We studied 61 CD20– B-cell lymphomas, including 29 cases of precursor B-cell lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/B-LBL), 25 cases of CD20– recurrent mature B-cell lymphoma after rituximab therapy, and 7 cases of CD20– diffuse large B cell lymphoma (DLBCL). We used markers specific for B lineage: CD79a, Pax-5, OCT.2, and BOB.1. All B-ALL/B-LBLs expressed Pax-5 (29/29 [100%]), 25 (93%) of 27 expressed BOB.1, 23 (79%) of 29 expressed CD79a, and 6 (22%) of 27 expressed OCT.2. The percentages of cases expressing Pax-5, CD79a, OCT.2, and BOB.1 in CD20– recurrent mature B-cell lymphomas after rituximab treatment were 88% (21/24), 84% (21/25), 81% (17/21), and 73% (16/22), respectively. CD20– DLBCLs rarely express routine B-lineage markers, such as CD79a and Pax-5, but they expressed OCT.2 or BOB.1. Pax-5, BOB.1, and CD79a antigens are the most reliable B-lineage markers for paraffin immunophenotyping B-ALL/B-LBL. CD79a and Pax-5 should be used as the first-line B lineage–specific markers for rituximab-treated CD20–mature B-cell lymphomas. If negative, OCT.2 or BOB.1 may be useful. The newly identified B-lineage markers, OCT.2 and BOB.1, may be the most useful for the B-lineage determination of CD20– plasmablastic or primary effusion subtypes of DLBCL.
We describe a composite lymphoma with recurrent Hodgkin lymphoma and diffuse large B-cell lymphoma components manifesting as a single, perforated small intestinal tumor in a 56-year-old man with a history of classical Hodgkin lymphoma and recent relapse in the bone marrow. The resected mass had 2 morphologically and immunophenotypically distinct components; 1 showed a pleomorphic cellular infiltrate with fibrosis and contained numerous, large Hodgkin/Reed-Sternberg–like cells and variants. The tumor cells were CD30+ and focally positive for CD15 but CD20–, CD79a–, and PAX-5–. In situ hybridization for Epstein-Barr virus (EBV) was strongly positive in the large pleomorphic tumor cells. The adjacent component displayed sheets of relatively uniform, large lymphoid cells with typical morphologic features of diffuse large cell lymphoma. The tumor cells showed uniform expression of tested B-cell antigens, absence of CD30 or CD15, and complete absence of EBV-encoded RNA. Separate molecular studies with immunoglobulin heavy and light chain gene rearrangements clearly demonstrated an identical rearrangement pattern, indicating derivation from the same clone, which was confirmed by direct DNA sequencing analysis. Such distinctly different morphology, immunophenotype, and EBV status in different components within a clonally related single tumor mass is striking.
Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare secondary leukemia following chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormality, frequently detected in therapy-related acute myeloid leukemia, is the most common cytogenetic alteration in t-ALL. However, t-ALL cases without 11q23 abnormality have been rarely described. We describe 6 adults with secondary t-ALL without 11q23 abnormalities following various treatment regimens for primary malignancies. We also reviewed 48 t-ALL cases, with complete chromosomal karyotyping, reported in the literature from 1992 to 2007. In the 48 cases, an 11q23 abnormality involving the MLL gene locus was the predominant chromosomal aberration (32 [67%]), followed by t(9;22) (6 [13%]) and a normal karyotype (4 [8%]). Compared with t-ALL cases with an 11q23 abnormality, cases without an 11q23 abnormality had a relatively longer latency period (median, 36 vs 19 months) and a different primary malignancy spectrum. No major difference was observed between groups in regard to age, sex, or receipt of a topoisomerase II inhibitor. The t(8;14)(q11.2;q32), a rare, nonrandom, balanced chromosomal translocation differing from the more common translocation involving c-MYC on chromosome 8q24, was seen in 1 adult t-ALL case, which may suggest another possible pathogenesis of this disease.
Abstract It is well agreed that measurable residual disease (MRD) testing in acute leukemia patients following induction chemotherapy has profound prognostic implications. Flow cytometry is well suited to be the mainstay for MRD testing due to the heterogenous immunophenotypic and molecular natures of leukemia. Current flow cytometry MRD testing involves examination of more than 15 antigens, requiring multiple tubes to be run for each patient as current clinical flow cytometers are limited to examining 12 parameters per tube. Because multiple tubes are required, hematopathologists must infer antigen expression between tubes, which can be difficult. As MRD testing has such prognostic implications and defines treatment stratifications and outcomes, MRD testing requires very high sensitivity. While several groups have improved sensitivity by increasing the number of cells analyzed, we propose that increasing the antigenic targets in a single immunophenotyping assay will improve sensitivity by enhancing our ability to differentiate normal from abnormal hematopoietic cells. To test this, we utilized spectral flow cytometry, which allows for targeting more parameters with the same number of lasers for a single instrument. We developed a 23-color flow cytometry panel which was designed to thoroughly examine myelomonocytic differentiation and included multiple other antigenic targets which are known to be aberrantly expressed on leukemia cells. The panel also included a live-dead stain to exclude dead cells from analysis. All data was collected with a 3-laser Cytek Northern Lights spectral flow cytometer, which can analyze 10 million events in ~10 minutes. We tested this panel on more than 50 bone marrow aspirate samples, including normal samples, multiple myeloid leukemias, myelodysplastic samples, as well as more than 20 aspirate samples which also had MRD testing completed at a reference laboratory. Our results for MRD testing had excellent concordance with results from the gold-standard reference laboratory method. As our method only required one tube to be run per sample, we were routinely able to analyze at least 10 million cells per sample. Using in silico modelling from our data, we determined the sensitivity of our assay to be an average of 0.005% (range 0.002 – 0.015%) depending on the specific immunophenotype, when analyzing 10 million cells. As we examined all marker expression in a single tube, we were able to model sensitivity as if only 10-parameters were collected per tube and inference was required between tubes for analysis as is the current standard practice. We found that our 23-color assay was significantly more sensitive (p =0.02) compared to running multiple 10-color tubes and inferring between samples. Overall, higher parameter flow cytometric assays (>20 markers) allow for a more sensitive and robust MRD analysis than current gold-standard methods and should be explored for utilization in the clinical setting.
Edited by D. Geraint James and Alimuddin Zumla, 616 pp, with illus, Cambridge, United Kingdom, Cambridge University Press, 1999.“With the growing numbers of immunosuppressed patients due to the Human Immunodeficiency Virus (HIV) epidemic, granulomatous infections are becoming clinically more important worldwide.” In The Granulomatous Disorders, Drs James and Zumla, as well as a distinguished group of clinical and experimental investigators, provide an up-to-date and comprehensive review of granulomatous disorders. This book is well crafted, combining the basic biology, immunology, molecular features, and clinical data from numerous experienced specialists to cover a broad scope of granulomatous disorders. The book is organized into 4 main parts, each comprising several well-written chapters and each followed by well-selected and complete references.The first part of the book discusses the general biologic and immunologic aspects of various types of granulomas, including classification, clinicopathologic relationship, imaging studies, ultrastructure, and biologic behavior. Interestingly, the authors provide some evidence to suggest the concept of granulomatous lesions of unknown significance.Part 2 of the book discusses the most common etiology of granulomatous disorders, namely, infectious granulomas. The authors review various granulomatous disorders caused by specific bacterial, mycobacterial, fungal, parasitic, and viral etiologies. Clinical presentation and microbiological diagnosis of those infectious granulomas are described extensively.The third part of the book addresses the relationship between granulomas and general pathologic conditions, such as cancer, autoimmune disease, vasculitis, and sarcoidosis. In addition, granulomas in primary immunodeficiency are discussed separately.In the last part of the book, a detailed review of granulomas in human body systems is presented. This part is well written by different specialists and provides extensive information about granulomas in different organ systems, including pediatric granulomas. With very few exceptions, the gross and microscopic photographs and radiologic images are excellent.Overall, this book provides a thorough and comprehensive review of granulomas and granulomatous disorders. It is designed not only for those working in specific areas related to granulomatous disorders, but also for general pathologists and clinicians.
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