent T-lymphoblastic proliferations in extrathymic lymphoid tissues: 1 in a patient suffering from Castleman disease (CD) associated with a follicular dendritic cell sarcoma/tumor, 1 in a patient with a history of angioimmunoblastic T-cell lymphoma (AITL), and 1 in association with acinic cell carcinoma. Interestingly, in the case of the patient with a history of AITL, these TdT+ T cells were seen in multiple anatomic sites over the span of 5 years. Here we review these 3 cases and extend our findings by demonstrating that TdT+ T-lymphoblastic populations are increased in lymph nodes of patients with CD (P=0.011), CD in association with follicular dendritic cell tumors, and AITL (P<0.01) compared with other T-cell or B-cell lymphomas or reactive lymph nodes. Finally, analysis of 352 nonhematolymphoid tumors including carcinomas, melanomas, and sarcomas demonstrates that TdT+ T cells are not increased in these tumors. Our studies not only present several detailed cases of indolent T-lymphoblastic proliferations, but also correlate these populations with specific hematologic diseases.

    View details for DOI 10.1097/PAS.0b013e318264e223

    View details for Web of Science ID 000310059600004

    View details for PubMedID 23060347

  • Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features MODERN PATHOLOGY Chang, D. T., Pai, R. K., Rybicki, L. A., DiMaio, M. A., Limaye, M., Jayachandran, P., Koong, A. C., Kunz, P. A., Fisher, G. A., Ford, J. M., Welton, M., Shelton, A., Ma, L., Arber, D. A., Pai, R. K. 2012; 25 (8): 1128-1139


    Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (?40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients >40 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients ?40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients >40 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (P<0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P=0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P=0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P=0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P=0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P=0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two groups with regard to tumor stage, tumor size, number of lymph node metastases, lymphatic invasion, tumor budding, mucinous histology, or tumor-infiltrating lymphocytes. Both groups had similar recurrence-free (P=0.28) and overall survival (P=0.73). However, patients in the early-onset colorectal carcinoma group more frequently either presented with or developed metastatic disease during their disease course compared with the control colorectal carcinoma group (25/55, 45% vs 18/73, 25%, P=0.014). In addition, 8/55 patients (15%) in the early-onset colorectal carcinoma group developed local recurrence of their tumor while no patients in the control colorectal carcinoma group developed local recurrence (P<0.001), likely due to the increased incidence of rectal carcinoma in the patients with early-onset colorectal carcinoma. Our study demonstrates that colorectal carcinoma is not infrequently diagnosed in patients ?40 years of age and is not frequently the result of underlying Lynch syndrome or associated with other cancer-predisposing genetic conditions or chronic inflammatory conditions. These tumors have a striking predilection for the distal colon, particularly the sigmoid colon and rectum and are much more likely to demonstrate adverse histologic factors, including signet ring cell differentiation, venous invasion, and perineural invasion.

    View details for DOI 10.1038/modpathol.2012.61

    View details for Web of Science ID 000307222200008

    View details for PubMedID 22481281

  • Acute myeloid leukemia. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Goorha, S., Lancet, J., Maness, L. J., Marcucci, G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S., Naganuma, M., Gregory, K. M. 2012; 10 (8): 984-1021


    Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ? 65 years) adult patients, and key supportive care considerations.

    View details for PubMedID 22878824

  • Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Kohrt, H. E., Gotlib, J., Coutre, S. E., Zhang, B., Arber, D. A., Zehnder, J. L. 2012; 87 (1): 45-50


    Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on as #NCT00611247.

    View details for DOI 10.1002/ajh.22191

    View details for Web of Science ID 000298257700010

    View details for PubMedID 22052619

  • Immature T-Cell Populations in Lymph Nodes of Castleman Disease and Angioimmunoblastic T-Cell Lymphoma Suggest Alternate Sites of T-Cell Development Ohgami, R. S., Chun, S., Ohgami, J., Zehnder, J. L., Van de Rijn, M., Arber, D. A., Natkunam, Y., Warnke, R. AMER SOC HEMATOLOGY. 2011: 1395-1396
  • The frequency of dual TCR-PCR clonality in granulomatous disorders JOURNAL OF CUTANEOUS PATHOLOGY Dabiri, S., Morales, A., Ma, L., Sundram, U., Kim, Y. H., Arber, D. A., Kim, J. 2011; 38 (9): 704-709


    A granulomatous infiltrate in association with cutaneous T-cell lymphoma is uncommon. The diagnosis of mycosis fungoides can be difficult in the setting of an exuberant granulomatous infiltrate that obscures the neoplastic lymphoid infiltrate, thereby mimicking a granulomatous dermatitis. Therefore, the clinical context and supplemental molecular analysis, such as the demonstration of a monoclonal T-cell population, may assist in diagnosis. Monoclonal T-cell populations have been reported in association with inflammatory conditions and serve as a diagnostic pitfall. The frequency of T-cell clonality in association with granulomatous dermatitides has not yet been established.We identified 29 patients with granulomatous dermatitis who had biopsies at two distinct body sites. Results were correlated with clinical follow up and with clonal T-cell receptor-gamma chain rearrangement as detected by polymerase chain reaction-based analysis (dual TCR-PCR).Clinical follow up was obtained in 17 of 29 cases (58.6%). Twenty-five of 29 cases of granulomatous dermatitis lacked T-cell monoclonality. Three cases of granuloma annulare contained a T-cell clone in one of the two biopsies. One case of necrobiotic xanthogranuloma showed an identical T-cell clone in multiple biopsies.The use of dual TCR-PCR analysis, that is, T-cell clonality analysis in biopsy specimens from two different sites, serves as an adjunct to assist in distinguishing granulomatous inflammatory reactions from granulomatous T-cell lymphoma, including granulomatous mycosis fungoides. The occasional finding of a T-cell clone in a granulomatous dermatitis underscores the importance of clinicopathological correlation in daily diagnosis.

    View details for DOI 10.1111/j.1600-0560.2011.01727.x

    View details for Web of Science ID 000293177000005

    View details for PubMedID 21645036

  • Histologic and Molecular Analyses of Colonic Perineurial-like Proliferations in Serrated Polyps: Perineurial-like Stromal Proliferations Are Seen in Sessile Serrated Adenomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Mojtahed, A., Rouse, R. V., Soetikno, R. M., Kaltenbach, T., Ma, L., Arber, D. A., Plesec, T. P., Goldblum, J. R., Pai, R. K. 2011; 35 (9): 1373-1380


    Colonic perineuriomas are recently described benign mucosal polyps that are composed of a bland spindle cell proliferation surrounding crypts that often demonstrate hyperplastic/serrated epithelial changes. However, the origin of this unique stromal proliferation is still unclear, and the association with serrated polyps, including sessile serrated adenomas, has not been fully described. We evaluated the pathologic and molecular features of colonic polyps associated with perineurial-like proliferations in 2 retrospective cohorts: (1) a series of 198 consecutive sessile serrated adenomas and (2) 20 colonic polyps diagnosed as a perineurioma irrespective of the presence of serrated colonic crypts. Thirteen of 198 (6.5%) sessile serrated adenomas demonstrated a perineurial-like stromal proliferation, with most (12 of 13, 92%) involving the right (9 cases) and transverse colon (3 cases). In all 13 cases, the perineurial-like proliferation surrounded serrated colonic crypts and typically involved only a small area of the sessile serrated adenoma (average 9% of polyp size; range, 2% to 19%). All 11 polyps evaluated for epithelial membrane antigen (EMA) expression demonstrated stromal EMA staining limited to the perineurial-like proliferation. Twelve of 13 (92%) sessile serrated adenomas with perineurial-like proliferations demonstrated a pV600E BRAF mutation. Of the 20 colonic polyps diagnosed as a perineurioma, 18 (90%) demonstrated serrated crypts intimately associated with the perineurial-like proliferation. In 13 of 18 polyps with associated serrated crypts, all serrated crypts were invested with the perineurial proliferation. In 5 cases, serrated crypts were seen away from the perineurial proliferation. Of these 18 polyps, the majority (16 of 18, 89%) were microvesicular hyperplastic polyps involving the left colon. However, 2 (11%) polyps in the right colon demonstrated histologic features diagnostic of sessile serrated adenoma. All 18 polyps with serrated crypts demonstrated a pV600E BRAF mutation. In contrast, the 2 polyps not associated with serrated crypts were negative for a BRAF mutation. Our results show for the first time that perineurial-like stromal proliferations frequently occur in sessile serrated adenomas. The presence of focal perineurial-like stromal proliferations in sessile serrated adenomas and the common finding of serrated crypts in colonic perineuriomas are likely indicative of an epithelial-stromal interaction, possibly related to some factor elaborated by the serrated epithelium.

    View details for DOI 10.1097/PAS.0b013e318224d9df

    View details for Web of Science ID 000293834400015

    View details for PubMedID 21836484

  • Lymphoma in Pregnancy Initially Diagnosed as Vaginal Intraepithelial Neoplasia and Lichen Planus OBSTETRICS AND GYNECOLOGY Thuong-Thuong Nguyen, T. T., Gubens, M., Arber, D. A., Advani, R., Juretzka, M., Aziz, N. 2011; 118 (2): 486-489


    Non-Hodgkin's lymphoma presenting as a vaginal mass in pregnancy is uncommon.A 38-year-old primigravid woman presented at 27 weeks of gestation with vaginal lesions, bleeding, and discharge. Previous vaginal biopsies had been consistent with vaginal intraepithelial neoplasia 1 and lichen planus. After admission for this enlarging vaginal mass and bleeding, she was noted to have a newly palpable breast mass. Biopsy of the breast mass and subsequent re-evaluation of original vaginal biopsies were consistent with diffuse large B-cell lymphoma. She was treated with chemoimmunotherapy during pregnancy and delivered a viable neonate at term.Although benign vaginal conditions are common, non-Hodgkin's lymphoma should be considered in the differential diagnosis of persistent or enlarging vaginal lesions in pregnancy.

    View details for DOI 10.1097/AOG.0b013e3182234d12

    View details for Web of Science ID 000293115000027

    View details for PubMedID 21768862

  • Quality management in the transfusion service: case studies in process improvement TRANSFUSION Goodnough, L. T., Viele, M., Fontaine, M., Chua, L., Ferrer, Z., Jurado, C., Quach, P., Dunlap, M., Arber, D. A. 2011; 51 (3): 600-609


    Laboratory-based quality improvement (QI) initiatives can improve clinical outcomes and patient safety.We present three cases of QI that impact processes from the transfusion service (TS) laboratory to the patient's bedside.Case 1 was event discovery reporting (EDR). We were able to reduce our biologic product deviation reports from 41 (17%) of 238 EDRs to only 19 (7%) of 272 (p < 0.01) EDRs after implementation of a QI workflow process. Case 2 was antibody evaluation before elective surgery. We implemented process improvement strategies: 1) surgical safety checklist with confirmation of type-and-screen completion and antibody evaluation before patients can proceed to surgery; 2) specimen retention policy of 30 days to allow advance testing; and 3) daily review to identify specimens needed on day of surgery. After intervention, only 7 (0.3%) of 2298 patients required antibody evaluation on day of surgery, compared to 65 (0.75%) of 8656 patients (p < 0.01) before intervention. Case 3 was wrong blood in tube (WBIT). We have a two-specimen requirement for blood type verification before transfusion. To determine whether trauma patients should be exempted, we reviewed WBIT errors. Six WBIT errors were from the emergency department (an error rate of 1:400) and nine WBIT specimens were institution-wide. Three patients were transfused after correction of the WBIT error. Based on this analysis, our institution agreed that no clinical units shall be exempted from our policy.Successful QI in the TS improves processes that promote efficiency, effectiveness, and patient safety.

    View details for DOI 10.1111/j.1537-2995.2010.02857.x

    View details for Web of Science ID 000288166200023

    View details for PubMedID 20738826

  • Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1357-1358
  • Quality Improvement (QI) for Event Discovery Reporting (EDRs) in the Transfusion Service (TS) Goodnough, L. T., Viele, M., Fontaine, M., Chua, L., Ferrer, Z., Jurado, C., Quach, P., Dunlap, M., Arber, D. A. WILEY-BLACKWELL. 2010: 270A-271A
  • Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge AMERICAN JOURNAL OF HEMATOLOGY Arredondo, A. R., Gotlib, J., Shier, L., Medeiros, B., Wong, K., Cherry, A., Corless, C., Arber, D. A., Valent, P., George, T. I. 2010; 85 (8): 600-606

    View details for DOI 10.1002/ajh.21713

    View details for Web of Science ID 000280562800011

    View details for PubMedID 20658589

  • Rare presentation of classical Hodgkin lymphoma with a clonal T-cell receptor gene rearrangement in the tissue LEUKEMIA & LYMPHOMA Nguyen, T. T., Warnke, R. A., Seo, K., Rosenberg, S. A., Arber, D. A. 2010; 51 (7): 1356-1359

    View details for DOI 10.3109/10428194.2010.486094

    View details for Web of Science ID 000279485700026

    View details for PubMedID 20496992

  • Protocol for the Examination of Specimens From Patients With Non-Hodgkin Lymphoma/Lymphoid Neoplasms ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Hussong, J. W., Arber, D. A., Bradley, K. T., Brown, M. S., Chang, C. (., de Baca, M. E., Ellis, D. W., Foucar, K., Hsi, E. D., Jaffe, E. S., Lill, M., McClure, S. P., Medeiros, L. J., Perkins, S. L. 2010; 134 (6): E40-E47

    View details for Web of Science ID 000278642000001

    View details for PubMedID 20524855

  • Combined Use of PCR-Based TCRG and TCRB Clonality Tests on Paraffin-Embedded Skin Tissue in the Differential Diagnosis of Mycosis Fungoides and Inflammatory Dermatoses JOURNAL OF MOLECULAR DIAGNOSTICS Zhang, B., Beck, A. H., Taube, J. M., Kohler, S., Seo, K., Zwerner, J., Viakhereva, N., Sundram, U., Kim, Y. H., Schrijver, I., Arber, D. A., Zehnder, J. L. 2010; 12 (3): 320-327


    The distinction between mycosis fungoides (MF) and inflammatory dermatoses (ID) by clinicopathologic criteria can be challenging. There is limited information regarding the performance characteristics and utility of TCRG and TCRB clonality assays in diagnosis of MF and ID from paraffin-embedded tissue sections. In this study, PCR tests were performed with both TCRG and TCRB BIOMED-2 clonality methods followed by capillary electrophoresis and Genescan analysis using DNA samples from 35 MF and 96 ID patients with 69 and 133 paraffin-embedded specimens, respectively. Performance characteristics were determined for each test individually and in combination. TCRG and TCRB tests demonstrated identical sensitivity (64%) and specificity (84%) when analyzed as individual assays. The positive predictive value, negative predictive value, and change of posttest MF probability over a range of MF pretest probabilities were obtained. These data were used to construct an algorithm for sequential use of TCRG and TCRB. As single tests, commercially available BIOMED-2 PCR-based TCRG and TCRB clonality tests on paraffin-embedded tissue have no significant difference in terms of sensitivity and specificity. Combined use of the two tests in patients with intermediate pretest probabilities as proposed in the algorithm could improve test utility.

    View details for DOI 10.2353/jmoldx.2010.090123

    View details for Web of Science ID 000277531700009

    View details for PubMedID 20203005

  • Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) LEUKEMIA RESEARCH Medeiros, B. C., Kohrt, H. E., Arber, D. A., Bangs, C. D., Cherry, A. M., Majeti, R., Kogel, K. E., Azar, C. A., Patel, S., Alizadeh, A. A. 2010; 34 (5): 594-597


    Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts.

    View details for DOI 10.1016/j.leukres.2009.08.029

    View details for Web of Science ID 000276945300009

    View details for PubMedID 19781775

  • Can cytoplasmic nucleophosmin be detected by immunocytochemical staining of cell smears in acute myeloid leukemia? HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Mattsson, G., Turner, S. H., Cordell, J., Ferguson, D. J., Schuh, A., Grimwade, L. F., Bench, A. J., Weinberg, O. K., Marafioti, T., George, T. I., Arber, D. A., Erber, W. N., Mason, D. Y. 2010; 95 (4): 670-673


    Mutations in the C-terminal region of nucleophosmin in acute myeloid leukemia (AML) result in aberrant cytoplasmic nucleophosmin (cNPM) in leukemic blast cells which is detectable by immunocytochemistry in bone marrow trephine (BMT) biopsy sections. We tested whether cNPM is detectable by immunocytochemistry in air-dried smears of AML with nucleophosmin1 (NPM1) mutations. An immunoalkaline phosphatase method was developed using the OCI-AML3 cell line, known to have mutated NPM1, and assessed on blood and marrow smears of 60 AML cases. NPM was detectable in all blast cell nucleoli and cNPM in 21 of 31 of NPM1 mutated and 15 of 29 wild-type cases. Paired air-dried smears and BMT biopsies from the same case (mutated and wild-type) gave discrepancies in cNPM expression and there was no correlation in 10 of 22 cases. Due to the high false positive and negative rates for cNPM in cell smears, this method should not be used as a surrogate for NPM1 mutations in AML.

    View details for DOI 10.3324/haematol.2009.011817

    View details for Web of Science ID 000277144800023

    View details for PubMedID 20015883

  • Coexisting Follicular and Mantle Cell Lymphoma With Each Having an In Situ Component AMERICAN JOURNAL OF CLINICAL PATHOLOGY Roullet, M. R., Martinez, D., Ma, L., Fowler, M. H., McPhail, E. D., Judkins, A., Arber, D. A., Bagg, A. 2010; 133 (4): 584-591


    A diagnosis of composite lymphoma is typically prompted by the observation of morphologic discordance. We present a case of a spleen revealing histologic features of follicular lymphoma, without any indication of a second lymphoma. Immunohistochemical stains supported this diagnosis and showed the follicular lymphoma to be BCL2-. However, these studies revealed 2 additional unexpected findings: cyclin D1+ mantle zone cells surrounding neoplastic and reactive follicles (indicative of in situ mantle cell lymphoma) and BCL2-bright, histologically nonneoplastic follicles (indicative of in situ follicular lymphoma). ImmunoFISH and microdissection and polymerase chain reaction analysis documented the clonal nature of the cyclin D1+ mantle zones and illustrated clonal independence from the follicular lymphoma. This case illustrates an uncommon and unusual composite follicular and mantle cell lymphoma, with the follicular lymphoma accompanied by an in situ component, whereas the only manifestation of the mantle cell lymphoma was in situ.

    View details for DOI 10.1309/AJCP5RT4MRSDGKSX

    View details for Web of Science ID 000275821400010

    View details for PubMedID 20231612

  • Protocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms of the Ocular Adnexa ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Bradley, K. T., Arber, D. A., Brown, M. S., Chang, C., Coupland, S. E., de Baca, M. E., Ellis, D. W., Foucar, K., Hsi, E. D., Jaffe, E. S., Lill, M. C., McClure, S. P., Medeiros, L. J., Perkins, S. L., Hussong, J. W. 2010; 134 (3): 336-340

    View details for Web of Science ID 000275529200003

    View details for PubMedID 20196660

  • PD-1 Expression in T-cell Lymphomas and Reactive Lymphoid Entities: Potential Overlap in Staining Patterns Between Lymphoma and Viral Lymphadenitis AMERICAN JOURNAL OF SURGICAL PATHOLOGY Krishnan, C., Warnke, R. A., Arber, D. A., Natkunam, Y. 2010; 34 (2): 178-189


    Peripheral T-cell lymphomas are a heterogeneous group that often requires the use of ancillary testing for accurate diagnosis. This is particularly applicable to the diagnosis of angiommunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unclassified (PTCLU), because of their histologic and immunophenotypic overlap with reactive lymphoid proliferations. Recently, immunohistochemistry for programmed death-1 (PD-1), a marker of follicular helper T cells, was shown to be sensitive in the detection of AITL and PTCLU. The sensitivity of this marker in reactive entities, however, has not been adequately evaluated. We confirm that PD-1 staining is a highly sensitive marker in the diagnosis of peripheral T-cell lymphomas: increased extrafollicular PD-1-positive cells were seen in 93% (76/82) of AITL, 62% (16/26) of PTCLU, and 11% (2/18) of anaplastic-lymphoma-kinase (ALK)-negative anaplastic large-cell lymphomas. The majority of reactive lymphadenopathies including Cat-scratch disease, Kikuchi lymphadenitis, Castleman disease, and reactive follicular hyperplasia showed no PD-1 staining outside follicles. Some reactive lymph nodes, showed increased extrafollicular PD-1-positive cells in a pattern similar to AITL and PTCLU, and include progressive transformation of germinal centers, viral lymphadenitis (Epstein-Barr virusand human immunodeficiency virus) and Rosai-Dorfman disease. This study shows that PD-1-positive cells may be increased in a number of settings other than T-cell lymphomas. We conclude that staining for PD-1 in reactive and atypical lymphadenopathies should be interpreted with caution and in the context of other ancillary immunophenotypic and molecular studies before a diagnosis of AITL or PTCLU is entertained.

    View details for Web of Science ID 000274219800005

    View details for PubMedID 20087161

  • Comparative Genomic Hybridization Array of Angioimmunoblastic T-Cell Lymphomas with and without Large B-Cell Proliferations Kurzer, J. H., Ma, L., Arber, D. A. NATURE PUBLISHING GROUP. 2010: 307A-308A
  • T-Cell Receptor PCR from Separate Biopsies Distinguishes Granulomatous Dermatitis from Granulomatous Mycosis Fungoides Dabiri, S., Arber, D. A., Kim, Y. H., Sundram, U. N., Kim, J. NATURE PUBLISHING GROUP. 2010: 112A?112A
  • Microtubule-associated Protein-2 is a Sensitive Marker of Primary and Metastatic Neuroblastoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Krishnan, C., Higgins, J. P., West, R. B., Natkunam, Y., Heerema-McKenney, A., Arber, D. A. 2009; 33 (11): 1695-1704


    Microtubule-associated protein-2 (MAP-2) is a protein expressed in high levels in cells derived from the neural crest. To the best of our knowledge, MAP-2 expression has not been thoroughly evaluated in tissues outside of the central nervous tissue. We examined the diagnostic utility of MAP-2 as a marker of neuroblastoma and attempted to characterize the expression of this protein in other tumors in the morphologic differential diagnosis of neuroblastoma.MAP-2 showed significant cytoplasmic reactivity in 95% of primary and 100% of metastatic neuroblastomas. Included within this set of tumors were 3 undifferentiated neuroblastomas, all of which showed strong staining. MAP-2 did not show significant staining in the majority of other small round blue cell tumors within the morphologic differential. Additionally, MAP-2 showed comparable sensitivity in staining primary neuroblastomas as compared with synaptophysin, chromogranin, CD56, and beta-catenin. In contrast to other markers of neuroblastoma, MAP-2 did not show significant cross reactivity to native bone marrow precursors, thus eliminating a potential source of confusion. In normal tissues, MAP-2 staining was essentially restricted to organs derived from the neural crest (adrenal medulla, endocrine organs). Variant patterns of staining were seen in exocrine organs, monocyte/macrophages and solitary fibrous tumor/hemangiopericytoma family of tumors. Rarely, high-grade adult sarcomas exhibiting strong cytoplasmic MAP-2 staining were seen.MAP-2 is a sensitive and specific marker of neuroblastoma, both in the primary tumor and bone marrow biopsy settings. We think that MAP-2, in conjunction with synaptophysin, is a very powerful immunohistochemical marker in differentiating neuroblastoma from its morphologic mimics.

    View details for Web of Science ID 000271795800016

    View details for PubMedID 19701075

  • A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia JOURNAL OF MOLECULAR DIAGNOSTICS Ahn, J., Seo, K., Weinberg, O., Boyd, S. D., Arber, D. A. 2009; 11 (4): 319-323


    The goal of the study was to compare the performance of a fluorescence-based multiplex PCR fragment analysis to a direct sequencing method for detecting CEBPA mutations in patients with acute myeloid leukemia. Thirty-three samples were selected from a larger study of 107 cases of acute myeloid leukemia by screening for CEBPA mutations by sequence analysis. Of ten identified mutations, six (insertions and deletions) were detected by both sequencing and fragment methods. The fragment analysis method did not detect the remaining four base substitutions because the method cannot detect changes that result in identically sized products. The multiplex PCR fragment length analysis method therefore failed to detect substitution mutations accounting for 40% of total CEBPA mutations in our patient set. Our results indicate that fragment length analysis should not be used in isolation, and that direct sequencing is required to evaluate CEBPA gene mutational status in acute myeloid leukemia. A combination of the two assays may offer some advantages, chiefly in permitting more sensitive detection by fragment length analysis of insertions and deletions.

    View details for DOI 10.2353/jmoldx.2009.080121

    View details for Web of Science ID 000267562000008

    View details for PubMedID 19525338

  • Marked downregulation of the granulopoiesis regulator LEF1 is associated with disease progression in the myelodysplastic syndromes BRITISH JOURNAL OF HAEMATOLOGY Pellagatti, A., Marafioti, T., Paterson, J. C., Malcovati, L., Della Porta, M. G., Jadersten, M., Pushkaran, B., George, T. I., Arber, D. A., Killick, S., Giagounidis, A., Hellstrom-Lindberg, E., Cazzola, M., Wainscoat, J. S., Boultwood, J. 2009; 146 (1): 86-90


    Lymphoid enhancer-binding factor 1 (LEF1) is a neutrophilic granulopoiesis regulator whose absence is critical in congenital neutropenia. We have shown LEF1 downregulation in the CD34(+) cells of the majority of myelodysplastic syndromes (MDS) patients. LEF1 was the most significant differentially expressed gene between early and advanced MDS. Marked LEF1 downregulation was found in 27/32 patients with advanced MDS and in 6/35 patients with early MDS, and was associated with neutropenia. Downregulation of LEF1 mRNA was reflected at the protein level. Immunostaining for CD34/LEF1 may represent a marker of advanced MDS. LEF1 may play a role in the defective maturation of myeloid progenitors in MDS.

    View details for DOI 10.1111/j.1365-2141.2009.07720.x

    View details for Web of Science ID 000266921600010

    View details for PubMedID 19438482

  • High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Chen, W., Lau, S. K., Fong, D., Wang, J., Wang, E., Arber, D. A., Weiss, L. M., Huang, Q. 2009; 33 (6): 863-873


    The diagnosis of histiocytic/dendritic cell (H/DC) sarcomas is currently based on morphology and the presence of immunophenotypic features of H/DC differentiation. The issue whether clonal immunoglobulin receptor gene rearrangements are present in H/DC sarcomas has been debated over decades until the recent data by Feldman et al, which provided compelling evidence that patients with follicular lymphoma and concurrent/synchronous H/DC sarcoma share identical genotypic features, suggested the possibility of transdifferentiation or dedifferentiation of 2 otherwise morphologically and immunophenotypically distinctive neoplasms. Here we investigated the molecular characteristics of 23 patients with sporadic H/DC sarcoma. Nine of the 23 cases (39%) showed clonal IGH (+/-IGK) gene rearrangements, whereas 2 (9%) cases showed only clonal IGK gene rearrangements, which were further validated and confirmed by direct DNA sequencing. One histiocytic sarcoma showed t(14;18) by quantitative-polymerase chain reaction, which was confirmed by fluorescence in situ hybridization analysis showing IGH/BCL2 fusions in neoplastic histiocytes. Notably, all IGH/IGK-positive H/DC sarcomas were negative for B-cell-associated transcription factors PAX5 and BOB.1, whereas 4 of 7 IGH/IGK-positive histiocytic sarcoma cases were positive for Oct2. In addition, no evidence of Epstein-Barr virus infection was detected in 8 of 11 IGH/IGK-positive H/DC sarcoma cases by in situ hybridization, suggesting that Epstein-Barr virus infection may not play an important role in the pathogenesis of these tumors. This study provides evidence that clonal immunoglobulin receptor gene rearrangements may be detected at a high frequency in sporadic H/DC sarcomas. The findings suggest that a large subset of H/DC sarcomas have inherited B-cell genotypes, thus providing new insights for the pathogenesis of these rare but aggressive neoplasms.

    View details for Web of Science ID 000266464200007

    View details for PubMedID 19145200

  • Features of hemolysis due to Clostridium perfringens infection INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Boyd, S. D., Mobley, B. C., Regula, D. P., Arber, D. A. 2009; 31 (3): 364-367


    Infection by Clostridium perfringens can be an unsuspected cause of hemolysis in emergency room patients. Historically, this condition has been associated with wound contamination and other tissue infections. We report the case of an autistic patient who presented to our emergency department with a distended abdomen and hemolysis of unknown etiology. The patient had no history of recent surgery. Exploration of the abdomen revealed a hepatic abscess. Blood cultures tested culture positive for C. perfringens. We present images demonstrating the salient features of the peripheral blood smear in cases of this uncommon but deadly cause of hemolysis.

    View details for DOI 10.1111/j.1751-553X.2007.01018.x

    View details for Web of Science ID 000265407400013

    View details for PubMedID 18177433

  • Detection of Isolated Tumor Cells in Neuroblastoma by Immunohistochemical Analysis in Bone Marrow Biopsy Specimens Improved Detection With Use of beta-Catenin AMERICAN JOURNAL OF CLINICAL PATHOLOGY Krishnan, C., Twist, C. J., Fu, T., Arber, D. A. 2009; 131 (1): 49-57


    Evaluation of the bone marrow is a critical component of accurate staging and surveillance for recurrent disease in neuroblastoma. The value of routine immunohistochemical analysis of otherwise histologically negative bone marrow biopsy specimens has not been adequately evaluated. By using synaptophysin, chromogranin, and beta-catenin, immunohistochemical analysis performed on otherwise histologically negative bone marrow specimens identified isolated tumor cells (ITCs) in 9.1%, 5.0%, and 10.0% of 220 biopsy specimens, respectively. Overall survival, as estimated by the Kaplan-Meier method, was not significantly different between patients with and without ITCs (P = .357). Of the immunohistochemical markers evaluated, beta-catenin showed the greatest sensitivity for identifying ITCs in the bone marrow and showed reactivity in primary tumor samples. We found that the presence of ITCs identified by immunohistochemical analysis may predict the persistence of disease but does not show significant overall survival differences. We also identified beta-catenin as a sensitive immunohistochemical marker of primary and metastatic neuroblastoma.

    View details for DOI 10.1309/AJCPAJODRJYD3OB2

    View details for Web of Science ID 000262314500007

    View details for PubMedID 19095565

  • High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Sarcomas Chen, W., Lau, S. K., Fong, D., Wang, J., Wang, E., Arber, D. A., Huang, Q. NATURE PUBLISHING GROUP. 2009: 258A-259A
  • Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2009: 291A-291A
  • Myelomastocytic Leukemia: A Clinical, Pathologic, and Molecular Genetic Study McGuire, A., Shier, L. R., Gotlib, J., Medeiros, B., Wong, K., Corless, C., Arber, D. A., George, T. I. NATURE PUBLISHING GROUP. 2009: 277A-277A
  • Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J. D., Gotlib, J. R., Zehnder, J. L., Arber, D. A. AMER SOC HEMATOLOGY. 2008: 341-342
  • The Frequency of Immunoglobulin Heavy Chain Gene and T-Cell Receptor gamma-Chain Gene Rearrangements and Epstein-Barr Virus in ALK(+) and ALK(-) Anaplastic Large Cell Lymphoma and Other Peripheral T-Cell Lymphomas JOURNAL OF MOLECULAR DIAGNOSTICS Tan, B. T., Seo, K., Warnke, R. A., Arber, D. A. 2008; 10 (6): 502-512


    We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.

    View details for DOI 10.2353/jmoldx.2008.080054

    View details for Web of Science ID 000260533600007

    View details for PubMedID 18832464

  • Evaluation of B-cell clonality using the BIOMED-2 PCR method effectively distinguishes cutaneous B-cell lymphoma from benign lymphoid infiltrates AMERICAN JOURNAL OF DERMATOPATHOLOGY Morales, A. V., Arber, D. A., Seo, K., Kohler, S., Kim, Y. H., Sundram, U. N. 2008; 30 (5): 425-430


    Primary cutaneous B-cell lymphomas (CBCL) are a diverse group of lymphomas that are limited to the skin at the time of diagnosis. Recently, standardized polymerase chain reaction protocols for immunoglobulin (Ig) rearrangement in nodal malignancies using the BIOMED-2 method have been studied extensively. However, reports of investigations of Ig clonality in CBCL using the BIOMED-2 method have been scant. We hypothesized that clonality detection in CBCL with the BIOMED-2 method could effectively distinguish malignant from benign B-cell-rich infiltrates in the skin. Formalin-fixed tissue samples from 26 patients with CBCL and 23 with benign lymphoid infiltrates were analyzed for Ig clonality using standardized BIOMED-2 polymerase chain reaction protocols. The (14;18) translocation was also assessed. A clone was detected in 22 (85%) of the 26 patients with CBCL [12/15 (80%) marginal zone B-cell lymphoma; 10/11 (91%) follicle center lymphoma] and in 1 (4%) of the 23 patients with benign infiltrates. The (14;18) translocation was present in 3 (12%) of the 26 patients with CBCL [1/15 (7%) marginal zone B-cell lymphoma; 2/11 (18%) follicle center lymphoma]. Our preliminary data indicate that Ig clonality can be detected in formalin-fixed samples of CBCL with meaningful sensitivity (85%) and high specificity (96%) using the BIOMED-2 method. This study forms the basis for further investigating the role of Ig clonality in distinguishing CBCL from benign lymphoid infiltrates that may pose a challenge in morphologic diagnosis.

    View details for Web of Science ID 000259325000002

    View details for PubMedID 18806482

  • Prevalence of bone marrow involvement in systemic anaplastic large cell lymphoma: are immunohistochemical studies necessary? HUMAN PATHOLOGY Weinberg, O. K., Seo, K., Arber, D. A. 2008; 39 (9): 1331-1340


    The frequency of bone marrow involvement in anaplastic large cell lymphoma has been reported with great variation. A prior study found that anaplastic large cell lymphoma involvement of bone marrow was often not evident on routine stains and advocated using immunohistochemical studies. We evaluated 70 bone marrow biopsies from 41 patients with anaplastic large cell lymphoma and found 10 morphologically involved cases (14% of all biopsies, 22% of all patients). In most cases (9/10 biopsies), the involvement of the bone marrow by anaplastic large cell lymphoma was massive and, thus, was evident on the hematoxylin and eosin section. In only 1 biopsy (1% of all biopsies, 2% of all patients), the involvement was minimal and more difficult to detect. To determine if the hematoxylin and eosin evaluation missed bone marrow involvement, we used a panel of antibodies including CD30, ALK-1, epithelial membrane antigen, and granzyme. Only the 10 morphologically involved cases showed anaplastic large cell lymphoma cells with distinct CD30 expression. Other stains highlighted only a subset of the CD30-positive cases. Clinical follow-up was available for 30 patients and shows correlation of marrow involvement with lower overall survival (P = .033). Overall, marrow involvement in anaplastic large cell lymphoma was relatively uncommon, and when present, it was identified on hematoxylin and eosin sections.

    View details for DOI 10.1016/j.humpath.2008.01.005

    View details for Web of Science ID 000258626500008

    View details for PubMedID 18602674

  • Chromosomal aberrations in a case of synchronous extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type and bronchogenic adenocarcinoma APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Cupp, J. S., Wrede, J. E., Cherry, A. M., Arber, D. A., George, T. I. 2008; 16 (3): 296-300


    We present the chromosomal aberrations in a case of synchronous extranodal marginal zone B-cell lymphoma and bronchogenic adenocarcinoma with bronchioloalveolar features. Using fluorescence in situ hybridization, we identified deletion of the immunoglobulin heavy chain gene in the lymphomatous component, but not the carcinomatous component. The presence of differing genetic compositions suggests a biclonal environment composed of 2 distinct neoplastic processes.

    View details for Web of Science ID 000255692800015

    View details for PubMedID 18301237

  • Nodular lymphocyte-predominant Hodgkin lymphoma presenting as fulminant hepatic failure in a pediatric patient: A case report with pathologic, immunophenotypic, and molecular findings APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Woolf, K. M., Wei, M. C., Link, M. P., Arber, D. A., Warnke, R. A. 2008; 16 (2): 196-201


    A 7-year-old boy presented with fulminant hepatic failure requiring liver transplant. Serologic testing ruled out infectious and autoimmune causes. During transplant surgery he was found to have enlarged periportal lymph nodes that were biopsied. Nodular lymphocyte-predominant Hodgkin lymphoma was diagnosed based on histologic examination of the lymph node and liver. The L&H cells within the lymph node were positive for CD20 whereas those within the liver were not, although they were positive for other B-cell markers. After extensive work-up, the cause of liver failure could only be attributed to the involvement by lymphoma. In addition, B-cell clonality was established among the neoplastic cells with the same clone detected in all sampled tissues. Hodgkin lymphoma as a cause of hepatic failure is rare and has not been previously reported in a pediatric patient.

    View details for Web of Science ID 000253788700016

    View details for PubMedID 18227720

  • Significance of NPM1 and FLT3 mutations in acute myeloid leukemia with multilineage dysplasia: Does NPM1 identify a lower risk group? Weinberg, O., Merker, J., Beck, A., Seetharam, M., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2008: 281A-281A
  • Lymphoplasmacytic lymphoma arising in the setting of hepatitis c and mixed Cryoglobulinemia JOURNAL OF CLINICAL ONCOLOGY Krishnan, C., Cupp, J. S., Arber, D. A., Faix, J. D. 2007; 25 (27): 4312-4314

    View details for DOI 10.1200/JCO.2007.12.8876

    View details for Web of Science ID 000251073200027

    View details for PubMedID 17878484

  • Molecular diagnostics of non-Hodgkin lymphoma. Expert opinion on medical diagnostics Merker, J. D., Arber, D. A. 2007; 1 (1): 47-63


    Non-Hodgkin lymphomas (NHLs) represent a diverse group of hematopoietic neoplasms. Morphology and immunophenotypic characterization are the cornerstone of the diagnosis and classification of NHLs; however, cytogenetic and molecular studies are being increasingly used to provide further information about classification and prognosis. In addition, these molecular techniques are being used for the detection of minimal residual or recurrent disease after the patient has undergone treatment. This review will discuss the major genetic changes associated with NHLs and describe the methods currently used in the clinical laboratory for cytogenetic and molecular detection of these abnormalities.

    View details for DOI 10.1517/17530059.1.1.47

    View details for PubMedID 23489268

  • Bone marrow metastases: A survey of nonhematologic metastases with immunohistochemical study of metastatic carcinomas APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Krishnan, C., George, T. I., Arber, D. A. 2007; 15 (1): 1-7


    With current therapies and imaging methods, staging bone marrow biopsies, and subsequently found metastases to the bone marrow, are less frequent. Historically, the most common metastatic nonhematologic tumors to the bone marrow in adult and pediatric patients included breast carcinoma, neuroblastoma, prostatic carcinoma, Ewing sarcoma, and lung tumors. Although the staining patterns of these primary tumors have been extensively examined, the utility of these immunohistochemical profiles has not been studied in the context of metastatic lesions to the bone marrow. In our review of 111 metastases to the bone marrow over an 18-year period, the most common primary tumor types are, in order of frequency: breast carcinoma, neuroblastoma, lung tumors, rhabdomyosarcoma, Ewing sarcoma, prostate carcinoma, and gastrointestinal tract tumors. Additionally, in an analysis of 44 adult metastatic carcinomas, we confirm that immunohistochemical panels are useful in identifying the primary tumor site. Overall, the immunohistochemical characterization of metastatic carcinomas to the bone marrow show good correlation with the established staining pattern of the primary tumors.

    View details for Web of Science ID 000244917400001

    View details for PubMedID 17536301

  • Low CD27 expression in plasma cell dyscrasias correlates with high-risk disease: An immunohistochemical analysis AMERICAN JOURNAL OF CLINICAL PATHOLOGY Morgan, T. K., Zhao, S., Chang, K. L., Haddix, T. L., Domanay, E., Cornbleet, P. J., Arber, D. A., Natkunam, Y. 2006; 126 (4): 545-551


    Genome-wide expression studies using complementary DNA microarrays recently suggested a number of intriguing candidate genes for distinguishing plasma cell dyscrasias. Our objective was to test select markers using immunohistochemical analysis and a tissue microarray from paraffin-embedded bone marrow core biopsy specimens obtained from 8 patients with monoclonal gammopathy of undetermined significance, 17 with plasmacytoma, 160 with multiple myeloma, and 15 with plasma cell leukemia (PCL). We immunostained serial sections for CD138, CD27, CD56, p27, Ki-67, CD3, and CD20. Each core was scored in duplicate by observers blinded to phenotype and reported as the average percentage of CD138+ cells. The Mann-Whitney U test was used to determine significance between groups. PCL showed significantly less immunostaining for CD27 (P < .01) and p27 (P < .05) compared with plasmacytoma and multiple myeloma. Low CD27 expression also was associated with plasmacytoma progression to multiple myeloma (P <.05). Our results support the hypothesis that low CD27 expression correlates with high-risk disease, including primary PCL and decreased progression-free survival in solitary plasmacytoma.

    View details for DOI 10.1309/ELGMGX81C2UTP55R

    View details for Web of Science ID 000240638900007

    View details for PubMedID 16938662

  • Metastasizing splenic littoral cell hemangioendothelioma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fernandez, S., Cook, G. W., Arber, D. A. 2006; 30 (8): 1036-1040


    Littoral cell angioma is a unique splenic tumor that is generally considered to be benign. We present a case of a low-grade littoral cell splenic tumor that metastasized to the liver and retroperitoneum 4 years after splenectomy. Although the splenic lesion showed the typical morphology of a littoral cell angioma, it also contained areas with unusual solid nests of cytologically bland, plump cells with clear cytoplasm. The liver was diffusely infiltrated exclusively by cells with similar clear cell features. Both splenic and liver lesions demonstrated identical immunophenotypes, typical of littoral cell angioma, expressing CD31, CD68, CD21, and CD163, although negative for CD8 and CD34. A single prior description of a littoral cell hemangioendothelioma showed nuclear atypia and necrosis, and this is the first case report of a splenic littoral cell hemangioendothelioma with a completely bland histologic appearance. This case suggests that the presence of solid areas of clear cells in a littoral cell angioma may be a marker of low-grade malignant potential in these tumors.

    View details for Web of Science ID 000239414400016

    View details for PubMedID 16861977

  • Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias - Report of six cases and review of literature AMERICAN JOURNAL OF CLINICAL PATHOLOGY Wu, Y. P., Slovak, M. L., Snyder, D. S., Arber, D. A. 2006; 125 (2): 260-266


    We report 5 cases of chronic myelogenous leukemia (CML) and 1 case of acute myeloid leukemia (AML) with the dual presence of t(9;22) and inv(16). The 6 patients were 5 men and 1 woman with a median age of 42.5 years. All cases were BCR-ABL+ with p210 products detected in all CML cases and a p190 product detected in the AML case. An increase in bone marrow eosinophils was detected in 3 of 5 cases, and abnormal eosinophils were identified in these 3 cases. The CBFbeta-MYH11 fusion gene was confirmed in all 3 CML cases and the 1 AML case tested, and this correlated with the presence of abnormal eosinophils with coarse basophilic granules. Of 5 patients with CML, 4 had a rapid transformation to myeloid accelerated phase of blast crisis. The coexistence of t(9;22) and inv(16) in CML seems to correlate with more rapid transformation.

    View details for DOI 10.1309/F0MX5CL8CEDY3W86

    View details for Web of Science ID 000234725200013

    View details for PubMedID 16393682

  • Lack of expression of platelet-derived growth factor receptor beta (PDGFR beta) in langerhans cell tumors: An in situ hybridization study George, T. I., Mest, R. B., Blais, S., Montgomery, K., Gotlib, J., van de Rijn, M., Arber, D. A. NATURE PUBLISHING GROUP. 2006: 227A-227A
  • Identification of novel RUNX1 (AML1) translocation partner genes in acute myeloid leukemia Nguyen, T. T., Ma, L. N., Slovak, M. L., Bangs, C. D., Cherry, A. M., Arber, D. A. NATURE PUBLISHING GROUP. 2006: 240A-240A
  • Fluorescence in situ hybridization investigation of cutaneous lesions in acute promyelocytic leukemia MODERN PATHOLOGY Wrede, J. E., Sundram, U., Kohler, S., Cherry, A. M., Arber, D. A., George, T. I. 2005; 18 (12): 1569-1576


    Cutaneous manifestations of acute promyelocytic leukemia are rare but well documented. Skin biopsies of leukemia can be difficult to confirm using morphology alone, and paraffin section immunophenotyping is not specific in separating acute promyelocytic leukemia from other acute myeloid leukemias involving the skin or inflammatory conditions, such as Sweet's syndrome and all-trans retinoic acid-associated genital ulcers, which may mimic leukemia cutis. Fluorescence in situ hybridization has been shown to be a fast and effective method of detecting the PML/RARA fusion gene characteristic of acute promyelocytic leukemia in fresh blood and bone marrow samples. Fluorescence in situ hybridization has also been demonstrated to be effective in detecting other chromosomal rearrangements in paraffin-embedded tissue. This retrospective study of cutaneous lesions from four patients with acute promyelocytic leukemia evaluates the utility of performing fluorescence in situ hybridization to confirm the presence of cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed, paraffin-embedded skin biopsies. All patients had previous bone marrow findings of acute promyelocytic leukemia with characteristic morphology, immunophenotype, and cytogenetic studies, which detailed the presence of the t(15;17)(q22;q12) rearrangement. Two skin biopsies showed an infiltrate of blastic cells involving the dermis in a diffuse pattern and one biopsy had a perivascular/periadnexal pattern. The fourth case, involving the scrotum, showed a predominant neutrophilic infiltrate diffusely involving the dermis and epidermis with a subset of blastic cells. Nuclei were extracted from core biopsies of the formalin-fixed paraffin-embedded tissue and fluorescence in situ hybridization was performed using a dual color, dual fusion PML / RARA probe. All cases showed evidence of the t(15;17) rearrangement, with 90, 79, 51 and 16% positive signal patterns, each well above background limits. Fluorescence in situ hybridization appears to be a robust technique to detect cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed paraffin-embedded skin biopsies.

    View details for DOI 10.1038/modpathol.3800465

    View details for Web of Science ID 000233372100006

    View details for PubMedID 16056248

  • Assessment of genetic aberrations in plasma cells using a sequential morphology (phenotype)/FISH (genotype) approach significantly improves the detection of residual disease in post treatment multiple myeloma. Slovak, M. L., Bedell, V., Pagel, K., Weiss, L., Smith, D., Yen, Y., Shum, C. C., Arber, D. A., Somlo, G. AMER SOC HEMATOLOGY. 2005: 444A-445A
  • Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation BLOOD Gotlib, J., Berube, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y. F., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., GALLI, S. J., Gilliland, D. G., Coutre, S. E. 2005; 106 (8): 2865-2870


    The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

    View details for DOI 10.1182/blood-2005-04-1568

    View details for Web of Science ID 000232466000047

    View details for PubMedID 15972446

  • Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides JOURNAL OF CLINICAL ONCOLOGY Molina, A., Zain, J., Arber, D. A., Angelopolou, M., O'Donnell, M., Murata-Collins, J., Forman, S. J., Nademanee, A. 2005; 23 (25): 6163-6171


    Sezary syndrome (SS) and tumor-stage mycosis fungoides (MF) are generally incurable with currently available treatments. We conducted a retrospective study to evaluate the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) in this patient population.From August 1996 through October 2002, eight patients with advanced MF/SS underwent allogeneic HSCT at our institution. All patients were heavily pretreated, having failed a median number of seven prior therapies (range, five to 12). Clonal T-cell populations in peripheral blood or bone marrow were detectable by polymerase chain reaction analyses of T-cell receptor gamma-chain gene rearrangements in six patients and cytogenetics in three patients. The conditioning regimen included total-body irradiation and cyclophosphamide (n = 3), busulfan and cyclophosphamide (n = 1), and the reduced-intensity regimen of fludarabine and melphalan (n = 4). Allogeneic hematopoietic stem cells were obtained from HLA-matched siblings (n = 4) and unrelated donors (n = 4).All patients achieved complete clinical remission and resolution of molecular and cytogenetic markers of disease within 30 to 60 days after HSCT. Two patients died from transplantation-related complications; graft-versus-host disease (GVHD; n = 1) and respiratory syncytial virus pneumonia (n = 1). With a median follow-up of 56 months, six patients remain alive and without evidence of lymphoma.Our results suggest that allogeneic HSCT from both HLA-matched sibling and unrelated donors can induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma that is refractory to standard therapies.

    View details for DOI 10.1200/JCO.2005.02.774

    View details for Web of Science ID 000231606300042

    View details for PubMedID 16135483

  • Low-grade B-cell lymphomas with plasmacytic differentiation lack PAX5 gene rearrangements JOURNAL OF MOLECULAR DIAGNOSTICS George, T. I., Wrede, J. E., Bangs, C. D., Cherry, A. M., Warnke, R. A., Arber, D. A. 2005; 7 (3): 346-351


    The chromosomal translocation t(9;14)(p13;q32) has been reported in association with lymphoplasmacytic lymphoma (LPL). Although this translocation involving the paired homeobox-5 (PAX5) gene at chromosome band 9p13 and the immunoglobulin heavy chain (IgH) gene at 14q32 has been described in approximately 50% of LPL cases, the actual number of cases studied is quite small. Many of the initial cases associated with t(9;14)(p13;q32) were actually low-grade B-cell lymphomas with plasmacytic differentiation other than LPL. Thus, we analyzed a series of low-grade B-cell lymphomas for PAX5 gene rearrangements. We searched records from the Department of Pathology, Stanford University Medical Center for low-grade B-cell lymphomas, with an emphasis on plasmacytic differentiation, that had available paraffin blocks or frozen tissue. We identified 37 cases, including 13 LPL, 18 marginal zone lymphomas (nodal, extranodal, splenic, and alpha-heavy chain disease), and 6 small lymphocytic lymphomas. A novel dual-color break-apart bacterial artificial chromosome probe was designed to flank the PAX5 gene, spanning previously described PAX5 breakpoints, and samples were analyzed by interphase fluorescence in situ hybridization. All cases failed to demonstrate a PAX5 translocation, indicating that t(9;14)(p13;q32) and other PAX5 translocations are uncommon events in low-grade B-cell lymphomas with plasmacytic differentiation. This study also confirms recent reports that found an absence of PAX5 rearrangements in LPL, suggesting the reassessment of PAX5 rearrangements in LPL.

    View details for Web of Science ID 000231054600004

    View details for PubMedID 16049306

  • Identification of mislabeled specimen by molecular methods: Case report and review INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Mariappan, M. R., Zehnder, J., Arber, D. A., Lay, M., Fadare, O., Schrijver, R. 2005; 13 (3): 253-258


    Specimen misidentification is a common cause of errors in surgical pathology. We report a case where bone-marrow biopsies from patients of different genders were mislabeled and molecular methods were applied to resolve the identity. A short tandem repeat (STR)-polymerase chain reaction-based assay, commonly used in paternity testing, was employed in an attempt to assign the correct identity to the specimens. However, the specimens had been processed by decalcification and the DNA yield was poor. One of the markers in the assay is the non-STR amelogenin locus that distinguishes the X and Y chromosomes. This amelogenin marker results in a product of low molecular weight, enabling unequivocal resolution of identity despite a poor DNA yield. The prevalence of errors in pathology due to specimen misidentifications is reviewed.

    View details for Web of Science ID 000231185700004

    View details for PubMedID 16086080

  • Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nguyen, T. D., Schwartz, E. J., West, R. B., Warnke, R. A., Arber, D. A., Natkunam, Y. 2005; 29 (5): 617-624


    CD163, a hemoglobin scavenger receptor, is expressed in monocytes and macrophages. We tested the expression of the CD163 protein in 1,105 human malignancies and normal tissues using tissue microarrays and conventional paraffin-embedded tissue sections. Besides staining nonneoplastic monocytes and histiocytes (tissue macrophages), membranous/cytoplasmic staining for CD163 was primarily limited to neoplasms with monocytic/histiocytic differentiation. CD163 reactivity was not observed in normal tissues, lymphomas, carcinomas, and in a majority of mesenchymal neoplasms, including follicular dendritic cell tumors (0 of 4), although it stained admixed histiocytes. Staining for CD163 was seen in Rosai-Dorfman disease (5 of 6), histiocytic sarcoma (3 of 4), littoral cell angioma (6 of 6), and Langerhans cell histiocytosis (3 of 5). A subset of atypical fibrous histiocytomas (9 of 16), benign fibrous histiocytomas (6 of 9), and atypical fibroxanthomas (1 of 3) also showed CD163 staining. Our studies also confirm earlier work showing that CD163 is expressed in acute myeloid leukemia with monocytic differentiation (AML, FAB subtype M5) (2 of 6), as well as a majority of giant cell tenosynovial tumors (7 of 8). Its limited range of expression and tissue specificity indicate that CD163 may have significant diagnostic utility in separating specific tumors with monocytic and histiocytic derivation from other entities in their differential diagnosis.

    View details for Web of Science ID 000228707200007

    View details for PubMedID 15832085

  • Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: Case report and review of the literature PEDIATRIC BLOOD & CANCER George, T. I., Jeng, M., Berquist, W., Cherry, A. M., Link, M. P., Arber, D. A. 2005; 44 (3): 270-276


    Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.

    View details for DOI 10.1002/pbc.20231

    View details for Web of Science ID 000226798300015

    View details for PubMedID 15468305

  • CD117 expression in mesothelioma MODERN PATHOLOGY Arber, D. A., Weiss, L. M., West, R. B. 2004; 17 (8): 1021-1021

    View details for DOI 10.1038/modpathol.3800159

    View details for Web of Science ID 000223118300016

    View details for PubMedID 15263910

  • Pathology of the myeloproliferative diseases HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA George, T. I., Arber, D. A. 2003; 17 (5): 1101-?


    The classification of myeloid neoplasms now includes CMPD, mixed CMPD/ MDS, MDS, and acute myeloid leukemias. CMPD and CMPD/MDS, both clonal stem cell diseases, share myeloproliferative features, including typical hypercellular marrows, organomegaly, and cell lineage maturation. The CMPD generally differ by which myeloid cell lineage dominates hematopoiesis, and the main diseases include CML, PV, ET, and CIM. The mixed CMPD/MDS disorders also show dysplastic features and variable amounts of effective hematopoiesis; these disorders include CMML, JMML, and atypical CML. Given the overlap in morphology among these diseases, correlation with clinical, hematologic, and cytogenetic/molecular genetic findings is imperative for precise classification.

    View details for DOI 10.1016/S0889-8588(03)00093-5

    View details for Web of Science ID 000185617300004

    View details for PubMedID 14560777

  • Expression of T/NK-cell and plasma cell antigens in nonhematopoietic epithelioid neoplasms - An immunohistochemical study of 447 cases AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chu, P. G., Arber, D. A., Weiss, L. M. 2003; 120 (1): 64-70


    We studied the expression of CD2, CD3, CD4, CD5, CD7, CD8, CD56, and CD138 in 447 cases of common human neoplasms with epithelioid features. CD2, CD3, CD4, and CD8 antigens were detected in none of 447 cases of nonhematopoietic tumors. CD5 and CD7 antigens were expressed in 12.3% and 19.5% of cases of nonhematopoietic tumors, respectively. Their expression was found primarily in adenocarcinomas from the gastrointestinal tract, breast, and female reproductive organs. The high expression of CD5 and CD7 antigen in pancreatic ductal carcinoma and cholangiocarcinoma and high expression of CD7 in epithelioid sarcoma may have diagnostic value. One quarter of cases were positive for CD56. Overexpression of CD56 antigen was detected mainly in neuroendocrine tumors or adenocarcinomas with neuroendocrine differentiation. Its consistent overexpression in adrenal cortical and thyroid tumors may have diagnostic usefulness. Virtually all tumor types studied were CD138+ with a variable positivity rate. The negative staining of CD138 in malignant mesothelioma may be useful for separating mesothelioma from metastatic adenocarcinoma.

    View details for DOI 10.1309/48KC17WAU69BTBXQ

    View details for Web of Science ID 000183730300008

    View details for PubMedID 12866374

  • Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment BLOOD Bhatia, R., Holtz, M., Niu, N., Gray, R., Snyder, D. S., Sawyers, C. L., Arber, D. A., Slovak, M. L., Forman, S. J. 2003; 101 (12): 4701-4707


    The BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown remarkable efficacy in the treatment of chronic myelogenous leukemia (CML), with a high proportion of patients achieving complete cytogenetic responses (CCRs). However, it is not clear whether remissions will be durable and whether imatinib mesylate can eliminate the malignant primitive progenitors in which the disease arises. We investigated whether residual BCR/ABL+ hematopoietic progenitors were present in patients who achieved CCRs with imatinib mesylate treatment. CD34+ progenitor cells were selected from bone marrow mononuclear cells (MNCs) and analyzed for the presence of the BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). CD34+ cells were also plated in committed progenitor (colony-forming cell, or CFC) and primitive progenitor (long-term bone marrow culture-initiating cell, or LTCIC) cultures and resulting colonies analyzed for the presence of BCR/ABL+ cells by FISH. Using these assays, residual BCR/ABL+ progenitors were detected in all patients studied. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased levels of BCR/ABL mRNA in CD34+ cells compared with total MNCs. Evaluation of samples collected at different time points demonstrated persistence of BCR/ABL+ progenitors despite continued treatment with imatinib mesylate. Our results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients. Patients in CCR with imatinib mesylate treatment need to be followed carefully to assess for risk of relapse.

    View details for DOI 10.1182/blood-2002-09-2780

    View details for Web of Science ID 000183481700017

    View details for PubMedID 12576334

  • Interleukin-2 after autologous stem-cell transplantation for adult patients with acute myeloid leukemia in first complete remission JOURNAL OF CLINICAL ONCOLOGY Stein, A. S., O'Donnell, M. R., Slovak, M. L., Snyder, D. S., Nademanee, A. P., Parker, P., Molina, A., Somlo, G., Fung, H. C., Krishnan, A., Rodriguez, R., Spielberger, R. T., Wang, S. R., Dagis, A., Vora, N., Arber, D. A., Niland, J. C., Forman, S. J. 2003; 21 (4): 615-623


    To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation.Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery.Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate.These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

    View details for DOI 10.1200/JCO.2003.12.125

    View details for Web of Science ID 000181002500009

    View details for PubMedID 12586797

  • Expression of SHP-1 phosphatase indicates post-germinal center cell derivation of B-cell posttransplant lymphoproliferative disorders LABORATORY INVESTIGATION Paessler, M., Kossev, P., Tsai, D., Raghunath, P., Majewski, M., Zhang, Q., Ramalingam, P., Schuster, S., Tomaszewski, J., Arber, D. A., Hsi, E., Wasik, M. A. 2002; 82 (11): 1599-1606


    SHP-1 tyrosine phosphatase acts as a negative regulator of signaling by receptors for growth factors, cytokines, and chemokines and by receptors involved in immune response. Our recent study showed that SHP-1 is tightly regulated at various stages of B-cell differentiation and is expressed in the mantle and marginal zones, interfollicular B cells, and plasma cells, whereas it is nondetectable in germinal center cells. In this study we evaluated expression of SHP-1 in vitro and in vivo in nine cell lines representing three different types of EBV+ B-cell populations closely resembling or derived from posttransplant lymphoproliferative disorders (PTLDs). Furthermore, we examined tissue samples from 58 patients with B-cell PTLDs, both EBV+ (85% of the cases analyzed) and EBV- (15%). SHP-1 protein was strongly expressed in all cell lines and PTLD cases. In addition, the PTLD cases were essentially negative for germinal center B-cell markers: none expressed CD10 and only one expressed BCL-6. More than 40% expressed a late post-germinal B-cell marker, CD138. The universal expression of SHP-1, lack of expression of CD10 and BCL-6, and frequent expression of CD138 suggest that PTLDs are derived from post-germinal center B cells regardless of the EBV cell infection status. Based on the immunophenotype, B-cell PTLDs could be divided into two broad categories corresponding to the early (CD10-/BCL-6-/SHP-1+/CD138-) and late (CD10-/BCL-6-/SHP-1+/CD138+) post-germinal center cells. By being expressed earlier, SHP-1 is a more sensitive marker of post-germinal center B cells than CD138, which is seen on the terminally differentiated immunoblasts and plasma cells.

    View details for DOI 10.1097/01.LAB.0000036873.16297.A5

    View details for Web of Science ID 000179479900015

    View details for PubMedID 12429820

  • Primary effusion lymphoma with subsequent development of a small bowel mass in an HIV-seropositive patient - A case report and literature review AMERICAN JOURNAL OF SURGICAL PATHOLOGY Huang, Q., Chang, K. L., Gaal, K., Arber, D. A. 2002; 26 (10): 1363-1367


    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 Kaposi's 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.

    View details for DOI 10.1097/01.PAS.0000027302.89469.AB

    View details for Web of Science ID 000178356400014

    View details for PubMedID 12360052

  • Effect of prolonged formalin fixation on the immunohistochemical reactivity of breast markers APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Arber, D. A. 2002; 10 (2): 183-186


    Prolonged formalin fixation is known to reduce the immunohistochemical reactivity of many paraffin section antibodies. Before the common use of heat induced epitope retrieval methods, vimentin reactivity was proposed as a marker of antigen preservation. To evaluate the effect of formalin fixation on breast tumor markers, multitumor blocks of tissue fixed in formalin for varying time intervals from 33 different infiltrating breast carcinomas were analyzed for the expression of estrogen receptor (ER), progesterone receptor (PR), c-erb-B2, Ki-67, p27, and vimentin. The mean/median length of the longest fixation time per specimen was 53/42 days (range 7 days-154 days). Formalin fixation did not significantly reduce immunoreactivity for Ki-67, p27, or vimentin, even in tissue fixed for 154 days. Of 23 ER-positive cases, a significant reduction in immunoreactivity (2 grades or more) was identified in three samples, occurring at 57 to 64 days. For 21 PR-positive cases, only one showed a significant reduction (from 3+ to 1+) at 120 days. Of nine c-erb-B2 positive (2 + or 3+) cases, four became negative (1+ or 0) at 20, 42, 49, and 99 days. The immunoreactivity of some breast prognostic markers is reduced by formalin over-fixation, but only after extensive fixation that may not be clinically relevant. The loss of antigen preservation is not accompanied by a loss of vimentin immunoreactivity, making vimentin a suboptimal marker for ER, PR, or c-erb-B2 preservation.

    View details for Web of Science ID 000175774500015

    View details for PubMedID 12051639

  • Immunoglobulin heavy chain gene analysis in lymphomas - A multi-center study demonstrating the heterogeneity of performance of polymerase chain reaction assays JOURNAL OF MOLECULAR DIAGNOSTICS Bagg, A., Braziel, R. M., Arber, D. A., Bijwaard, K. E., Chu, A. Y. 2002; 4 (2): 81-89


    Determination of monoclonality through an evaluation of immunoglobulin heavy chain (IgH) gene rearrangements is a commonly performed and useful diagnostic assay. Many laboratories that perform this assay do so by the polymerase chain reaction (PCR). To evaluate current methods for performing IgH gene testing, 19 different Association of Molecular Pathology (AMP) member laboratories analyzed 29 blinded B cell and T cell lymphoid neoplasm samples of extracted DNA and formalin-fixed, paraffin-embedded (FFPE) tissue and were asked to complete a technical questionnaire. From this study, it is clear that Southern blot analysis remains the diagnostic gold standard, with a 100% diagnostic sensitivity and specificity. There was, however, remarkable heterogeneity in the performance of, and results obtained from, IgH PCR assays with diagnostic sensitivity ranging from over 90% to as low as 20%, when evaluating the same specimens. Many laboratories overestimate the diagnostic sensitivity of their IgH PCR assay, and there was a significant, and under appreciated, drop-off (from 61.3% to 41.8%) in detection in paired FFPE as compared with fresh/frozen tissues. Fixation has a dramatic impact on the inability to perform the test on FFPE (43.1%) versus DNA already extracted from fresh or frozen tissue (2.8%). A number of variables that affected the outcome of IgH PCR were identified. Strategies that improved the detection of monoclonal IgH rearrangements include: the addition of FRII to the FRIII upstream primer (increasing detection from 57.3% to 73.6%) and the use of the FR3A rather than the FR3 FRIII primer (increasing detection from 54.7% to 69.7%). Although numerous variables (from DNA extraction to PCR product detection) were evaluated, making it difficult to mandate alterations in laboratory practice, these findings ought to prompt diagnostic molecular pathology laboratories to reevaluate their claims of sensitivity, as well as their methodologies. Both pathologists and surgeons need to ensure that not all submitted material is fixed, if there is adequate sample. Importantly, there is a need for greater standardization to reduce the unacceptably high false negative rate of this crucial diagnostic assay.

    View details for Web of Science ID 000175462900002

    View details for PubMedID 11986398

  • 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: Report from an international workshop GENES CHROMOSOMES & CANCER Slovak, M. L., Bedell, V., Popplewell, L., Arber, D. A., Schoch, C., Slater, R. 2002; 33 (4): 379-394


    The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).

    View details for DOI 10.1002/gcc.10042

    View details for Web of Science ID 000174208300005

    View details for PubMedID 11921272

  • Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients LEUKEMIA Chang, K. L., O'Donnell, M. R., Slovak, M. L., Dagis, A. C., Arber, D. A., Niland, J. C., Forman, S. J. 2002; 16 (4): 623-631


    Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1-32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.

    View details for DOI 10.1038/sj/leu/2402391

    View details for Web of Science ID 000175193000024

    View details for PubMedID 11960342

  • Recurrent B-cell neoplasms after rituximab therapy: An immunophenotypic and genotypic study LEUKEMIA & LYMPHOMA Chu, P. G., Chen, Y. Y., Molina, A., Arber, D. A., Weiss, L. M. 2002; 43 (12): 2335-2341


    Rituximab has been widely used to treat relapsing or advanced stage B-cell neoplasms with an efficacy of about 50%. However, approximately 40-50% of Rituximab treated patients will recur. It is not clear whether these recurrent diseases have the same immunophenotype as that of the original tumors. At the City of Hope, we treated 91 cases of CD20-positive B-cell neoplasms with Rituximab in combination with chemotherapy and hematopoietic stem cell transplantation between August 1999 and December 2000. Thirty-five of 91 patients (38%) experienced recurrence during the time period within one year from treatment. Tumor cells from all of the recurrent patients expressed one or more B cell antigens (CD19, CD20, CD22, CD45RA, or CD79a). However, thirteen of 35 recurrent cases showed aberrant loss of CD20 expression (37%) by immunohistochemical or flow cytometric studies. Pre- and post-Rituximab treated tumor cell DNA was successfully extracted from archival paraffin sections, hematoxylin and eosin (H and E) stained slides, smears, or frozen cells in 10 of 13 CD20 negative recurrent cases. PCR studies for immunoglobulin (Ig) heavy chain gene rearrangements were performed in all these cases. Five cases showed identical Ig heavy chain gene rearrangements in the paired specimens. PCR assay for Ig kappa (kappa) gene rearrangement was performed in the five paired specimens lacking detectable Ig heavy chain gene rearrangements; 2 of them showed identical Igkappa gene rearrangements. Three pairs showed unmatched Ig heavy chain and Igkappa gene rearrangements, probably due to poor quality of recovered DNA. Aberrant loss of CD20 antigens may be a mechanism of treatment resistance and should be considered in the immunophenotyping of recurrent Rituximab-treated B-cell neoplasms; therefore, a panel of B cell markers is recommended for the immunologic diagnosis of recurrent B cell malignancies after Rituximab therapy. Seven of ten pairs of recurrent CD20-negative cases showed identical Ig heavy chain and Igkappa gene rearrangements by PCR assay, strongly suggesting that the pre- and post-Rituxan treated B cell neoplasms are clonally-related.

    View details for DOI 10.1080/1042819021000040044

    View details for Web of Science ID 000178910400013

    View details for PubMedID 12613521

  • Targeting multiple genetic aberrations in isolated tumor cells by spectral fluorescence in situ hybridization CANCER DETECTION AND PREVENTION Slovak, M. L., Zhang, F. Y., Tcheurekdjian, L., Bobadilla, D., Bedell, V., Arber, D. A., Persons, D. L., Sosman, J. A., Murata-Collins, J. L. 2002; 26 (3): 171-179


    Tumorigenesis is characterized by the stepwise accumulation of multiple genetic changes that modify specific growth controls and cell survival. Conventional fluorescence in situ hybridization (FISH) assays reliably target one to three probes in a single hybridization. Simultaneous detection of more than three chromosomal or gene targets should increase the overall power of molecular cytogenetics by permitting detection of multiple genetic aberrations at the single cell level.Spectral FISH (S-FISH) is an innovative molecular cytogenetic approach that can target many specific chromosomal aberrations in interphase and metaphase cells in a single hybridization, using combinatorial fluorescence and digital imaging microscopy.S-FISH is a reliable means to identify disease-specific aberrations at the DNA level in individual tumor cells in hematopoietic disorders and malignant melanoma.S-FISH is a sensitive assay for the diagnosis and monitoring of disease-specific or patient-specific genetic aberrations, with significant clinical application in oncology for early detection of new or re-emerging abnormal clones, allowing for earlier therapeutic intervention.

    View details for Web of Science ID 000178129200001

    View details for PubMedID 12269763

  • Inflammatory pseudotumor and follicular dendritic cell tumor AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Weiss, L. M. 2001; 25 (12): 1558-1559

    View details for Web of Science ID 000172428900017

    View details for PubMedID 11717550

  • Angiotropic lymphoma: An immunophenotypically and clinically heterogeneous lymphoma MODERN PATHOLOGY Yegappan, S., Coupland, R., Arber, D. A., Wang, N., Miocinovic, R., Tubbs, R. R., Hsi, E. D. 2001; 14 (11): 1147-1156


    Angiotropic lymphoma (AL) is an uncommon lymphoma often presenting with nonspecific clinical features and having a high mortality rate. Although not specifically recognized by the Revised European-American Classification of Lymphoid Neoplasms, it likely will appear as a subtype of diffuse large B-cell lymphoma in the upcoming WHO classification. Some authors may also consider it to be a subtype of cutaneous lymphomas. Recent studies have reported an immunophenotypic heterogeneity of AL, and in rare instances, an association with other NHL. To further characterize AL, we studied the immunophenotype by immunohistochemistry for CD5, CD10, CD20, bcl-2, and bcl-6 in 18 cases of B-cell AL identified at three medical centers in North America. Bcl-2 gene rearrangement status by polymerase chain reaction and Epstein Barr virus status by in situ hybridization also were evaluated. Eight men and 10 women were identified with AL (median age 71 years). Eleven patients were diagnosed in life and seven were diagnosed at autopsy. Neurologic symptoms were the most common presentation, seen in six patients. Skin was the most commonly biopsied site. All showed classic intravascular localization; in two cases, there was also a minor diffuse large cell lymphoma component observed in some organs. Most (89%) of the cases expressed bcl-2 protein; CD10, bcl-6 and CD5 were each expressed in 22% of cases. Based on CD5 and CD10 expression, three major groups were evident: CD5-, CD10- (11 cases); CD5+, CD10- (3 cases), and CD5-, CD10+ (3 cases). Even though a follicle center lymphoma preceded the AL in one patient, we did not detect bcl-2 gene rearrangement in any of these cases. All cases were negative for Epstein Barr virus. Of the five treated with chemotherapy, two achieved a complete remission. Based on these findings, we conclude that ALs are clinically and immunophenotypically heterogeneous and may represent more than one pathogenetic entity. In some instances AL may be preceded by another lymphoproliferative disorder, raising the possibility that some cases of AL may represent a transformation from another type of lymphoma. Cutaneous manifestations of AL are common; however, it appears to be a systemic lymphoma. Although often fatal, patients with AL who are diagnosed early and treated with chemotherapy may achieve remission.

    View details for Web of Science ID 000172160400012

    View details for PubMedID 11706077

  • Histological and immunohistochemical characterization of extranodal diffuse large-cell lymphomas with prominent spindle cell features HISTOPATHOLOGY Wang, J., Sun, N. C., Nozawa, Y., Arber, D. A., Chu, P., Chang, K. L., Weiss, L. M. 2001; 39 (5): 476-481


    To describe five cases of diffuse large-cell lymphoma with prominent spindle cell components involving skin, nasal-ocular mucosa, and soft tissue. Because of the spindle cell morphology, such cases must be differentiated from true sarcomas arising in or metastasizing to soft tissue, skin, bone, lymph node, or other organs and sites.Formalin-fixed paraffin-embedded archival tissue from five consultation cases of diffuse large-cell lymphoma with prominent spindle cell features involving the skin, nasal-ocular mucosa, and soft tissue in three male and two female patients was studied by histology and immunohistochemistry. Clinicopathological findings were also reviewed for all the patients. By morphology, initial evaluation of the cases suggested spindle cell sarcoma in two cases, inflammatory pseudotumour in one case, large-cell lymphoma in another case, and one case was considered suspicious for malignant lymphoma. Immunohistochemistry demonstrated a B-cell lineage in four of the spindle cell lesions, with a diagnosis of primary cutaneous CD30+ anaplastic large cell lymphoma made for the fifth case. Four of five cases also showed actin reactivity.Although extremely rare, lymphomas with prominent spindle cell morphology can be encountered in daily surgical pathology practice, and should be included in the differential diagnosis of spindle cell lesions in skin and soft tissue. The observed actin reactivity in four of the five spindle cell lymphomas may lead to a misdiagnosis of leiomyosarcoma if lymphoid markers are not included in the immunohistochemical panel.

    View details for Web of Science ID 000172341300006

    View details for PubMedID 11737305

  • Large solitary fibrous tumor of the kidney - Report of two cases and review of the literature AMERICAN JOURNAL OF SURGICAL PATHOLOGY Wang, J., Arber, D. A., Frankel, K., Weiss, L. M. 2001; 25 (9): 1194-1199


    Solitary fibrous tumors are spindle cell neoplasms frequently arising in the serosal surface as well as a variety of other sites. We report two cases of large solitary fibrous tumor arising in the kidney, clinically thought to be renal cell carcinoma, in 41- and 72-year-old men. Although large in size (13.0 and 14.0 cm in greatest dimension, respectively), both lesions were well circumscribed and composed of a mixture of spindle cells and dense collagenous bands with no areas of necrosis or cystic changes noted macroscopically or microscopically. Immunohistochemical studies revealed reactivity for vimentin, CD34, collagen IV, and bcl-2 protein in both cases, with no staining for keratin, S-100 protein, or muscle markers, confirming the diagnosis of solitary fibrous tumor of the kidney. Solitary fibrous tumor of the kidney is rare but may present as a large mass that may be clinically confused with carcinoma or sarcoma.

    View details for Web of Science ID 000170652600011

    View details for PubMedID 11688580

  • Myeloperoxidase immunoreactivity in adult acute lymphoblastic leukemia AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A., Snyder, D. S., Fine, M., Dagis, A., Niland, J., Slovak, M. L. 2001; 116 (1): 25-33


    To evaluate the frequency and significance of myeloperoxidase positivity in adult acute lymphoblastic leukemia (ALL), bone marrow biopsy material from 82 adults with ALL was evaluated with a polyclonal myeloperoxidase (pMPO) antibody. Nineteen cases (23%) demonstrated evidence of pMPO immunoreactivity. Positive cases were precursor B-cell lineage, and CD13 or CD15 expression was more frequent than in the pMPO-negative cases. A subset of pMPO-positive cases studied with a monoclonal MPO antibody was negative. Western blot analysis using the pMPO antibody showed the expected 55-kd band for myeloperoxidase in pMPO-positive and pMPO-negative ALLs, suggesting a lack of specificity of this antibody in ALL. Forty-two percent (8/19) of the pMPO-positive ALL cases demonstrated evidence of t(9;22) by either karyotype or polymerase chain reaction analysis. The pMPO-positive ALLs had a lower frequency of extramedullary disease than the pMPO-negative group and a trend toward improved overall survival compared with the pMPO-negative group. Immunoreactivity with pMPO in adult ALL may lead to an incorrect interpretation of biphenotypic acute leukemia using a recently described scoring system, and a revision to that scoring system is proposed to accommodate pMPO-positive ALL.

    View details for Web of Science ID 000169531900004

    View details for PubMedID 11447748

  • The Burkitt-like lymphomas: a Southwest Oncology Group study delineating phenotypic, genotypic, and clinical features BLOOD Braziel, R. M., Arber, D. A., Slovak, M. L., Gulley, M. L., Spier, C., Kjeldsberg, C., Unger, J., MILLER, T. P., Tubbs, R., Leith, C., Fisher, R. I., Grogan, T. M. 2001; 97 (12): 3713-3720


    The Revised European-American Lymphoma classification gives Burkitt-like lymphoma (BLL) provisional status, leaving unresolved the differential diagnosis with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). This study compared the biologic features of adult BLL and DLBCL. The phenotypic distinction between BLL and DLBCL was determined by immunohistochemical staining of frozen tissue from 13 patients with BLL and 55 patients with DLBCL by using an extensive antibody panel including Ki-67, CD10, CD11a/lymphocyte function-associated antigen 1alpha (LFA-1alpha), CD18/LFA-1beta, CD58/LFA-3, and CD54/intercellular adhesion molecule, CD8 for tumor-infiltrating cytotoxic T cells (T-TILs), CD44 homing receptor, and p53 and Bcl-2 oncogenic proteins. Compared with DLBCL, BLL had a higher proliferative rate (mean Ki-67, 88% versus 53%), greater expression of CD10 and p53 antigens, and decreased expression of Bcl-2. BLL cases had a consistent absence of one or more cell adhesion molecules (92% versus 27%), low T-TIL numbers, and absence of CD44 homing receptor (92% versus 14%). The t(8;14) translocation was identified in 80% of BLL cases, but no patients with BLL had the t(14;18) translocation. In a 10-year analysis, median survival of patients with BLL was 1.2 years, and that of patients with DLBCL was 2.5 years. Although the proportion of patients cured was similar in the 2 groups, BLL patients had an increased risk of early death. We conclude that BLL can be recognized by its combined morphologic and phenotypic features and that it represents a high-grade lymphoma much closer to BL than DLBCL. Retention of the BLL category or inclusion of BLL as a variant of BL is biologically and clinically more appropriate than absorbing the category of BLL into DLBCL. (Blood. 2001;97:3713-3720)

    View details for Web of Science ID 000169164300009

    View details for PubMedID 11389007

  • CD79: A review APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Chu, P. G., Arber, D. A. 2001; 9 (2): 97-106


    CD79 is composed of CD79a and CD79b components expressed almost exclusively on B cells and B-cell neoplasms. CD79a and CD79b expression precedes immunoglobulin (Ig) heavy-chain gene rearrangement and CD20 expression during B-cell ontogeny and disappears later than CD20 in the late (plasma cell) stage of B-cell differentiation. Therefore, antibodies to CD79a and CD79b are useful in the differential diagnosis of B-cell neoplasms from T-cell neoplasms or myeloid neoplasms, or L and H lymphocyte predominance Hodgkin's lymphoma from classic Hodgkin's lymphoma. In addition, CD79a and CD79b antibodies are useful markers in the diagnosis of precursor B-acute lymphoblastic leukemia (pre-B-ALL) because many of these tumors are negative for other B-cell markers, such as CD20 and CD45RA. Furthermore, for B-cell neoplasms, wherein CD20 expression is aberrantly lost, such as in diffuse large B-cell lymphoma, or for B-cell neoplasms after CD20-antibody therapy, CD79a may be used as a first-line B-cell marker for the diagnosis. In this review, the authors discuss the molecular biology of CD79 and the frequency and usefulness of CD79 expression in these neoplasms.

    View details for Web of Science ID 000168915500001

    View details for PubMedID 11396639

  • Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: An immunohistochemical comparison of 34 cases MODERN PATHOLOGY Chu, P. G., Arber, D. A., Weiss, L. M., Chang, K. L. 2001; 14 (5): 465-471


    Endometrial stromal sarcoma (ESS), uterine cellular leiomyoma (UCL), and uterine leiomyosarcoma (ULS) are composed mainly of spindle cells that express similar antigens such as desmin, smooth muscle actin (SMA), and muscle-specific actin (MSA). The differential diagnosis of an ESS versus a uterine smooth muscle tumor or an extrauterine spindle cell sarcoma can be problematic based solely on clinical presentation, histologic assessment, or routine immunohistochemistry. Recently, we reported that normal endometrium, but not myometrium, as well as five cases of ESS, were positive for CD10. We now report the results of CD10 immunohistochemistry in an additional 11 cases of ESS (total 16 cases), 10 cases of UCL, and nine cases of ULS. CD10 immunoreactivity was detected in 16 of 16 cases of ESS (100%) as compared to only 2 of 10 cases of UCL (20%) and none of nine cases of ULS (0%). We compared the utility of CD10 immunoreactivity with that of desmin, SMA, MSA, estrogen receptor (ER), and inhibin in these tumors. Although the majority of cases of UCL and ULS were positive for SMA, MSA, and desmin, a substantial portion of cases of ESS were also positive for SMA, MSA, and desmin. We conclude that in combination with SMA, MSA, and desmin, CD10 is a useful immunohistochemical marker in the differential diagnosis of ESS versus UCL or ULS.

    View details for Web of Science ID 000168791800015

    View details for PubMedID 11353058

  • Immunohistochemical detection of CD10 in paraffin sections of hematopoietic neoplasms - A comparison with flow cytometry detection in 56 cases APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Chu, P. G., Chang, K. L., Weiss, L. M., Arber, D. A. 2000; 8 (4): 257-262


    Paraffin-section immunohistochemistry with heat-induced epitope retrieval using a newly characterized monoclonal antibody (clone 56C6) against the CD10 antigen was performed on 56 hematopoietic tumors previously studied for CD10 expression by flow cytometry. The cases included 33 precursor B-lymphoblastic leukemias, 10 acute myeloid leukemias, five precursor T-lymphoblastic leukemias, five follicular lymphomas, and three Burkitt cell leukemias. Forty of the 56 cases were CD10 positive by flow cytometry studies, including all five follicular lymphomas (100%); 30 of 33 (91%) cases of precursor B-lymphoblastic leukemias, two of three (66%) cases of Burkitt cell leukemias, two of five (40%) cases of precursor T-lymphoblastic leukemias, and none of the 10 cases of acute myeloid leukemia. Thirty-nine of the 40 (97%) flow cytometric CD10-positive cases also expressed CD10 by immunohistochemistry in formalin- or B5-fixed, paraffin-embedded tissue, with only one case of precursor B-lymphoblastic leukemia being positive by flow cytometry and negative by immunohistochemistry. The 16 CD10-negative flow cytometry specimens were all also negative by immunohistochemistry. Thirty-seven CD10 immunohistochemistry positive cases showed a diffuse membranous staining pattern and two cases demonstrated a Golgi staining pattern. The fixation methods (10% neutral buffered formalin versus B5) and decalcification did not affect the CD10 immunostaining results. This study demonstrates that the new CD10 monoclonal antibody clone 56C6 is a reliable marker for detection of CD10 antigen expression in formalin-and B5-fixed paraffin-embedded tissue after heat-induced epitope retrieval when compared with flow cytometry detection of fresh tissue samples.

    View details for Web of Science ID 000165547800001

    View details for PubMedID 11127916

  • CD20-positive peripheral T-cell lymphoma: Report of a case after nodular sclerosis Hodgkin's disease and review of the literature MODERN PATHOLOGY Mohrmann, R. L., Arber, D. A. 2000; 13 (11): 1244-1252


    We present a case of peripheral T-cell lymphoma co-expressing CD3 and CD20, as well as demonstrating T-cell receptor gene rearrangement, in a patient who had been diagnosed with nodular sclerosis Hodgkin's disease 5 years previously. Although 15 cases of CD20-positive T-cell neoplasms have been previously reported in the literature, this is the first report of CD20-positive T-cell lymphoma occurring subsequent to treatment of Hodgkin's disease. The current case affords an opportunity to review the rarely reported expression of CD20 in T-cell neoplasms as well as the relationship between Hodgkin's disease and subsequently occurring non-Hodgkin's lymphomas. In addition, the identification of this case supports the suggestion that the use of CD20 antibodies alone in paraffin sections may lead to an incorrect determination of cell lineage in some cases.

    View details for Web of Science ID 000165570500013

    View details for PubMedID 11106083

  • Chronic myelogenous leukemia LABORATORY MEDICINE Gaal, K., Arber, D. A. 2000; 31 (10): 557-562
  • Transplantation and growth characteristics of human fetal lymph node in immunodeficient mice EXPERIMENTAL HEMATOLOGY Shih, C. C., Hu, J., Arber, D., LeBon, T., Forman, S. J. 2000; 28 (9): 1046-1053


    The lymph node is an integral component of the immune system and the major site of antigen-dependent lymphocyte proliferation and differentiation. Development of animal models possessing functional primary human lymph nodes will have a significant impact on research in lymphopoiesis and immune response. To date, successful transplantation of primary human lymph nodes in rodents has not yet been reported. This work was undertaken to develop a reliable methodology to engraft primary human fetal lymph nodes in immunodeficient mice.Three different sets of parameters, including three different transplantation sites in the mice, two different strains of immunodeficient mice, and two different preconditioning regimens, were evaluated. The growth characteristics of the implanted primary human fetal lymph nodes were examined 3 months after transplantation by histologic, immunocytochemical, and flow cytometric methods.Transplantation of primary human fetal lymph nodes into subcutaneous pouches in the ears in severe combined immunodeficiency (SCID) mice preconditioned with etoposide reproducibly give rise to >80% engraftment. The engrafted primary human fetal lymph nodes undergo massive growth (>200-fold) and retain the same histology and cellular composition as fresh human fetal lymph nodes from the same donors.We report, for the first time, the development of a reliable methodology to successfully engraft human fetal lymph node in SCID mice. The engrafted human lymph nodes are visible and accessible to experimental manipulations. This SCID-hu mouse model with human lymph node should provide a physiologically relevant system to investigate lymphopoiesis, immunologic response, and virus-mediated immunosuppression.

    View details for Web of Science ID 000089394900007

    View details for PubMedID 11008017

  • Immunophenotyping of hematopoietic neoplasms SEMINARS IN DIAGNOSTIC PATHOLOGY Chu, P. G., Chang, K. L., Arber, D. A., Weiss, L. M. 2000; 17 (3): 236-256


    Advances in the staging and treatment of hematopoietic neoplasms have necessitated a high degree of accuracy in the diagnosis and classification of these tumors. A greater degree of diagnostic precision has resulted from recent advances in immunophenotyping and genotyping of hematopoietic neoplasms. This review discusses several new immunohistochemical reagents, many of which are derived from results of molecular studies.

    View details for Web of Science ID 000088969300009

    View details for PubMedID 10968709

  • High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission LEUKEMIA Stein, A. S., O'Donnell, M. R., Slovak, M. L., Nademanee, A., Dagis, A., Schmidt, G. M., Parker, P. M., Snyder, D. S., Smith, E. P., Somlo, G., Margolin, K. A., Arber, D., Niland, J., Forman, S. J. 2000; 14 (7): 1191-1196


    Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.

    View details for Web of Science ID 000088063600004

    View details for PubMedID 10914541

  • Amplification and overexpression of HER-2/neu are uncommon in advanced stage melanoma ANTICANCER RESEARCH Persons, D. L., Arber, D. A., Sosman, J. A., Borelli, K. A., Slovak, M. L. 2000; 20 (3B): 1965-1968


    The HER-2/neu proto-oncogene is a useful prognostic and predictive biomarker in breast cancer. In addition, use of a humanized monoclonal antibody against HER-2/neu has recently been shown to have efficacy in the treatment of metastatic breast cancer. In order to examine the potential of HER-2/neu as a biomarker and as a target for HER-2/neu monoclonal antibody treatment in melanoma, we examined the HER-2/neu status in 40 advanced stage melanomas. Using fluorescence in situ hybridization for determining the gene amplification status and immunohistochemistry for detecting protein overexpression, we found that only one out of 40 cases of melanoma had an altered HER-2/neu status. These results demonstrated that HER-2/neu amplification and overexpression are not common in advanced stage melanoma and thus, HER-2/neu would have limited value as a biomarker or as a target for immunotherapy in melanoma.

    View details for Web of Science ID 000089222500014

    View details for PubMedID 10928135

  • Coexisting thymic and gastric lymphomas of mucosa-associated lymphoid tissues in a patient with Sjogren syndrome ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Nagasaka, T., Lai, R., Harada, T., Chen, Y. Y., Chen, W. G., Arber, D. A., Weiss, L. M. 2000; 124 (5): 770-773


    Lymphomas of mucosa-associated lymphoid tissues (MALTomas) arising from the thymus are extremely rare. In this case report, we describe a 36-year-old woman with an 11-year history of Sjgren syndrome who was found to have a thymic MALToma coexisting with a gastric MALToma. Both tumors shared similar histologic features, showing clusters of centrocytic-like B cells, lymphoepithelial lesions, and prominent plasmacytic differentiation. They also showed the following identical immunohistochemical features: CD20(+), IgA/lambda(+), CD5(-), and CD43(-). Molecular studies using polymerase chain reaction methods revealed monoclonal gene rearrangement of the immunoglobulin heavy chain in the gastric MALToma, but not in the thymic MALToma. The possible pathogenesis of this unusual case is discussed.

    View details for Web of Science ID 000086926900026

    View details for PubMedID 10782167

  • Paraffin section immunophenotype of cutaneous and extracutaneous mast cell disease - Comparison to other hematopoietic neoplasms AMERICAN JOURNAL OF SURGICAL PATHOLOGY Yang, F., Tran, T. A., Carlson, J. A., Hsi, E. D., Ross, C. W., Arber, D. A. 2000; 24 (5): 703-709


    Mast cell disease (MCD) is a rare proliferation that may be easily confused with other hematopoietic tumors. Several paraffin section antibodies immunoreact with mast cells but most are not specific. Tryptase, a specific marker of mast cells, may not be cost-effective to maintain in a laboratory because of the rarity of these lesions. This study was undertaken to assess the immunoreactivity of MCD and attempt to select a limited antibody panel for diagnosing MCD among hematopoietic tumors that morphologically mimic MCD. Immunophenotyping of cutaneous ( 10 cases) and extracutaneous (18 cases) MCD, as well as 94 other hematopoietic neoplasms, was performed on paraffin sections. All cases of MCD showed strong and diffuse positivity for CD68 and tryptase. In the vast majority of the cases, the mast cells were also positive for CD117 (27 of 28) and CD43 (25 of 27). Four cases (40%) of cutaneous MCD demonstrated a subpopulation of mast cells expressing myeloperoxidase (MPX), whereas all extracutaneous MCD were negative for MPX. Two (40%) extramedullary myeloid tumors (EMT) expressed CD43, CD68, CD 117, and MPX, but none expressed tryptase. CD43, CD68, CD117, and tryptase were expressed by 25%, 1%, 15%, and 1%, respectively, of all B-cell lymphoid neoplasms, and none expressed more than one of these four antigens. We conclude that (1) cutaneous MCDs may demonstrate a subpopulation of MPX antigen expressing tumor cells and may be confused with cutaneous involvement by myeloid leukemia if other antibodies are not used; (2) tryptase is the most specific mast cell marker among the antibodies studied; and, (3) the detection of tryptase, together with CD68, CD117, and usually CD43, is unique to MCD among hematopoietic tumors.

    View details for Web of Science ID 000086829600009

    View details for PubMedID 10800989

  • Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors BLOOD Krishnan, A., Bhatia, S., Slovak, M. L., Arber, D. A., Niland, J. C., Nademanee, A., Fung, H., Bhatia, R., Kashyap, A., Molina, A., O'Donnell, M. R., Parker, P. A., Sniecinski, I., Snyder, D. S., Spielberger, R., Stein, A., Forman, S. J. 2000; 95 (5): 1588-1593


    We analyzed data on 612 patients who had undergone high-dose chemoradiotherapy (HDT) with autologous stem cell rescue for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the City of Hope National Medical Center, to evaluate the incidence of therapy-related myelodysplasia (t-MDS) or therapy-related acute myeloid leukemia (t-AML) and associated risk factors. A retrospective cohort and a nested case-control study design were used to evaluate the role of pretransplant therapeutic exposures and transplant conditioning regimens. Twenty-two patients developed morphologic evidence of t-MDS/t-AML. The estimated cumulative probability of developing morphologic t-MDS/t-AML was 8.6% +/- 2.1% at 6 years. Multivariate analysis of the entire cohort revealed stem cell priming with VP-16 (RR = 7.7, P = 0.002) to be independently associated with an increased risk of t-MDS/t-AML. The influence of pretransplant therapy on subsequent t-MDS/t-AML risk was determined by a case-control study. Multivariate analysis revealed an association between pretransplant radiation and the risk of t-MDS/t-AML, but failed to reveal any association with pretransplant chemotherapy or conditioning regimens. However, patients who had been primed with VP-16 for stem cell mobilization were at a 12. 3-fold increased risk of developing t-AML with 11q23/21q22 abnormalities (P = 0.006). Patients undergoing HDT with stem cell rescue are at an increased risk of t-MDS/t-AML, especially those receiving priming with VP-16 for peripheral stem cell collection. (Blood. 2000;95:1588-1593)

    View details for Web of Science ID 000085564700009

    View details for PubMedID 10688812

  • The use of archival bone marrow specimens in detecting B-cell non-Hodgkin's lymphomas using polymerase chain reaction methods LEUKEMIA & LYMPHOMA Nagasaka, T., Lai, R., Chen, Y. Y., Chen, W. G., Arber, D. A., Chang, K. L., Weiss, L. M. 2000; 36 (3-4): 347-352


    The detection of B-cell non-Hodgkin's lymphoma (B-NHL) involving the bone marrow (BM) can be enhanced by assessing immunoglobulin heavy chain (IgH/JH) gene rearrangement using PCR. While the fresh BM aspirate has been the most commonly used specimen, the utility of archival BM tissues has not been extensively evaluated. We studied the BM from 13 patients with nodal B-NHL (7 low-grade and 6 intermediate grade), which were categorized into three groups based on the histologic finding of lymphoma (H) and the presence of a monoclonal IgH/JH band by PCR using fresh BM aspirates (M): (1) H(+)/M(+), 4 cases; (2) H(+)/M(-), 4 cases; and (3) H(equivocal)/M(-), 5 cases. Archival tissues available for study included paraffin-embedded trephine biopsy (TB)/aspirate clots (AC) and air-dried aspirate smears (AS). All TB (13/13) and a subset of AC (5/13) were B5-fixed, and all these tissues failed to yield analyzable DNA. In contrast, sufficient DNA was consistently obtained in AC that were formalin-fixed (8/13). Of these 8 cases, 2/3 of group 1, 3/3 of group 2, and 0/2 of group 3 had a monoclonal IgH band. Using DNA extracted from microdissected lymphoid aggregates morphologically evident in the AC sections, additional positive cases were identified: 1/3 of group 1 and 2/2 of group 3. In those 5 cases that did not have formalin-fixed TB/AC, sufficient DNA was extracted from AS in all cases; one additional positive case was identified in group 1. Overall, 4/4 (100%) of group 1, 3/4 (75%) of group 2, and 2/5 (40%) of group 3 showed molecular evidence of lymphoma. To conclude, archival BM specimens are a useful source of DNA for molecular detection of B-NHL involvement, and formalin appears to be a better fixative than B5. The use of these samples may improve the overall detection sensitivity.

    View details for Web of Science ID 000085020700014

    View details for PubMedID 10674907

  • Allogeneic bone marrow transplantation (BRIT) for high risk all in first remission (1CR). Fung, H., Jamieson, C., Snyder, D., O'Donnell, M., Chao, N., Stein, A., Nademanee, A., Molina, A., Palmer, M., Negrin, R., Hilger, J., Slovak, M. L., Spielberger, R., Parker, P., Forman, S., Kashyap, A., Vora, N., Krishnan, A., Rodriguez, R., Bhatia, R., Niland, J. C., Senitzer, D., Arber, D., Amylon, M., Arbayo, C., Blume, K. G., Forman, S. J. AMER SOC HEMATOLOGY. 1999: 609A-609A
  • Allogeneic bone marrow transplantation (BMT) for AML in first remission (1CR) utilizing fractionated total body irradiation (FTBI) and VP-16: Analysis of risk factors for relapse and disease-free survival. Fung, H., Jamieson, C., Snyder, D., O'Donnell, M., Chao, N., Stein, A., Nademanee, A., Molina, A., Palmer, J. M., Negrin, R., Hilger, J., Slovak, M. L., Spielberger, R., Parker, P., Forman, S., Kashyap, A., Vora, N., Krishnan, A., Rodriguez, R., Bhatia, R., Niland, J. C., Senitzer, D., Arber, D., Amylon, H., Arbayo, C., Blume, K. G., Forman, S. J. AMER SOC HEMATOLOGY. 1999: 167A-167A
  • Detection of t(2;5) in anaplastic large cell lymphoma - Comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue AMERICAN JOURNAL OF SURGICAL PATHOLOGY Cataldo, K. A., Jalal, S. M., Law, M. E., Ansell, S. M., Inwards, D. J., Fine, M., Arber, D. A., Pulford, K. A., Strickler, J. G. 1999; 23 (11): 1386-1392


    Anaplastic large cell lymphoma (ALCL) is associated with the t(2;5)(p23;q35) translocation involving the anaplastic lymphoma kinase gene (ALK) and the nucleophosmin gene (NPM), which result in expression of a novel fusion protein, NPM-ALK (p80). Clinicopathologic studies have shown that ALK expression in ALCL is associated with improved 5-year survival rates when compared with ALCL lacking ALK expression. This study used paraffin-embedded tissue to compare interphase fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of t(2;5) with immunohistochemical analysis for the detection of ALK protein expression in 27 patients with CD30-positive ALCLs. ALK protein expression was detected with ALK1 antibody in 14 of the 27 patients. The neoplastic cells in 13 of these 14 lymphomas reacted with the p80NPM/ALK antibody. FISH, using a two-color ALK DNA probe, correlated 100% with the immunohistochemical results: a translocation involving the ALK gene was detected in all 14 lymphomas that reacted with anti-ALK1. RT-PCR, performed on 21 lymphomas, detected NPM-ALK mRNA in five of the lymphomas, all of which reacted with anti-ALK1 and showed ALK gene rearrangement by FISH. Lymphomas showing ALK1 reactivity occurred in a younger patient population (median age, 19.5 years) and were associated with improved 5-year survival rates (84%), as compared with lymphomas lacking ALK1 reactivity (median age, 68.0 years; 5-year survival rate, 35%; p = 0.008). We conclude that immunohistochemical studies, using antibody ALK1. and FISH for ALK gene rearrangement are equally effective for identifying patients with ALCL who have a favorable clinical outcome.

    View details for Web of Science ID 000083467900009

    View details for PubMedID 10555007

  • Indolent T-lymphoblastic proliferation - Report of a case with a 16-year course without cytotoxic therapy AMERICAN JOURNAL OF SURGICAL PATHOLOGY Velankar, M. M., NATHWANI, B. N., Schlutz, M. J., Bain, L. A., Arber, D. A., Slovak, M. L., Weiss, L. M. 1999; 23 (8): 977-981


    T-lymphoblastic lymphoma is a high-grade malignant lymphoma. Clinically indolent T-lymphoblastic proliferations have not been described. We present a case report of an indolent T-cell lymphoblastic proliferation studied by histopathology, immunohistochemistry, flow cytometry, antigen receptor gene rearrangement studies, and cytogenetics. The patient had recurrent masses in the upper aerodigestive tract over a 16-year period, was treated by multiple surgical excisions, and never received either chemotherapy or radiotherapy. A proliferation of lymphoblasts was present histologically. The cells were positive for terminal deoxynucleotidyl transferase, CD1, and CD3, and coexpressed CD4 and CD8. No clonal rearrangements of the T-cell receptor beta or gamma chain genes were identified. Cytogenetic studies revealed a questionable inversion of the short arm of chromosome 9, affecting the 9p21-22 region. Although ectopic thymic tissue was considered, the case was considered to be an indolent lymphoblastic proliferation. It should be recognized that rare lymphoblastic proliferations may not behave in a high grade fashion as typically seen in T-lymphoblastic lymphoma.

    View details for Web of Science ID 000081740400017

    View details for PubMedID 10435569

  • Extranodal follicular dendritic cell tumor of the abdominal wall JOURNAL OF CLINICAL ONCOLOGY Schwarz, R. E., Chu, P. G., Arber, D. A. 1999; 17 (7): 2290-2292

    View details for Web of Science ID 000081264300043

    View details for PubMedID 10561286

  • Peripheral T-cell lymphoma with Toutonlike tumor giant cells associated with HIV infection - Report of two cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Chang, K. L., Weiss, L. M. 1999; 23 (5): 519-522


    T-cell lymphoma in patients infected with HIV is much less common than B-cell lymphoma. We describe two cases of HIV-associated extranodal lymphoma that showed Toutonlike tumor giant cells and mononuclear large lymphoma cells. Both cell types expressed T-cell-associated antigens, including CD3, CD5, CD43, and CD45RO, and were CD4- and CD30-positive and negative for all B-lineage-associated antigens. Both cases showed T-cell receptor gamma chain gene rearrangements using the polymerase chain reaction and were negative for the Epstein-Barr virus by in situ hybridization. Despite the expression of CD30 by the multinucleated cells, both cases were negative for ALK1 by immunohistochemistry and failed to show evidence of the nucleophosmin-anaplastic lymphoma kinase fusion product characteristic of t(2;5) using the reverse-transcriptase polymerase chain reaction. Although rare, CD4-positive, T-cell lymphoma with Toutonlike giant cells may be a distinct type of HIV-associated malignant lymphoma.

    View details for Web of Science ID 000080178200004

    View details for PubMedID 10328082

  • Soft tissue masses of the chest wall and axilla - Has metastatic melanoma been considered? AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Schwarz, R. E., Chow, W. A., Andersen, J. S., Arber, D. A., Balch, C. M. 1999; 22 (2): 174-177


    Isolated axillary and chest wall soft tissue masses are an uncommon presentation of metastatic cancer. The authors present three patients in whom malignant melanomas metastatic to these sites had been misdiagnosed, leading to inappropriate oncologic treatment planning in all three cases. The presumed diagnoses, even after fine-needle aspiration or trucut biopsies, were soft-tissue sarcoma (n = 2) and undifferentiated breast cancer (n = 1). The combination of taking a thorough history and performing proper immunohistochemical analysis of the biopsy material would have suggested the presence of malignant melanoma in all cases. As the disease appeared locoregionally limited in all patients, radical surgical resection with extended lymphadenectomy was performed without significant dysfunction of the upper extremity. One patient agreed to postoperative immunotherapy with interferon-alpha. Two patients are currently alive 17 and 14 months after operation. One patient was found to have systemic recurrence at 5 months, one experienced two isolated local recurrences in a prior operative site that were amenable to reresection and presently has no evidence of disease 12 months after resection, and one patient remains free of disease at 14 months. Clinical presentation, suggested diagnostic workup, and therapeutic implications are discussed to avoid misdiagnoses in this setting of possible clinical presentations of metastatic melanoma.

    View details for Web of Science ID 000079433900014

    View details for PubMedID 10199454

  • Practical applications of immunohistochemistry in hematolymphoid neoplasms. Annals of diagnostic pathology Chu, P. G., Chang, K. L., Arber, D. A., Weiss, L. M. 1999; 3 (2): 104-133


    Immunohistochemistry plays a key role in the diagnosis and classification of hematolymphoid neoplasms. New cell and lineage markers are constantly being discovered and added to the existing long list of antibodies. In this review article we provide general information and new applications of the commonly used hematolymphoid markers. We also discuss the features and applications of some newly discovered markers, such as ALK, fascin, granzyme/perforin, and tryptase. There is no universal "panel" for the diagnosis of hematolymphoid neoplasms. However, in this review article, we provide suggested panels for a given hematolymphoid neoplasm that is based on our experience and that reported in the literature.

    View details for PubMedID 10196391

  • Acute lymphoblastic leukemia - Survey of immunophenotype, French-American-British classification, frequency of myeloid antigen expression, and karyotypic abnormalities in 210 pediatric and adult cases AMERICAN JOURNAL OF CLINICAL PATHOLOGY Khalidi, H. S., Chang, K. L., Medeiros, L. J., Brynes, R. K., Slovak, M. L., Murata-Collins, L., Arber, D. A. 1999; 111 (4): 467-476


    Immunophenotypic studies are essential to distinguish acute lymphoblastic leukemia (ALL) from minimally differentiated acute myeloid leukemia (AMLM0) and to classify ALL into immunologic subtypes. Frequently, immunophenotyping identifies myeloid antigen expression in ALL, causing a potential diagnostic problem. To evaluate the immunophenotype of ALL, we studied 210 cases of pediatric and adult ALL by flow cytometry and compared the results with the French-American-British (FAB) Cooperative Group classification and the karyotypic findings. Myeloid-associated antigens were expressed in 78 (45.6%) of precursor B-cell ALL cases. Pediatric precursor B ALLs had a higher frequency of myeloid antigen expression than did adult cases. All mature B-cell ALL cases were negative for TdT and myeloid antigens. Myeloid antigen expression was less frequent in T-cell ALL cases compared with precursor B-cell ALL cases. Of the 192 cases submitted for cytogenetic analysis, 147 were abnormal. The most common chromosomal translocation was the Philadelphia chromosome, which was more likely to have L2 blast morphology and a precursor B immunophenotype. Myeloid antigen expression was present in 70.8% of Ph-positive cases (P = .008). Chromosome rearrangements involving 11q23 also showed an increased frequency of myeloid antigen expression. Chromosome translocations involving regions of T-cell receptor genes were present in 24% of T-cell ALL cases. A high percentage of ALL cases, however, had various other cytogenetic abnormalities, many of which involved less well-studied chromosomal regions.

    View details for Web of Science ID 000079385100004

    View details for PubMedID 10191766

  • Frequency of CD43 expression in non-Hodgkin lymphoma - A survey of 742 cases and further characterization of rare CD43(+) follicular lymphomas AMERICAN JOURNAL OF CLINICAL PATHOLOGY Lai, R., Weiss, L. M., Chang, K. L., Arber, D. A. 1999; 111 (4): 488-494


    CD43 expression on B cells is an immunophenotypic feature suggestive of malignancy. In the light of its diagnostic importance, we performed a comprehensive survey of CD43 expression in various types of non-Hodgkin lymphoma (NHL) and determined the frequency of its expression in routinely fixed paraffin-embedded tissues. Tissue sections in 742 cases of NHL, pretreated by the heat-induced epitope retrieval technique, were immunostained using an anti-CD43 antibody. Three categories of CD43 positivity were found: (1) more than 90% of T-cell lymphoma, mantle cell lymphoma, B-cell small lymphocytic lymphoma, and Burkitt lymphoma cases were positive; (2) 20% to 40% of nodal and extranodal marginal zone lymphoma (MZL), diffuse large B-cell lymphoma, Burkitt-like B-cell lymphoma, and lymphoplasmacytoid lymphoma cases were positive; and (3) 0% to 6% of primary splenic MZL and various types of follicular lymphoma cases were positive. Most CD43+ follicular lymphomas were predominantly large cell type with focally diffuse areas; their follicular center cell origin in 4 of 8 cases was supported by the presence of CD10 immunoreactivity and/or t(14;18) fusion gene product. CD43 is frequently detectable in a subset of B-NHL, and, thus, it seems to be a highly sensitive marker for these tumors. CD43 also may be a useful marker for classifying B-cell NHLs by virtue of its differential expression in these tumors.

    View details for Web of Science ID 000079385100006

    View details for PubMedID 10191768

  • Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome - A report of five cases and review of the literature AMERICAN JOURNAL OF CLINICAL PATHOLOGY Lai, R., Arber, D. A., Brynes, R. K., Chan, O., Chang, K. L. 1999; 111 (3): 373-378


    Although it has been known that patients with chronic lymphocytic leukemia (CLL) have a higher frequency of second malignant neoplasms, the development of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in these patients is extremely rare. Most reported cases have been therapy-related. In this article, we report the clinical and immunophenotypic features of 5 cases of untreated CLL concurrent with or followed by the development of AML or MDS. All 5 patients were men, with ages ranging from 57 to 87 years (mean, 73.8 years). Four patients had AML and 1 patient had refractory anemia with ringed sideroblasts. In the 4 cases of AML and CLL, 2 distinct cell populations (i.e., myeloblasts and lymphocytes) were identified morphologically and/or immunophenotypically. Our findings support that this rare concurrence of AML or MDS and untreated CLL may represent 2 separate disease processes.

    View details for Web of Science ID 000078840700012

    View details for PubMedID 10078113

  • Adult precursor-B acute lymphoblastic leukemia with translocations involving chromosome band 19p13 is associated with poor prognosis CANCER GENETICS AND CYTOGENETICS Khalidi, H. S., O'Donnell, M. R., Slovak, M. L., Arber, D. A. 1999; 109 (1): 58-65


    Cytogenetic translocations involving chromosome band 19p13, the site of the E2A gene, have previously been reported in pediatric acute lymphoblastic leukemias (ALL) in association with a precursor-B cell immunophenotype and poor prognosis. We studied the frequency, pathologic findings, and clinical course of adults with leukemia with 19p13 translocations. Six patients with t(1;19) (q23;p13) and one patient with t(17;19)(q21;p13), all with ALL, were identified over an 8-year period from among 183 adult ALL patients (2.7%); t(1;19) was observed in 2.2% and t(17;19) in 0.5% of these patients. The seven patients (four females and three males) ranged from 18 to 59 years of age (median 33). All cases had a precursor-B cell immunophenotype, and a distinctive expression of surface markers (CD10, CD19, TdT, and HLA-Dr positive, usually negative for CD20, CD34, and negative for myeloid-associated antigens CD13, CD14, and CD33). The blast cells in one case expressed CD15. All patients were treated with combination chemotherapy and three patients received allogeneic bone marrow transplantation. All patients had early (range 6-20 months) relapses, and died due to progressive disease 7-29 months after diagnosis. Similar to pediatric patients, adults with 19p13 leukemias usually do not respond to intensive therapy and have short survival. The poor prognosis of this group of adult ALL patients highlights the importance of detecting 19p13 translocations by cytogenetic analysis or molecular studies.

    View details for Web of Science ID 000078251300009

    View details for PubMedID 9973961

  • Remission of refractory Sezary syndrome after bone marrow transplantation from a matched unrelated donor. Biology of blood and marrow transplantation Molina, A., Nademanee, A., Arber, D. A., Forman, S. J. 1999; 5 (6): 400-404


    Sezary syndrome is a leukemic variant of mycosis fungoides (MF)/cutaneous T-cell lymphoma (CTCL). Bone marrow transplantation (BMT) from a matched unrelated donor was performed in a 22-year-old woman with a 10-year history of Sezary syndrome who had failed treatment with corticosteroids, methotrexate, photochemotherapy, photopheresis, hydroxyurea, interferon-alpha, and cladarabine. At the time of BMT, she had persistent erythrodermic skin disease, adenopathy, circulating Sezary cells and bone marrow (BM) involvement. The patient underwent BMT from a 6/6 HLA-matched unrelated male donor in August 1996. A BM biopsy obtained on day 30 after BMT showed no evidence of lymphoma and complete male donor engraftment. Her skin lesions resolved within 100 days after transplant. Complete staging studies, including T-cell receptor gene rearrangement studies performed at 36 months post-BMT, showed no evidence of recurrent Sezary syndrome. This represents her first durable remission since the initial diagnosis more than 12 years ago. To our knowledge, this is the first patient with refractory Sezary syndrome who has been successfully treated with allogeneic unrelated donor BMT. Our results indicate that this modality may be effective in inducing remission in refractory MF/CTCL, including Sezary syndrome.

    View details for PubMedID 10595818

  • The immunophenotype of blast transformation of chronic myelogenous leukemia: A high frequency of mixed lineage phenotype in "lymphoid" blasts and a comparison of morphologic, immunophenotypic, and molecular findings MODERN PATHOLOGY Khalidi, H. S., Brynes, R. K., Medeiros, L. J., Chang, K. L., Slovak, M. L., Snyder, D. S., Arber, D. A. 1998; 11 (12): 1211-1221


    Immunophenotypic studies have a limited role in the diagnosis of chronic myelogenous leukemia (CML) but are increasingly being used in CML blast transformation (BT). Determination of the cell lineage of CML blasts is clinically important because patients with lymphoid blast transformation have a better response to chemotherapy and longer survival than those with other lineages. We studied the morphologic, cytochemical, immunophenotypic, cytogenetic, and molecular features of 20 patients with Philadelphia chromosome-positive CML and more than 10% blast cells in peripheral blood or bone marrow. The blasts were morphologically heterogeneous. CD33 was expressed in 19 cases (95%), followed by CD13 (85%), CD11c (80%), CD36 (60%), CD117 (40%), and CD15 (30%). Seven cases (35%) had a precursor-B lymphoid immunophenotype, and 13 (65%) had a predominantly myeloid immunophenotype. Of the former group, of which only one had a pure lymphoid phenotype, terminal deoxynucleotidyl transferase (TdT) and CD19 were expressed in 100%, CD10 in 85.7%, and CD20 in 14.3%. Of the latter group, all 13 expressed from 3 to 6 myeloid antigens, with 46.2% myeloperoxidase positive and 69.2% CD61 positive. No cases were interpreted as T lineage, but the T-cell antigens CD3, CD4, CD5, and CD7 were expressed in 5.0, 40.0, 5.3. and 30.0% of all cases, respectively. In most cases, the immunophenotype of the CML blasts could not be predicted from their morphologic features. Polymerase chain reaction showed that 80.0% of the lymphoid group and 37.5% of the myeloid group had immunoglobulin heavy-chain gene rearrangements. The frequent lineage infidelity of the blast cells in CML BT seems to be related to the stem cell origin of this disorder. Such lineage infidelity, however, makes classification of many cases difficult and the significance of and criteria for biphenotypic blast crisis of CML is yet to be determined.

    View details for Web of Science ID 000077641100011

    View details for PubMedID 9872654

  • Co-expression of CD79a (JCB117) and CD3 by lymphoblastic lymphoma JOURNAL OF PATHOLOGY Pilozzi, E., Pulford, K., Jones, M., Muller-Hermelink, H. K., Falini, B., Ralfkiaer, E., Pileri, S., Pezzella, F., De Wolf-Peeters, C., Arber, D., Stein, H., Mason, D., Gatter, K. 1998; 186 (2): 140-143


    Acute lymphoblastic leukaemia/lymphoma is a malignant disorder derived from the clonal proliferation of lymphoid precursor cells. Whether the tumour cells are of B- or T-cell type is an important criterion for prognosis which has not been available previously to pathologists, due to the lack of a reliable early B-cell marker functioning on routinely processed material. This has changed with the production of monoclonal antibodies against the B-cell signalling molecule CD79a. CD79a is expressed on normal and neoplastic B cells from the early stages of B-cell maturation and has been considered to be B-cell-specific. Currently available antibodies against CD79a, in particular JCB117, allow the identification of B cells, and hence B lymphoblastic disease, in paraffin-embedded material. In this study, the expression of CD79a (JCB117) and CD3 has been investigated in 149 cases of T and 68 cases of B lymphoblastic leukaemia/lymphoma. For the first time, co-expression of CD79a (JCB117) and CD3 is reported in 10 per cent of cases of T lymphoblastic leukaemia/lymphoma. This finding raises questions about the co-expression of T- and B-cell markers in the development of lymphocytes, benign as well as malignant, and alerts pathologists to a potential problem in diagnosis.

    View details for Web of Science ID 000076288600005

    View details for PubMedID 9924428

  • Frequency of bcl-2 expression in non-Hodgkin's lymphoma: A study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-Cell hyperplasia MODERN PATHOLOGY Lai, R., Arber, D. A., Chang, K. L., Wilson, C. S., Weiss, L. M. 1998; 11 (9): 864-869


    The oncoprotein, bcl-2, is expressed in various types of non-Hodgkin's lymphoma (NHL). Immunodetection of this protein is a useful method for distinguishing follicular hyperplasia from follicular lymphoma. Although bcl-2 might also be a useful marker for distinguishing reactive monocytoid B-cell hyperplasia from its putative malignant counterpart, marginal zone lymphoma, there were no extensive studies to date that tested this. Therefore, we performed a survey of bcl-2 expression in 778 cases of NHL using immunohistochemical techniques applied to routinely processed and paraffin-embedded tissues. Of 20 reactive monocytoid B-cell hyperplasias, none were bcl-2 positive, compared with 118 (79%) of 150 marginal zone lymphomas (P = .001). With respect to the follicular lymphomas in our study, of the 110 Grade I lymphomas, 107 (97%) were bcl-2 positive, 119 (83%) of the 143 Grade II lymphomas were positive, and 71 (74%) of the 96 Grade III lymphomas were positive. The bcl-2 positivity of Burkitt-like high-grade B-cell lymphoma was significantly different from that of Burkitt's lymphoma (4 [67%] of 6 vs. 0 of 5; P = .02). T-cell NHL had a significantly lower bcl-2 positivity than did B-cell NHL (10 [45%] of 22 vs. 627 [83%] of 756; P = .0001). Therefore, bcl-2 is a highly sensitive marker for follicular lymphoma and a useful marker for distinguishing reactive monocytoid B-cell hyperplasia from marginal zone lymphoma The significant difference in bcl-2 positivity between Burkitt-like high-grade B-cell lymphoma and Burkitt's lymphoma suggests an additional diagnostic use for this protein.

    View details for Web of Science ID 000075966200008

    View details for PubMedID 9758366

  • Surface immunoglobulin light chain-positive acute lymphoblastic leukemia of FAB L1 or L2 type - A report of 6 cases in adults AMERICAN JOURNAL OF CLINICAL PATHOLOGY Vasef, M. A., Brynes, R. K., Murata-Collins, J. L., Arber, D. A., Medeiros, L. J. 1998; 110 (2): 143-149


    Acute lymphoblastic leukemia (ALL) of B-cell lineage may be classified using the French-American-British (FAB) classification as L1, L2, or L3 type. L1 and L2 ALLs characteristically express terminal deoxynucleotidyl transferase (TdT) and are surface immunoglobulin (sIg)-negative. In contrast, L3 ALL is typically TdT-negative and sIg-positive. However, in a few large studies of children with ALL, sIg expression has been reported in less than 2% of L1 and L2 neoplasms. In these sIg-positive cases, IgM usually has been detected, with Ig light chain in a subset of tumors. Surface Ig expression in L1 or L2 ALL in adults is extremely rare; we found only 1 case report in the English literature. We report 6 cases of L1 or L2 ALL with an unusual immunophenotype arising in adults. In each tumor, the neoplastic cells expressed monotypic sIg light chain (4 lambda, 2 kappa) and TdT. Three tumors expressed CD34. Cytogenetic studies in 4 cases at diagnosis or relapse revealed no evidence of chromosomal translocations involving the c-myc locus, such as the t(8;14), t(2;8), or t(8;22). Three patients responded completely to chemotherapy and are alive; follow-up ranges from 18 to 57 months. Three patients died at 3, 13, and 14 months after diagnosis.

    View details for Web of Science ID 000075403400003

    View details for PubMedID 9704611

  • Detection of Epstein-Barr virus in inflammatory pseudotumor SEMINARS IN DIAGNOSTIC PATHOLOGY Arber, D. A., Weiss, L. M., Chang, K. L. 1998; 15 (2): 155-160


    Inflammatory pseudotumors appear to represent a heterogeneous group of diseases that share common histopathologic features. A subset of these tumors, particularly those in the spleen and liver, harbor the Epstein-Barr virus (EBV) in spindled cells. Methods for detecting EBV in these tumors and the reliability of the different detection methods are discussed. Some EBV-positive inflammatory pseudotumors contain an increase in EBV-positive follicular dendritic cells and demonstrate monoclonal EBV genomes. At least one such case has recurred locally as an unusual EBV-positive follicular dendritic cell tumor. These rare reports support the concept of a distinct EBV-positive, follicular dendritic cell type of inflammatory pseudotumor that may be at increased risk for local recurrence. Many more cases of this rare type of inflammatory pseudotumor must be studied and reported before the clinical validity of such a distinction can be proven. Although EBV detection in spindled cells is unusual, it has been demonstrated in rare smooth muscle tumors arising in immunosuppressed children and young adults.

    View details for Web of Science ID 000073883300007

    View details for PubMedID 9606806

  • The immunophenotype of adult acute myeloid leukemia - High frequency of lymphoid antigen expression and comparison of immunophenotype, French-American-British classification, and karyotypic abnormalities AMERICAN JOURNAL OF CLINICAL PATHOLOGY Khalidi, H. S., Medeiros, L. J., Chang, K. L., Brynes, R. K., Slovak, M. L., Arber, D. A. 1998; 109 (2): 211-220


    Immunophenotyping has become common in the diagnosis and classification of acute leukemias and is particularly important in the proper identification of cases of minimally differentiated acute myeloid leukemia (AML-M0). To evaluate the immunophenotype of adult AML, 106 cases were studied by cytochemical analysis and by flow cytometry with a panel of 22 antibodies. The results were compared with the French-American-British (FAB) Cooperative Group classification, as well as with available cytogenetic data on each case. CD45, CD33, and CD13 were the most commonly expressed antigens (97.2%, 95.3%, and 94.3%, respectively). Lymphoid-associated antigens were expressed in 48.1% of cases. CD20 was the most commonly expressed lymphoid antigen (17%), although often expressed in only a subpopulation of leukemic cells, followed by CD7 (16%), CD19 (9.8%), CD2 (7.5%), CD3 (6.7%), CD5 (4.8%), and CD10 (2.9%). Some immunophenotypes correlated with FAB type, including increased frequency of CD2 expression in AML-M3; lack of CD4, CD11c, CD36, CD117, and HLA-DR expression in AML-M3; increased frequency of CD20 and CD36 expression and lack of CD34 expression in AML-M5; increased frequency of CD5 expression in AML-M5a; and increased frequency of CD14 expression in AML-M5b, when compared with all other AMLs (P < .05). When compared with AML-M5b, AML-M5a demonstrated a lack of CD4 expression and a high frequency of CD117 expression. Complete morphologic and cytogenetic agreement between AML-M3 and t(15;17) was present, and four of five cases of AML-M4Eo demonstrated inv(16). The remaining case of M4Eo was characterized by a 6;9 translocation, and two other inv(16) cases were not classified as M4Eo. Expression of CD2 was present in two t(15;17) cases and in one inv(16) case, but expression of this antigen was not restricted to AML cases with these karyotypic abnormalities. Similarly, expression of CD19 was not specific for t(8;21) AML. All t(8;21) leukemias demonstrated M2 morphology. With the exception of M3, M4Eo, and a subgroup of M2 leukemias, the FAB classification does not appear to define cytogenetically distinct disease groups in adult AML. Immunophenotypically distinct profiles were identified in the M3 and M5 morphologic groups of the FAB classification. Immunophenotyping studies are helpful in the determination of myeloid lineage. In general, however, they are not sufficiently specific alone to be useful in precisely identifying either FAB or cytogenetically defined disease subtypes.

    View details for Web of Science ID 000071749800012

    View details for PubMedID 9583894

  • Hepatosplenic gamma delta T-cell lymphoma--not just alphabet soup. Advances in anatomic pathology Chang, K. L., Arber, D. A. 1998; 5 (1): 21-29

    View details for PubMedID 9868510

  • Toward the validation of aneusomy detection by fluorescence in situ hybridization in bladder cancer: Comparative analysis with cytology, cytogenetics, and clinical features predicts recurrence and defines clinical testing limitations CLINICAL CANCER RESEARCH Zhang, F. Y., Arber, D. A., Wilson, T. G., Kawachi, M. H., Slovak, M. L. 1997; 3 (12): 2317-2328


    Fluorescence in situ hybridization (FISH) is regarded as a potential new tool for the clinical management of bladder cancer that works by detecting cytogenetic aberrations in noncycling, exfoliated cells from bladder irrigations. However, clinical validation steps must be addressed to define the true predictive potential in a clinical setting. Toward the validation of FISH with the use of bladder washings and prior to incorporation into a large, prospective clinical trial, a pilot study was designed to determine its clinical potential, define testing limitations, optimize a panel of probes specific for bladder cancer detection, and outline protocol/data collection parameters. Correlations with standard cytogenetics and clinicopathological features of bladder cancer were investigated. Exfoliated cells obtained from benign bladder washings served as normal controls. The results of this pilot study suggest the following: (a) FISH and cytology are complementary testing procedures; however, the FISH data provided valuable ploidy and specific genotypic information for recurrent tumors in "suspicious" cases; (b) chromosomal aberrations defined by FISH are associated with tumor grade and stage (i.e., simple numerical aberrations were associated with low-grade tumors, and high-grade and invasive tumors exhibited multiple, nonrandom chromosomal aberrations and vast intratumor heterogeneity); (c) somatic pairing or homologous centromeric association can give a false-positive result and appears to be linked to prior therapy; (d) dual hybridization with reference gene-specific probes must be used to control for somatic pairing; and (e) focal, deep muscle invasive lesions, with no surface exposure, may yield false-negative results. The data suggest that FISH analysis, with the use of cells isolated from bladder washings, is a powerful technique holding promise for early cancer detection, monitoring treatment outcome, and predicting recurrence of disease.

    View details for Web of Science ID 000071018600018

    View details for PubMedID 9815630

  • The effect of decalcification on in situ hybridization MODERN PATHOLOGY Arber, J. M., Weiss, L. M., Chang, K. L., Battifora, H., Arber, D. A. 1997; 10 (10): 1009-1014


    In situ hybridization (ISH) for mRNA polyadenylated sequences was performed on 25 non-neoplastic and neoplastic decalcified, paraffin-embedded tissues using a poly d(T) oligonucleotide probe to assess the efficacy of this molecular diagnostic tool on decalcified tissue samples. Three commercially available decalcifying agents were used, including one EDTA-based solution (Versenate) and two hydrochloric acid-based solutions (S/P Decal, RBD). Before decalcification, the tissues were fixed in formalin for 6, 24, and 72 hours, respectively. The results of ISH performed on decalcified tissues were compared with the results from the nondecalcified control samples for each tissue using a numeric scoring system (0, negative; 4, strong positivity equal to control; 5, stronger than control). There was generally excellent reactivity when using Versenate (mean, 4.15), good reactivity with S/P Decal (mean, 3.17), and fair-to-poor reactivity with RBD (mean, 1.69) (all P values < .0001). The length of time in formalin did not affect the outcome of ISH on these tissues. We conclude that ISH can be performed with success on decalcified, paraffin-embedded tissues when using Versenate, an EDTA-based agent. Although accurate results might be obtained with S/P Decal and RBD, caution should be exercised when using these two hydrochloric acid-based solutions because they might produce false-negative results.

    View details for Web of Science ID A1997YB11800007

    View details for PubMedID 9346180

  • CD10 - A review APPLIED IMMUNOHISTOCHEMISTRY Arber, D. A., Weiss, L. M. 1997; 5 (3): 125-140
  • Neuroendocrine stains and proliferative indices of prostatic adenocarcinomas in transurethral resection samples BRITISH JOURNAL OF UROLOGY Speights, V. O., Cohen, M. K., Riggs, M. W., Coffield, K. S., Keegan, G., Arber, D. A. 1997; 80 (2): 281-286


    To determine whether the quantification of certain neuroendocrine and proliferative markers would help in the prognostic evaluation of prostatic adenocarcinomas obtained during transurethral resection of the prostate (TURP).Samples from two groups of patients with prostate cancer were examined. One group comprised 23 patients, of whom 12 were stage IV and 11 stage III, all with Gleason scores of > or = 7; this group was designated as high-grade, high-stage (HGHS). The second group comprised 10 consecutive patients with stage T1a adenocarcinoma of the prostate with Gleason scores of < or = 6, designated as low-grade, low-stage (LGLS) tumours. Tumour tissue from each TURP was stained with MIB-1 (an indicator of cell proliferation), neuron-specific enolase (NSE), chromogranin A (ChA) and synaptophysin (Syn), and 1000 cells counted to determine the percentages of positive cells in both benign and malignant tissue. The percentage of MIB-1-positive cells was designated as the proliferative index (PI). Patients were clinically followed to evaluate tumour progression, documented by rising prostate-specific antigen (PSA) levels, X-ray evidence of recurrent or metastatic carcinoma, or tissue biopsy showing malignancy.The mean number of neuroendocrine cells (NEC) for each marker and the mean PI were greater in the HGHS tumours than in the LGLS tumours or surrounding benign tissue of either group (P < 0.01). The LGLS tumours were remarkable for a having mean PI of about twice that of the benign tissue (2.9 and 1.3, respectively, P < 0.01); the NEC in these cases were more frequent in the benign than in the malignant tissue. There was no significant difference between the mean PIs and the mean percentages of NEC in the 14 HGHS tumours that progressed and the nine HGHS tumours that did not (P values 0.37-0.96).Although the PI assessed by MIB-1 and the number of NEC-positive cells were much higher in HGHS than LGLS tumours, this finding did not appear to have independent prognostic significance. The significance of the higher PI in LGLS tumours than in corresponding benign tissue is uncertain; LGLS tumours had fewer NEC than the surrounding benign tissue. The quantification of any of these four markers (MIB-1, NSE, ChA, Syn) was not prognostically helpful in these groups of cancers present in TURP specimens.

    View details for Web of Science ID A1997XR06200019

    View details for PubMedID 9284203

  • Correlation among MIB-1, paraffin section proliferation index, and recurrence in low-stage breast carcinoma APPLIED IMMUNOHISTOCHEMISTRY Arber, J. M., Riggs, M. W., Arber, D. A. 1997; 5 (2): 117-124
  • Splenic mesothelial cysts mimicking lymphangiomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Strickler, J. G., Weiss, L. M. 1997; 21 (3): 334-338


    Lymphangiomas of the spleen may occur as part of lymphangiomatosis or may represent solitary lesions. Solitary splenic lymphangiomas are described traditionally as subcapsular, multicystic proliferations that are often incidental findings. Six cases of splenic tumors with morphologic features similar to those described for solitary lymphangioma were studied using an immunohistochemical panel that included epithelial and vascular markers. None of the patients had evidence of lymphangiomatosis, and all tumors were incidental findings in splenectomy specimens. All cases demonstrated lining cells that were positive for keratin and the mesothelial cell-associated antibody HBME-1 but were negative for the vascular markers Factor VIII-related antigens, CD31, and CD34. The immunohistochemical findings are suggestive of a mesothelial derivation of these multicystic proliferations rather than representing true lymphangiomas.

    View details for Web of Science ID A1997WN49000010

    View details for PubMedID 9060604

  • Chromosome 11 abnormalities in Bowen disease of the vulva CANCER GENETICS AND CYTOGENETICS Swanson, G. P., Dobin, S. M., Arber, J. M., Arber, D. A., CAPEN, C. V., Diaz, J. A. 1997; 93 (2): 109-114


    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.

    View details for Web of Science ID A1997WN73900001

    View details for PubMedID 9078294

  • Clonality in lymphocyte predominance Hodgkin's disease CANCER SURVEYS Weiss, L. M., Arber, D. A., Chang, K. L. 1997; 30: 125-141


    Abundant evidence has led to the clinical and biological separation of lymphocyte predominance from other types of Hodgkin's disease. However, it is still not clear whether lymphocyte predominance represents a polyclonal reactive lesion (possibly representing an abnormal immune disorder), a polyclonal or oligoclonal preneoplastic disorder or a monoclonal neoplastic disorder. The clinical and histological features are distinctive, but they do not provide clear indications of the nature of lymphocyte predominance. Some immunohistochemical and in situ hybridization studies have shown monotypic light chain restriction in the L&H cells, almost always of kappa type, implying a monoclonal process. Southern blotting studies are of limited utility, given their relatively low sensitivity and the rarity of L&H cells within involved tissues. Polymerase chain reaction studies have yielded conflicting results. Some, but not all, have demonstrated monoclonal populations in tissue extracts. Single cell PCR studies have generally not found monoclonal populations, although one case stands as an exception. Cases of large cell lymphoma complicating lymphocyte predominance have been monoclonal by polymerase chain reaction and clonospecific primers derived from these clones have demonstrated similar populations in the corresponding lymphocyte predominance tissues in some, but not all, studies.

    View details for Web of Science ID A1997XT52800009

    View details for PubMedID 9547990

  • Presence of t(8;21)(q22;q22) in myeloperoxidase-positive, myeloid surface antigen-negative acute myeloid leukemia AMERICAN JOURNAL OF CLINICAL PATHOLOGY Arber, D. A., Glackin, C., Lowe, G., Medeiros, L. J., Slovak, M. L. 1997; 107 (1): 68-73


    Although acute myeloid leukemias (AMLs) cytochemically negative for myeloperoxidase are now well recognized, myeloid surface antigen-negative AMLs are rare. The morphologic, cytochemical, immunologic, and cytogenetic or molecular features of such cases are described in four adults aged 19 to 60 years. All had AML with maturation (FAB M2) and were myeloperoxidase positive. Immunologic studies showed all to be HLA-DR positive but negative for the CD13, CD14, and CD33 antigens. Two of four were CD34 antigen positive. Cytogenetic studies were performed in three patients, and all demonstrated t(8;21)(q22;q22). In studies using the reverse transcriptase polymerase chain reaction in two patients, including the patient in whom karytypic analysis was not performed, the AML1-ETO fusion product of t(8;21) was identified. These findings suggest an association between the lack of myeloid antigen expression in myeloperoxidase-positive AML and the presence of t(8;21). In addition, the results demonstrate the continued need for cytochemical studies in the evaluation of acute leukemias.

    View details for Web of Science ID A1997VZ15500013

    View details for PubMedID 8980370

  • EBV in follicular dendritic cells AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Weiss, L. M. 1996; 20 (11): 1426-1426

    View details for Web of Science ID A1996VQ50300016

    View details for PubMedID 8898849

  • CD79 alpha expression in acute myeloid leukemia - High frequency of expression in acute promyelocytic leukemia AMERICAN JOURNAL OF PATHOLOGY Arber, D. A., Jenkins, K. A., Slovak, M. L. 1996; 149 (4): 1105-1110


    CD79 alpha is a subunit of an intracytoplasmic protein reported to be specific for B lymphocytes, including immature B lineage cells. To evaluate expression of the CD79 alpha antigen in acute myeloid leukemia (AML), we studied forty-eight cases of AML by paraffin section immunohistochemistry. The cases included four MO, nine M1, nine M2, ten M3, ten M4, and six M5 AMLs using criteria of the French-American-British cooperative group. Eleven cases demonstrated cytoplasmic staining for the CD79 alpha antigen, including one M1, nine M3, and one M5 AML. These CD79 alpha-positive cases represented 5% of all non-promyelocytic AMLs and 90% of all acute promyelocytic leukemias studied. All acute promyelocytic leukemias had the characteristic t(15;17)(q24;q21), including two cases of the microgranular variant (M3v). No other B-lineage-associated antigens were found in the CD79 alpha-positive cases, with the exception of a subpopulation of CD19-positive leukemic cells in one patient. The two non-promyelocytic leukemias that expressed CD79 alpha had no evidence of t(15;17) and did not express any additional B-lineage-associated antigens that might suggest a mixed lineage proliferation. This study demonstrates that CD79 alpha expression in acute leukemia is not restricted to B-lineage acute lymphoblastic leukemias and that CD79 alpha expression is frequently associated with t(15;17) acute myeloid leukemia.

    View details for Web of Science ID A1996VM31400004

    View details for PubMedID 8863659

  • Numerical cytogenetic abnormalities of chromosomes 3, 7, and 12 in marginal zone B-cell lymphomas MODERN PATHOLOGY Brynes, R. K., ALMAGUER, P. D., Leathery, K. E., McCourty, A., Arber, D. A., Medeiros, L. J., NATHWANI, B. N. 1996; 9 (10): 995-1000


    Monocytoid B-cell lymphoma, low-grade B-cell lymphoma of mucosa-associated lymphoid tissue, and primary splenic marginal zone cell lymphoma (SMZCL) were originally described as distinct clinicopathologic entities. On the basis of morphologic and immunologic similarities, monocytoid B-cell lymphoma and lymphoma of mucosa-associated lymphoid tissue recently have been grouped together as nodal and extranodal types of marginal zone B-cell lymphomas (MZBCLs) in the Revised European-American Classification of Lymphoid Neoplasms. Primary SMZCL, although related, is considered a separate provisional entity. Trisomies 3, 7, and 12 are common in non-Hodgkin's lymphomas. Several recent studies reported that MZBCLs arising in sites of mucosa-associated lymphoid tissue have a high frequency of trisomy 3. To assess whether similar numerical cytogenetic abnormalities are present in MZBCLs with prominent monocytoid B-cell cytologic features, we performed a retrospective study, using formalin-fixed, paraffin-embedded tissue blocks from 36 cases. By use of fluorescence in situ hybridization to detect chromosome trisomies, we identified trisomy 3 in 11 (85%) of 13 extranodal MZBCLs with monocytoid B cells (MZBCL-Es), in 6 (50%) of 12 nodal MZBCLs of monocytoid B-cell type (MZBCL-Ns), but in only 2 (18%) of 11 SMZCLs. Trisomies 7 and 12 were found at lower frequencies. These data suggest that trisomy 3 is a common numerical chromosomal abnormality of MZBCL-Es and MZBCL-Ns with monocytoid B-cell features. Despite similar morphologic and immunophenotypic characteristics, the low incidence of trisomy 3 in the SMZCL cases implies that this process may be genetically distinct.

    View details for Web of Science ID A1996VN50000009

    View details for PubMedID 8902837

  • Angiomatoid fibrous histiocytoma ANNALS OF PLASTIC SURGERY Grossman, L. D., White, R. R., Arber, D. A. 1996; 36 (6): 649-651


    This article reports a case of angiomatoid fibrous histiocytoma (AFH), a rare fibrous tissue tumor with unique clinical characteristics. Formerly, this tumor was classified as angiomatoid malignant fibrous histiocytoma. First described in 1979, AFH was felt to be a variant of malignant fibrous histiocytoma (MFH). One dominant characteristic that differentiates this tumor from the remainder of MFH subtypes is that it most often presents in individuals younger than 20 years of age. The usual MFH occurs in the seventh decade of life. Because of its rarity, AFH has been difficult to classify and, during this current year, has been designated as a separate entity, rather than a subtype of MFH. Clinically, the tumor presents as a soft-tissue mass in the subcutis or deep dermal layers of the body, often presenting on the extremities or neck. Local recurrence has been reported, but mortality figures are very favorable and wide local removal is sufficient treatment.

    View details for Web of Science ID A1996UQ36800020

    View details for PubMedID 8792977

  • Detection of the t(2;5)(p23;q35) chromosomal translocation in large B-cell lymphomas other than anaplastic large cell lymphoma HUMAN PATHOLOGY Arber, D. A., Sun, L. H., Weiss, L. M. 1996; 27 (6): 590-594


    In general, the large cell lymphomas are a cytogenetically heterogeneous group of diseases, and the cytogenetic findings do not correlate with morphological findings in this group of malignant lymphomas. The CD30-positive anaplastic large cell lymphomas, however, are thought to be an exception, with the t(2;5) reported to correlate with the morphological changes of this disease entity. A subgroup of Hodgkin's disease cases have been reported by some investigators to have the t(2;5) translocation, leading to speculation that these two diseases are related. In the current study, the authors used a sensitive reverse transcriptase polymerase chain reaction (RT-PCR) methodology to evaluate the frequency of t(2;5) in 33 cases of large cell lymphoma, of B lineage, other than anaplastic large cell lymphoma. The authors detected evidence of t(2;5) in four of the cases (12%), a frequency similar to that of the authors' previous study of cases of CD30 positive anaplastic large cell lymphoma. Three of the positive large B-cell lymphoma cases were CD30 negative and were morphologically indistinguishable from the cases without evidence of t(2;5). The fourth case had a subpopulation of CD30 positive cells but also did not have morphological features of anaplastic large cell lymphoma. These results would suggest that t(2;5) is not restricted to cases of malignant lymphomas with anaplastic morphology or to CD30 expression.

    View details for Web of Science ID A1996UQ84200014

    View details for PubMedID 8666370

  • Certification and training in molecular pathology HUMAN PATHOLOGY Arber, D. A., Battifora, H., Brynes, R. K., Chang, R. L., Weiss, L. M., Wilczynski, S. P. 1996; 27 (4): 430-431

    View details for Web of Science ID A1996UF10500022

    View details for PubMedID 8617491

  • Utility of a rapid polymerase chain reaction panel for the detection of molecular changes in B-cell lymphoma ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE AbdelReheim, F. A., Edwards, E., Arber, D. A. 1996; 120 (4): 357-363


    To evaluate the utility of a polymerase chain reaction (PCR)-based, B-cell-related molecular panel in the diagnostic workup of hematologic specimens.A PCR panel was applied to 89 specimens from 87 patients, including 55 cases (57 specimens) of known monoclonal B-cell lymphoma, 10 cases of Hodgkin's disease, 2 cases of T-cell lymphoma, and 20 specimens of polyclonal reactive lymphoid tissues. The panel comprised a seminested PCR procedure for immunoglobulin heavy-chain (IgH) gene rearrangement and unnested PCR detection of t(14;18) and t(11;14).Immunoglobulin heavy-chain was detected in 63%, evidence of t(14;18) in 35%, and evidence of t(11;14) in 3.5% of all the B-cell lymphoma cases. Seventy-seven percent of all cases demonstrated IgH- and/or bcl-2-associated translocations using these primers. The IgH primers alone detected clonality in 82% (28/34) of the nonfollicular lymphomas and 35% (8/23) of the follicular lymphomas, with no false positives in the non-B-cell lymphoma specimens. The addition of two primer sets for the detection of both IgH and bcl-2/JH significantly improved the detection of molecular abnormalities in the follicular lymphoma group from 35% to 70% (16/23). However, no change was noted in the overall detection rate for the nonfollicular lymphoma group. Adding primers for bcl-1/JH did not change the overall detection rate for either group.Seminested PCR for IgH detected monoclonality in the majority of the nonfollicular lymphomas and is a valuable diagnostic tool in this group. The combination of different primer sets for the detection of IgH gene rearrangement and bcl-2/JH is most desirable for follicular lymphomas.

    View details for Web of Science ID A1996UF81600010

    View details for PubMedID 8619747

  • CD20: A review APPLIED IMMUNOHISTOCHEMISTRY Chang, K. L., Arber, D. A., Weiss, L. M. 1996; 4 (1): 1-15
  • Coexistence of Hodgkin's disease and giant lymph node hyperplasia of the plasma-cell type (Castleman's disease) ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE AbdelReheim, F. A., Koss, W., Rappaport, E. S., Arber, D. A. 1996; 120 (1): 91-96


    Coexistence of Hodgkin's disease and giant lymph node hyperplasia (Castleman's disease) is well documented in the literature. We present a unique case in which the original lymph node biopsy revealed interfollicular Hodgkin's disease (CD15+, CD30+, CD45-, Reed-Sternberg cells) with coexistent histologic features of the plasma-cell variant of Castleman's disease. The patient experienced a long-term remission following combined chemotherapy and radiation therapy. He presented at 18 years and again at 22 years later with clinical, hematologic, and histologic features of a multicentric plasma-cell variant of Castleman's disease without evidence of Hodgkin's disease. This unique case report further strengthens the association of Castleman's disease and Hodgkin's lymphoma. Two pathogenetic mechanisms for this association have been suggested: (1) secretion of interleukin-6 by Hodgkin's Reed-Sternberg cells and histiocytes, and (2) manifestation of an abnormal immune state associated with Hodgkin's disease. These two mechanisms may, indeed, be related.

    View details for Web of Science ID A1996TP69500019

    View details for PubMedID 8554455

  • Effect of decalcification and fixation in paraffin-section immunohistochemistry APPLIED IMMUNOHISTOCHEMISTRY Arber, J. M., Arber, D. A., Jenkins, K. A., Battifora, H. 1996; 4 (4): 241-248


    We describe the gross and histologic features of nodular lymphocyte predominance Hodgkin's disease (NLPHD) occurring in extranodal sites. Fifty-one specimens of NLPHD from 16 patients were studied. The sites of involvement were the spleen, liver, tonsil, salivary glands, skin, colon, soft tissue, and bone marrow, and the morphologic features were similar to those described in node-based NLPHD, including characteristic lymphocytic and/or histiocytic (L&H) cells that were easily identified in a background of a nodular proliferation of small lymphocytes and histiocytes. In the spleen, the normal architecture was generally preserved, and the tumor was found predominantly in the white pulp; the red pulp was rarely involved. In the liver, the tumor involved both the portal and parenchymal areas. In the tonsil, the lympohproliferation closely resembled the typical appearance of NLPHD in a lymph node. In all specimens with materials available for immunohistochemical studies, there were demonstrable L&H cells with an immunophenotype similar to node-based NLPHD, that is, CD45-positive, CD20-positive, and CD15-negative. The unique morphologic and immunologic characteristics of NLPHD are preserved in extranodal sites and allow its distinction from classic Hodgkin's disease and other lymphoproliferative malignancies that may occur in extranodal sites.

    View details for Web of Science ID A1995TA13000012

    View details for PubMedID 7573694

  • CD57 - A REVIEW APPLIED IMMUNOHISTOCHEMISTRY Arber, D. A., Weiss, L. M. 1995; 3 (3): 137-152


    Neuroendocrine differentiation has been demonstrated by immunohistochemical preparations in many cases of acinar type prostatic adenocarcinoma (CAP). Some studies have suggested that this differentiation may indicate an adverse prognosis.Tissue samples from 38 consecutive patients with clinical Stage II (AJCC) CAP who underwent radical retropubic prostatectomy (RRP) were studied after preparations were made with antichromogranin (ChA) and neuron-specific enolase (NSE). All patients were followed for at least 4 years post-RRP or until disease progression was documented by rising serum prostate specific antigen concentration, X-ray evidence of recurrence, or a positive tissue biopsy.Nine of the 38 RRP specimens (24%) were positive for NSE, and 11 (29%) were positive for ChA. Neither of these neuroendocrine markers showed a significant correlation with tumor progression. Neuroendocrine differentiation in needle biopsy specimens from these same patients (when available) did not correlate with tumor progression either. Of the patients with tumor progression, 9 of 11 (82%) had pathologic Stage III disease after RRP; of those with no progression of CAP, only 7 of 27 (26%) had pathologic Stage III disease.Neuroendocrine differentiation, as demonstrated by NSE and ChA preparations, was not helpful in predicting tumor progression of CAP.

    View details for Web of Science ID A1994PH62500011

    View details for PubMedID 8082095



    Two recently described monoclonal antibodies, UCL3D3 and UCL4D12, have been reported to have some specificity for mantle zone B lymphocytes and marginal zone/follicular center B lymphocytes, respectively, in the spleen. Forty-nine B-cell neoplasms, including 20 cases of monocytoid B-cell lymphoma (MBCL), were studied by frozen section immunohistochemistry with these antibodies to evaluate their utility. Tonsil, lymph node, and reactive spleen also were studied with the antibodies. Although a wide overlap was observed among the different lymphomas, a majority of cases of MBCL and half of cases of hairy cell leukemia (HCL) reacted with both markers, suggesting both marginal/follicular and mantle cell antigen expression. None of four cases of mantle cell lymphoma reacted with the proposed mantle cell marker UCL3D3, whereas three of these cases immunoreacted with UCL4D12. This marker is known to react with a subpopulation of follicular center cells and possibly with marginal zone lymphocytes. A comparison of nodal and extranodal neoplasms failed to show a significant difference in the pattern of immunoreactivity with these antibodies. Tonsil and lymph node controls showed some mantle zone staining with both antibodies, and there was a slight overlap in mantle and marginal zone staining of the spleen controls. These findings suggest an immunologic similarity between some cases of HCL and MBCL. However, the findings also would suggest that these antibodies, particularly UCL4D12, have less specificity than has been previously assumed, and UCL4D12 may not have practical utility in the evaluation of low grade B-cell lymphomas.

    View details for Web of Science ID A1994PL44900015

    View details for PubMedID 7927314

  • FOLLICULAR SMALL LYMPHOCYTIC LYMPHOMA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Chang, K. L., Arber, D. A., Shibata, D., Rappaport, H., Weiss, L. M. 1994; 18 (10): 999-1009


    We herein provide evidence for the existence of a distinct morphologic form of small lymphocytic lymphoma (SLL) that we term follicular small lymphocytic lymphoma (FSLL). Nine specimens of FSLL from eight patients were studied. The lymphomas in this study showed a true follicular pattern that was independent of tissue planes; the cytologic composition was identical to that seen in SLL. All six of the specimens (from five patients) for which paraffin tissue was available marked as B cell phenotype and were positive for bcl-2 protein. Polymerase chain reaction studies performed on deparaffinized tissue sections showed bcl-2 major breakpoint region rearrangements in four of five cases for which study tissue was available. Clinical information was available for all eight patients. All patients presented with lymph node disease, and three patients also had extranodal involvement at the time of presentation. Three of the patients had a relapse of disease after 33-95 months, and two of these patients died soon after relapse. Another two of the eight patients never responded to chemotherapy and died of their disease after 2 and 8 months, respectively. Two patients died of causes unrelated to their lymphoma and unrelated to any lymphoma therapy. Only one patient remains disease-free, after 65 months; this patient had a relapse at 44 months. The finding of bcl-2 rearrangements suggests that the pathogenesis of FSLL is more closely related to follicular small cleaved cell lymphoma than to classic SLL.

    View details for Web of Science ID A1994PJ24100004

    View details for PubMedID 8092400

  • CD68 - A REVIEW APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Weiss, L. M., Arber, D. A., Chang, K. L. 1994; 2 (1): 2-8
  • NON-HODGKINS-LYMPHOMA INVOLVING THE BREAST AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arber, D. A., Simpson, J. F., Weiss, L. M., Rappaport, H. 1994; 18 (3): 288-295


    Breast involvement by non-Hodgkin's lymphoma is rare. Differences between primary and secondary breast lymphoma have been reported, and a relationship between primary breast lymphoma and lymphomas of mucosa-associated lymphoid tissue has been suggested. We reviewed 61 cases of breast lymphoma (41 primary, 13 secondary, and 7 unclear) that included 28 right-sided masses at presentation, 17 left-sided, 12 bilateral, and 4 in which the side was not known. A subgroup of bilateral breast lymphomas was identified that occurred in young women, four of which were pregnant or postpartum. A high incidence of intermediate- and high-grade lymphomas were present in both cases of primary and secondary lymphomas as was a high frequency of B-cell phenotype. Additional immunohistochemical studies failed to demonstrate evidence of marginal or mantle cell differentiation in seven of eight cases studied. Lymphoepithelial lesions were identified in a majority of cases, including 67% of primary and 64% of secondary lymphomas. This study failed to demonstrate a morphologic difference between primary or secondary lymphomas of the breast and suggests that breast lymphomas differ from other extranodal lymphomas in that the latter are frequently low grade.

    View details for Web of Science ID A1994MZ33100009

    View details for PubMedID 8116797

  • Nasal T-cell lymphoma. Annals of oncology Weiss, L. M., Arber, D. A., Strickler, J. G. 1994; 5: 39-42


    Nasal T-cell lymphomas represent a controversial subset of malignant lymphomas and include lesions previously termed midline malignant reticulosis, lymphomatoid granulomatosis, and polymorphic reticulosis. Nasal T-cell lymphomas are rare in Western populations and much more prevalent in Asian countries. Clinically, adult males are most often affected. Histologically, an angiocentric infiltrate composed of a spectrum of atypical cells is usually present. Phenotypically, the neoplastic cells lack expression of B-lineage markers, and usually express the T-lineage-associated markers CD2, CD45RO, and CD43; however, they often lack other pan-T-lineage markers. They often express the natural killer marker CD56, but usually lack the natural killer markers CD16 and CD57. Gene rearrangement studies have shown a germline configuration for the antigen receptor genes in the majority of cases. To date, evidence of Epstein-Barr virus has been consistently demonstrated, regardless of the geographic region studied. In situ hybridization studies have localized the Epstein-Barr virus to the atypical cells.

    View details for PubMedID 8172815

  • NASAL T-CELL LYMPHOMA ANNALS OF ONCOLOGY Weiss, L. M., Arber, D. A., Strickler, J. G. 1994; 5: S39-S42


    In an attempt to correlate the morphologic and immunophenotypic findings in extramedullary myeloid cell tumors (EMT), we studied 28 cases with a large panel of antibodies using paraffin section immunohistochemistry. A previous or concurrent diagnosis of acute myelogenous leukemia or chronic myelogenous leukemia was made in 25 cases. Six EMT were morphologically classified as well differentiated (WD-EMT), 17 as poorly differentiated (PD-EMT), and five as blastic EMT. The WD-EMT were easily recognized morphologically and displayed a relatively mature myeloid phenotype, with elastase, CD15, and CD68 positivity in all cases. On the other hand, the five blastic-EMT displayed no morphologic evidence of myeloid derivation, were completely negative for CD15, and were weakly positive for elastase in only one case. The PD-EMT, with a morphologic appearance that resembles large cell non-Hodgkin's lymphoma, variably expressed CD15 and elastase. CD68 and lysozyme were present in the majority of PD-EMT, with some variability, but were negative in most blastic-EMT. CD45 (LCA) was detected in 75% of all EMT and CD34 was positive in 36%; neither antigen was significantly associated with a specific morphology. CD30 reactivity was not evident in any case, but slight positive staining was seen with CD20 (L26) in one WD-EMT. CD43 (Leu 22) was the only antibody that was positive in 100% of cases; staining was always intense and widespread. Antimyeloperoxidase (MPO) was positive in all cases but two, both with a blastic morphology. We conclude that (a) an immunohistochemical panel including CD20, CD43, CD68, and MPO can successfully identify the vast majority (96%) of EMT in paraffin sections, and (b) there is an association between morphology and phenotype in these lesions.

    View details for Web of Science ID A1993LZ18200006

    View details for PubMedID 8372941

  • THE BONE-MARROW AGAR SECTION - A MORPHOLOGIC AND IMMUNOHISTOCHEMICAL EVALUATION MODERN PATHOLOGY Arber, D. A., Johnson, R. M., RAINER, P. A., Helbert, B., Chang, K. L., Rappaport, E. S. 1993; 6 (5): 592-598


    A technique for agar embedding of bone marrow aspirate particles is compared with the conventional aspirate smear and bone marrow biopsy by reviewing 503 consecutive bone marrow specimens. Immunohistochemical studies were performed on both agar sections and bone marrow biopsies on 43 paired specimens to compare the results between the two preparations. The results were also compared with traditional clot sections from ten control cases. Of the 382 cases with agar sections, 97.7% contained material in the agar that was diagnostic alone or supportive of the diagnosis made with the biopsy and aspirate smear. In two cases (0.4%), focal involvement by lymphoma was identified on the agar section but not in the biopsy sections or aspirate smears. The immunohistochemical studies showed superior immunoreactivity in agar sections by lymphoproliferative disorders when compared with bone marrow biopsy sections. Similar results between agar and conventional biopsy sections were found in cases of metastatic carcinoma and plasma cell dyscrasias.

    View details for Web of Science ID A1993MC75400017

    View details for PubMedID 8248117


    View details for Web of Science ID A1993KY26000019

    View details for PubMedID 8475916



    Virtually all reported cases of epithelioid sarcoma have been vimentin rich, and the coexpression of vimentin and keratin is considered a characteristic immunophenotype in these tumors. We report three cases of soft tissue tumors with histologic and clinical features consistent with epithelioid sarcoma, all of which failed to immunoreact by standard immunohistochemistry for vimentin using two different monoclonal antibodies. Antigen retrieval demonstrated focal vimentin staining in one case, whereas the other two remained negative. An extensive panel of immunohistochemical stains revealed strong diffuse staining with keratin and epithelial membrane antigen in all three cases as well as patchy membrane staining with an antibody to CD34. CD34 positivity is commonly seen in epithelioid sarcoma, but it is very rarely found in carcinomas. We conclude that these cases represent a unique immunophenotypic variant of epithelioid sarcoma that can be immunohistochemically confirmed, despite the lack of identifiable vimentin, by their immunoreactivity for keratin and CD34.

    View details for Web of Science ID A1993KN93700011

    View details for PubMedID 7679559

  • AGAR PROCESSING OF BONE-MARROW ASPIRATE MATERIAL LABORATORY MEDICINE Arber, D. A., RAINER, P., Helbert, B., Rappaport, E. S. 1992; 23 (7): 479-481


    Selection of the diploid reference cells used in flow cytometric DNA analysis of paraffin-embedded tissue is inconsistent in the literature. To determine which types of cells were most suitable for use as reference cells, benign paraffin-embedded tissue was evaluated from nine randomly selected autopsies. Benign kidney, lymph node, gastrointestinal mucosa, laryngeal mucosa, bronchial mucosa, bladder mucosa, pancreas, and, when available, prostate tissue were studied. Ten paraffin-embedded surgical specimens also were studied. In the autopsy specimens, great variability in the mean peak channels was noted on intrapatient evaluation and even more variability was present when comparing similar organs (especially lymph nodes) from different patients. Similar results were obtained using lymph nodes from surgical specimens. It is concluded that the most suitable diploid reference cells for DNA analysis of paraffin-embedded tissue are the benign cells present in the paraffin tumor block that have been processed in the same way as the tumor cells.

    View details for Web of Science ID A1992HG49200017

    View details for PubMedID 1543162



    To evaluate if the nuclear enlargement and irregularity of non-neoplastic seminal vesicle epithelium were associated with an abnormal DNA content, 30 seminal vesicles obtained from radical prostatectomies were analyzed by flow cytometry. Twenty-eight (93.3%) of the seminal vesicles showed characteristic diploid histograms, while two (6.7%) showed histograms characteristic of aneuploidy. These results are discussed and other reported examples of aneuploidy in nonmalignant tissues are reviewed.

    View details for Web of Science ID A1991GQ73000003

    View details for PubMedID 1788260

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