Robert Ohgami

All Publications

• Pediatric-type Follicular Lymphoma and Pediatric Nodal Marginal Zone Lymphoma: Recent Clinical, Morphologic, Immunophenotypic, and Genetic Insights. Advances in anatomic pathology Koo, M., Ohgami, R. S. 2017; 24 (3): 128-135

  Abstract

  Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are 2 of the rarest B-cell lymphomas. Although they are both predominantly seen in children, they can manifest in the adult population as well. Our understanding of these lymphomas has advanced rapidly in recent years such that we not only have a firm grasp of the morphologic and immunophenotypic findings, but also have a deeper insight into critical genetic and molecular pathways of these diseases. This review will cover the clinical and pathologic characteristics, treatment, prognosis, and important differential diagnoses of these entities.

  View details for DOI 10.1097/PAP.0000000000000144

  View details for PubMedID 28277421

• Focusing on frequent ASXL1 mutations in myeloid neoplasms, and considering rarer ASXL2 and ASXL3 mutations. Current medical research and opinion Oak, J. S., Ohgami, R. S. 2017: 1-2

  View details for DOI 10.1080/03007995.2017.1284049

  View details for PubMedID 28097878

• The clinicopathologic significance of lymphocyte subsets in acute myeloid leukemia. International journal of laboratory hematology Alcasid, M., Ma, L., Gotlib, J. R., Arber, D. A., Ohgami, R. S. 2017

  Abstract

  While the role of the immune system in altering and modulating the progression of solid tumors is well studied, the impact of the immune system on the outcome and progression of hematolymphoid neoplasms is still poorly understood.Here, we report a retrospective study detailing our analysis of 130 patients with acute myeloid leukemia (AML), with flow cytometry immunophenotypic evaluation of major lymphocyte subsets including B cells, T cells, and NK cells.Our study identifies differential signatures of lymphocyte subsets pertaining to distinct subcategories of AML, and prognostic correlations in patients. In multivariate analysis, NK cells (specifically CD56+/CD16+ NK cells at a cutoff of ?5%) were found to be an independent indicator of improved overall and disease-free survival; cytogenetic risk was also shown to be critical in stratifying patients with AML.In total, we demonstrate that in AML, the subset distribution of immune system lymphocytes is nonrandom, and suggest an important role for distinct lymphocyte subsets, particularly NK cells, in this disease.

  View details for DOI 10.1111/ijlh.12594

  View details for PubMedID 28133918

• 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

  Abstract

  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

• 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

  Abstract

  Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.

  View details for DOI 10.1016/j.humpath.2015.09.033

  View details for Web of Science ID 000368319200002

• 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

  Abstract

  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 PubMedID 26386085

• 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

  Abstract

  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

  View details for PubMedID 26071468

• 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

  Abstract

  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

  View details for PubMedID 25412851

• 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

  Abstract

  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

  View details for PubMedID 25780004

• 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

  Abstract

  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

• 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

  Abstract

  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

• Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia. American journal of clinical pathology Kunder, C., Cascio, M. J., Bakke, A., Venkataraman, G., O'Malley, D. P., Ohgami, R. S. 2017; 147 (6): 596-603

  Abstract

  T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized.Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016.In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia.Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation.

  View details for DOI 10.1093/ajcp/aqx034

  View details for PubMedID 28575178

• Immunohistochemistry for p53 is a useful tool to identify cases of acute myeloid leukemia with myelodysplasia-related changes that are TP53 mutated, have complex karyotype, and have poor prognosis. Modern pathology Fernandez-Pol, S., Ma, L., Ohgami, R. S., Arber, D. A. 2017; 30 (3): 382-392

  Abstract

  In this study, we evaluate the expression of p53 in core biopsies with acute myeloid leukemia and correlate the level of expression with acute myeloid leukemia subtype, TP53 mutation status, karyotype, and survival. Of the 143 cases evaluated, 71 fulfilled the WHO 2016 criteria for acute myeloid leukemia with myelodysplasia-related changes, 40 were acute myeloid leukemia-not otherwise specified, 25 were acute myeloid leukemia with recurrent genetic abnormalities, and 7 were therapy-related acute myeloid leukemia. By immunohistochemistry, 17% showed p53 expression in >5% of the cells. Of the 24 cases with >5% p53-positive cells, 17 were acute myeloid leukemia with myelodysplasia-related changes, 5 were acute myeloid leukemia-not otherwise specified, 1 was acute myeloid leukemia with recurrent genetic abormalities, and 1 was therapy-related acute myeloid leukemia. In cases for which data was available, expression of >5% p53-positive cells was significantly associated with genotype (n=67) and/or karyotype (n=130). Among the 115 cases for which clinical follow up was available, the overall survival of cases with p53 expression >15% (Median=102 days) was significantly shorter compared with cases with p53 expression ?15% (Median=435 days). Within the acute myeloid leukemia with myelodysplasia-related changes group, this association remained significant, with cases with ?15% p53-positive cells having a median overall survival of 405 days versus 102 days for cases with >15% p53-positive cells. Among acute myeloid leukemia with myelodysplasia-related changes cases with a complex karyotype, the finding of >15% p53-positive cells was significantly associated with worse overall survival. The poor prognosis associated with more than 15% p53-positive cells was independent of age and karyotype. In acute myeloid leukemia with myelodysplasia-related changes, p53 expression may be useful to infer TP53 mutation status, complex karyotype, and/or poor prognosis in situations where other modalities are not readily available.

  View details for DOI 10.1038/modpathol.2016.206

  View details for PubMedID 27934876

• Primary lymphoma of bone in the pediatric and young adult population. Human pathology Chisholm, K. M., Ohgami, R. S., Tan, B., Hasserjian, R. P., Weinberg, O. K. 2017; 60: 1-10

  Abstract

  Primary lymphoma of bone (PLB) accounts for 3% to 7% of primary neoplasms of bone and must be distinguished from more common bone tumors in the pediatric population such as osteosarcoma, Ewing sarcoma, and other small round blue cell tumors. In this study, pathology databases from 4 institutions were queried for PLB in individuals 1 to 21 years old. A total of 54 cases of PLB were identified, including 41 diffuse large B-cell lymphomas (DLBCL, 76%), 8 B-lymphoblastic lymphomas (BLL, 15%), 3 anaplastic large cell lymphomas (ALCL, 6%), and 2 low-grade follicular lymphomas (4%). The male/female ratio was 1.8:1 and median age was 16 years (range, 2-21). Patients with DLBCL were significantly older (P<.001), and patients with ALCL and BLL were significantly younger (P=.050 and P=.008, respectively) when compared with the other patients. Due to necrosis, crush artifact, and/or insufficient material, 30% of cases required multiple biopsies for diagnosis. The femur, tibia, pelvic bones, humerus, and vertebrae were most commonly involved. DLBCL patients had significantly more solitary bone involvement (P=.001), whereas BLL had significantly more polyostotic involvement (P<.001). Of the 37 patients with outcome data, all had no evidence of disease on last follow-up. This largest pediatric series of PLB identifies DLBCL as the most frequent subtype and documents rarer occurrences of BLL, ALCL, and follicular lymphomas. The differential diagnosis of bone neoplasms in pediatric patients, including those with necrosis, should include PLB.

  View details for DOI 10.1016/j.humpath.2016.07.028

  View details for PubMedID 27554207

• Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

  Abstract

  Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

  View details for DOI 10.1126/scitranslmed.aai8545

  View details for Web of Science ID 000389448100006

  View details for PubMedID 27831904

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1228-1230

  View details for DOI 10.5858/arpa.2016-0045-CP

  View details for Web of Science ID 000388360100012

  View details for PubMedID 27081879

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Diffuse Large B-Cell Lymphoma, Not Otherwise Specified ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1225-1227

  View details for DOI 10.5858/arpa.2015-0418-CP

  View details for Web of Science ID 000388360100011

  View details for PubMedID 27081876

• 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

  Abstract

  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

• 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

  Abstract

  Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.

  View details for DOI 10.1016/j.humpath.2015.09.033

  View details for PubMedID 26772393

• Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nature genetics Ungewickell, A., Bhaduri, A., Rios, E., Reuter, J., Lee, C. S., Mah, A., Zehnder, A., Ohgami, R., Kulkarni, S., Armstrong, R., Weng, W., Gratzinger, D., Tavallaee, M., Rook, A., Snyder, M., Kim, Y., Khavari, P. A. 2015; 47 (9): 1056-1060

  Abstract

  Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-?B signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

  View details for DOI 10.1038/ng.3370

  View details for PubMedID 26258847

• Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2 NATURE GENETICS Ungewickell, A., Bhaduri, A., Rios, E., Reuter, J., Lee, C. S., Mah, A., Zehnder, A., Ohgami, R., Kulkarni, S., Armstrong, R., Weng, W., Gratzinger, D., Tavallaee, M., Rook, A., Snyder, M., Kim, Y., Khavari, P. A. 2015; 47 (9): 1056-?

  View details for DOI 10.1038/ng.3370

  View details for Web of Science ID 000360394100016

• Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood Kurtz, D. M., Green, M. R., Bratman, S. V., Scherer, F., Liu, C. L., Kunder, C. A., Takahashi, K., Glover, C., Keane, C., Kihira, S., Visser, B., Callahan, J., Kong, K. A., Faham, M., Corbelli, K. S., Miklos, D., Advani, R. H., Levy, R., Hicks, R. J., Hertzberg, M., Ohgami, R. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2015; 125 (24): 3679-3687

  Abstract

  Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

  View details for DOI 10.1182/blood-2015-03-635169

  View details for PubMedID 25887775

  View details for PubMedCentralID PMC4463733

• 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

  Abstract

  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

  View details for PubMedID 25976970

• 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

  Abstract

  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

  View details for PubMedID 25701230

• Comprehensive genomic profiling identifies a novel TNKS2-PDGFRA fusion that defines a myeloid neoplasm with eosinophilia that responded dramatically to imatinib therapy. Blood cancer journal Chalmers, Z. R., Ali, S. M., Ohgami, R. S., Campregher, P. V., Frampton, G. M., Yelensky, R., Elvin, J. A., Palma, N. A., Erlich, R., Vergilio, J., Chmielecki, J., Ross, J. S., Stephens, P. J., Hermann, R., Miller, V. A., MILES, C. R. 2015; 5

  View details for DOI 10.1038/bcj.2014.95

  View details for PubMedID 25658984

• Indolent T-lymphoblastic proliferation: a name with specific meaning. Human pathology 2015

  View details for DOI 10.1016/j.humpath.2015.07.026

  View details for PubMedID 26363525

• Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression. American journal of surgical pathology Ohgami, R. S., Sendamarai, A. K., Atwater, S. K., Liedtke, M., Fleming, M. D., Natkunam, Y., Warnke, R. A. 2014; 38 (9): 1298-1304

  Abstract

  Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with disseminated multinodal involvement in an otherwise healthy 49-year-old woman. Multiple lymph node biopsies were performed over the course of several months demonstrating persistent and anatomically diffuse involvement. Over 18 months, and without therapy, she has remained healthy, and her lymphadenopathy significantly improved. No bone marrow or peripheral blood involvement was ever identified. Atypical T cells showed an immunophenotypic spectrum of T-cell antigen expression with partial CD33 on a subset of T cells detected by both flow cytometry and immunohistochemistry. Both T-cell clonality and Human Androgen Receptor Assay (HUMARA) studies, performed on lymph node biopsy specimens, were negative. This case represents the first detailed clinical, morphologic, molecular, and immunophenotypic description of disseminated multinodal involvement by nonclonal iT-LBP with partial CD33 expression on T cells.

  View details for DOI 10.1097/PAS.0000000000000197

  View details for PubMedID 24618611

• 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

  Abstract

  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 PubMedID 25015859

• Large B-Cell Lymphomas Poor in B Cells and Rich in PD-1+ T Cells Can Mimic T-Cell Lymphomas. American journal of clinical pathology Ohgami, R. S., Zhao, S., Natkunam, Y. 2014; 142 (2): 150-156

  Abstract

  To characterize the clinicopathologic features of cases of large B-cell lymphomas, poor in B cells and densely rich in programmed cell death-1 (PD-1)+ reactive T cells, which can mimic T-cell lymphomas.A single-institute retrospective review of cases between 2010 and 2013 was performed.Of 178 cases of large B-cell lymphomas, eight cases of large B-cell lymphomas poor in B cells and diffusely rich in sheets of PD-1+ T cells were identified. These cases either were initially misdiagnosed as a T-cell lymphoma or substantiated a broader differential diagnosis including a T-cell lymphoma. Five cases were T-cell histiocyte-rich large B-cell lymphomas, and three cases were diagnosed as large B-cell lymphomas rich in T cells. In three of these cases, a subset of the PD-1+ T cells showed either morphologic nuclear atypia or atypical expression of T-cell antigens on flow cytometry and/or immunohistochemistry.Large B-cell lymphomas poor in B cells and rich in T cells can have diffuse sheets of reactive PD-1+ T cells, some with atypical morphologic and immunophenotypic features mimicking a T-cell lymphoma. Careful assessment of the immunoarchitecture and background inflammatory and stromal cells can prevent erroneous diagnoses in such cases.

  View details for DOI 10.1309/AJCPFJWKQ6GTVQE6

  View details for PubMedID 25015854

• 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

  Abstract

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  View details for DOI 10.3324/haematol.2013.101543

  View details for PubMedID 24837465

• 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

  Abstract

  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 PubMedID 24713736

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

  Abstract

  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

• 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

• Profound plasmacytosis in a patient with dengue. International journal of hematology Ewalt, M. D., Abeynayake, J., Waggoner, J. J., Pinsky, B. A., Ohgami, R. S. 2013; 98 (5): 518-519

  View details for DOI 10.1007/s12185-013-1452-3

  View details for PubMedID 24114365

• 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

  Abstract

  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

  View details for PubMedID 23574769

• Challenges in Consolidated Reporting of Hematopoietic Neoplasms Surgical Pathology Clinics Ohgami, R. S., Arber, D. A. 2013
• 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

  Abstract

  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 = 0·0439) and specifically with megakaryocytic dysplasia (P = 0·0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0·0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2·57 and 1·86, 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 = 0·000411) as well as within AML NOS (DFS; P = 0·0023), AML with intermediate cytogenetic risk (OS; P = 0·0104) and normal karyotype AML (OS; P = 0·00636). 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

• The Efficacy of HGAL and LMO2 in the Separation of Lymphomas Derived From Small B Cells in Nodal and Extranodal Sites, Including the Bone Marrow AMERICAN JOURNAL OF CLINICAL PATHOLOGY Younes, S. F., Beck, A. H., Ohgami, R. S., Lossos, I. S., Levy, R., Warnke, R. A., Natkunam, Y. 2011; 135 (5): 697-708

  Abstract

  We studied the efficacy of 2 germinal center B-cell markers, HGAL and LMO2, in the separation of lymphomas derived from small B cells, particularly follicular lymphoma (FL) and marginal zone lymphoma occurring in nodal, extranodal, splenic, and bone marrow sites using immunohistochemical analysis for CD10, BCL6, BCL2, HGAL, and LMO2. Our results showed that HGAL and LMO2 are sensitive and specific markers for detecting FL in nodal and extranodal sites. In contrast, all markers were down-regulated in FL infiltrates in the bone marrow. CD10 and HGAL were expressed in a subset of FLs in the bone marrow and were highly correlated with each other and with CD21, a marker of follicular dendritic cells. We conclude that HGAL and LMO2 should be considered in immunohistochemical panels used for the routine workup of lymphomas derived from small B cells. In the bone marrow, staining for HGAL or CD10 can be helpful in making a diagnosis of FL, although they are absent in a subset of cases.

  View details for DOI 10.1309/AJCP7Z2BIBUNQPLZ

  View details for Web of Science ID 000289743400007

  View details for PubMedID 21502424

• PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from Heal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma MODERN PATHOLOGY Sangoi, A. R., Ohgami, R. S., Pai, R. K., Beck, A. H., McKenney, J. K., Pai, R. K. 2011; 24 (3): 412-424

  Abstract

  PAX (paired box) genes encode a family of transcription factors that regulate organogenesis in a variety of organs. Very little is known about the role of PAX8 in endocrine cell development and the expression of PAX8 in neuroendocrine tumors. The purpose of this study was to analyze PAX8 immunohistochemical expression in gastroenteropancreatic and pulmonary well-differentiated neuroendocrine tumors to determine whether PAX8 can reliably distinguish pancreatic neuroendocrine tumors from neuroendocrine tumors of other anatomic sites and other pancreatic non-ductal neoplasms. In total, 221 well-differentiated neuroendocrine tumors were evaluated: 174 primary neuroendocrine tumors (66 pancreatic, 31 ileal, 21 pulmonary, 20 gastric, 17 rectal, 11 appendiceal, and 8 duodenal) and 47 neuroendocrine tumors metastatic to the liver (31 pancreatic, 11 ileal, 2 pulmonary, 2 duodenal, and 1 rectal). Fifteen solid-pseudopapillary neoplasms and six acinar cell carcinomas of the pancreas were also evaluated. PAX8 was positive in 49/66 (74%) primary pancreatic neuroendocrine tumors. PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status, or the presence of liver or lymph node metastasis. PAX8 expression was identified in 0/31 (0%) ileal, 0/21 (0%) pulmonary, 2/20 (10%) gastric, 5/17 (29%) rectal, 1/11 (9%) appendiceal, and 6/8 (75%) duodenal neuroendocrine tumors. PAX8 was positive in 4/15 (27%) solid-pseudopapillary neoplasms of the pancreas, whereas all acinar cell carcinomas (0/6) lacked immunoreactivity. Among liver metastases, only pancreatic neuroendocrine tumors (20/31, 65%) were PAX8 positive, whereas no cases of ileal (0/11), pulmonary (0/2), duodenal (0/2), and rectal (0/1) neuroendocrine tumor metastases were PAX8 positive. PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, and its expression can reliably distinguish pancreatic from ileal and pulmonary well-differentiated neuroendocrine tumors. Duodenal neuroendocrine tumors and a subset of rectal, gastric, and appendiceal neuroendocrine tumors may also express PAX8. PAX8 expression can distinguish pancreatic neuroendocrine tumors from acinar cell carcinomas, but its utility in distinguishing neuroendocrine tumors from solid-pseudopapillary neoplasms is limited.

  View details for DOI 10.1038/modpathol.2010.176

  View details for Web of Science ID 000287986600009

  View details for PubMedID 20890270

• Diagnosing PNH in the era of FLAER Blood K, H., R, O. S., D, A. A., A, A., St, C. 2011; [e-letter]
• Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sendamarai, A. K., Ohgami, R. S., Fleming, M. D., Lawrence, C. M. 2008; 105 (21): 7410-7415

  Abstract

  The daily production of 200 billion erythrocytes requires 20 mg of iron, accounting for nearly 80% of the iron demand in humans. Thus, erythroid precursor cells possess an efficient mechanism for iron uptake in which iron loaded transferrin (Tf) binds to the transferrin receptor (TfR) at the cell surface. The Tf:TfR complex then enters the endosome via receptor-mediated endocytosis. Upon endosomal acidification, iron is released from Tf, reduced to Fe(2+) by Steap3, and transported across the endosomal membrane by divalent metal iron transporter 1. Steap3, the major ferrireductase in erythrocyte endosomes, is a member of a unique family of reductases. Steap3 is comprised of an N-terminal cytosolic oxidoreductase domain and a C-terminal heme-containing transmembrane domain. Cytosolic NADPH and a flavin are predicted cofactors, but the NADPH/flavin binding domain differs significantly from those in other eukaryotic reductases. Instead, Steap3 shows remarkable, although limited homology to FNO, an archaeal oxidoreductase. We have determined the crystal structure of the human Steap3 oxidoreductase domain in the absence and presence of NADPH. The structure reveals an FNO-like domain with an unexpected dimer interface and substrate binding sites that are well positioned to direct electron transfer from the cytosol to a heme moiety predicted to be fixed within the transmembrane domain. Here, we discuss possible gating mechanisms for electron transfer across the endosomal membrane.

  View details for DOI 10.1073/pnas.0801318105

  View details for Web of Science ID 000256378100015

  View details for PubMedID 18495927

• The Steap proteins are metalloreductases BLOOD Ohgami, R. S., Campagna, D. R., McDonald, A., Fleming, M. D. 2006; 108 (4): 1388-1394

  Abstract

  Iron and copper are essential for all organisms, assuming critical roles as cofactors in many enzymes. In eukaryotes, the transmembrane transport of these elements is a highly regulated process facilitated by the single electron reduction of each metal. Previously, we identified a mammalian ferrireductase, Steap3, critical for erythroid iron homeostasis. Now, through homology, expression, and functional studies, we characterize all 4 members of this protein family and demonstrate that 3 of them, Steap2, Steap3, and Steap4, are not only ferrireductases but also cupric reductases that stimulate cellular uptake of both iron and copper in vitro. Finally, the pattern of tissue expression and subcellular localization of these proteins suggest they are physiologically relevant cupric reductases and ferrireductases in vivo.

  View details for DOI 10.1182/blood-2006-02-003681

  View details for Web of Science ID 000239698800047

  View details for PubMedID 16609065

• nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse BLOOD Ohgami, R. S., Campagna, D. R., Antiochos, B., Wood, E. B., Sharp, J. J., Barker, J. E., Fleming, M. D. 2005; 106 (10): 3625-3631

  Abstract

  Hypochromic, microcytic anemias are typically the result of inadequate hemoglobin production because of globin defects or iron deficiency. Here, we describe the phenotypic characteristics and pathogenesis of a new recessive, hypochromic, microcytic anemia mouse mutant, nm1054. Although the mutation nm1054 is pleiotropic, also resulting in sparse hair, male infertility, failure to thrive, and hydrocephaly, the anemia is the focus of this study. Hematologic analysis reveals a moderately severe, congenital, hypochromic, microcytic anemia, with an elevated red cell zinc protoporphyrin, consistent with functional erythroid iron deficiency. However, serum and tissue iron analyses show that nm1054 animals are not systemically iron deficient. From hematopoietic stem cell transplantation and iron uptake studies in nm1054 reticulocytes, we provide evidence that the nm1054 anemia is due to an intrinsic hematopoietic defect resulting in inefficient transferrin-dependent iron uptake by erythroid precursors. Linkage studies demonstrate that nm1054 maps to a genetic locus not previously implicated in microcytic anemia or iron phenotypes.

  View details for DOI 10.1182/blood-2005-01-0379

  View details for Web of Science ID 000233187700052

  View details for PubMedID 15994289

• Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells NATURE GENETICS Ohgami, R. S., Campagna, D. R., Greer, E. L., Antiochos, B., McDonald, A., Chen, J., Sharp, J. J., Fujiwara, Y., Barker, J. E., Fleming, M. D. 2005; 37 (11): 1264-1269

  Abstract

  The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.

  View details for DOI 10.1038/ng1658

  View details for Web of Science ID 000233045200028

  View details for PubMedID 16227996