Reports from the 2021 SH/EAHP Workshop on Transformation and Transdifferentiation in Lymphoid Malignancies
Year: 2022
Type: article
Abstract: This issue of the American Journal of Clinical Pathology contains seven articles comprising a summary of nine sessions of the international hybrid workshop entitled “Transformation and Transdifferentiation in Lymphoid Malignancies” (https://www.society-for-hematopathology.org/2021/). As in the past, the biennial workshop of this type was organized under the joint auspices of the US-based Society for Hematopathology (SH) and European Association for Haematopathology. The workshop was held in Philadelphia from November 4 to 6, 2021, and had 401 registered participants (108 in person and 293 online) from 27 countries and received very high marks from the attendees: 95% to 100% satisfaction rate in various categories. Over 270 very interesting, often unusual, and diagnostically challenging entries were submitted with at least 1 pre- and posttransformation or transdifferentiation paired specimen for essentially all submissions. Essentially all cases contained gene mutational data, although of varying depth, depending on the mutational analytical panel used. Of note, approximately half of the submitted pre- and posttransition specimens with a sufficient amount of tissue were comparatively analyzed by whole-exome sequencing and RNA sequencing, performed by a data-driven bioscience team led by Sandeep Dave, MD. The generated genome-wide data, primarily on the mutational, expression, and gene copy number variation status of paired samples, were included in the case presentations as well as shared with all registered attendees. The workshop sessions and their chairs as well as the related articles and authors are listed in Table 1. As can be seen, the sessions covered a broad range of themes related to cell transformation and transdifferentiation of diverse lymphoid and plasmacytic malignancies, based on the spectrum of the submitted entities. The submitted cases have been grouped accordingly and exemplified reprogramming phenomena seen in these malignancies, cataloging the related morphologic, immunophenotypic, and molecular aberrations and, consequently, expanding our knowledge regarding these transitions. Workshop Sessions and Related Reports Workshop Sessions and Related Reports There were also six workshop-related, prerecorded primer presentations Table 2 that continue to be available at the time of this writing at the SH website with the link provided above. The aim of this set of seminars has been to introduce or refresh and, perhaps, expand the attendees’ knowledge on the topics of normal and malignant hematopoiesis of B-cell, T-cell, and diverse antigen-presenting cell populations as well as diagnostic application of genomics to facilitate analysis of the presented cases and implications of the related observations. Online “Primer” Presentations Online “Primer” Presentations Furthermore, there were 5 live lectures Table 3 at the workshop covering the salient studies regarding both the phenomenon of lymphoma transdifferentiation and its emerging underlying genetic and epigenetic mechanisms as well as transformation and its genetics and clinical implications. Finally, there were 2 sponsored symposia, one on flow cytometry application to detect residual disease in acute lymphoblastic leukemia with Kamaran Mahramzadeh, PharmD, as a chair and Brent Wood, MD, PhD, as the presenter and another one on diagnosis of Castleman disease with Ahmet Dogan, MD, PhD, as a chair and presenter, with other presenters being Joseph Khoury, MD, Amy Chadburn, MD, and Daisy Alapat, MD. On-Site Seminars On-Site Seminars Whereas unprecedented progress has been accomplished in recent years regarding mutational gene profiling of lymphoid and broadly defined histiocytic/dendritic cell malignancies, these studies had so far limited impact on diagnosis and therapy of lymphomas, although some attractive disease-associated biomarkers and therapeutic targets such as BRAF V600E mutation in hairy cell leukemia, Langerhans histiocytosis, and Erdheim-Chester disease have emerged. However, even the pathogenic genetic alterations affecting strong oncogenes or tumor suppressors such as c-MYC or TP53 are still considered only prognostic factors rather than being recognized as indicators of disease progression, including the cases in which their acquisition at the later stage of the disease has been documented. The current studies on genetics of diffuse large B-cell lymphoma (DLBCL) are quite telling in this regard. While heterogeneity of this entity is well established and resulted in its subclassification based on mutational profiling1 with the emerging potential therapeutic implications,2,3 very little is understood about molecular progression within DLBCL and its genetic subtypes. Recently developed ability to reliably sequence genome-scale DNA and even RNA using formalin-fixed, paraffin-embedded tissue blocks and comparative analysis of serial samples from the same patients, as done in the large subset of cases submitted for this workshop, should lead to a better understanding of the progression of lymphoid and plasmacytic malignancies on the molecular level. This advanced technical and conceptual approach may affect patient management, possibly impacting future World Health Organization classifications to recognize the dynamic nature of genetic changes in the malignant cells. It could be argued that the workshop has been a step in the right direction in this process. While underappreciated in the past, the ability of malignant cells to display remarkable lineage and state of differentiation plasticity has recently become very apparent in the era of therapy with chimeric antigen receptor T cells, kinase inhibitors, and other agents.4-6 Although the comparative analysis of the presence and identity of T-cell and B-cell receptor gene rearrangement typically provided the most direct evidence of a clonal relationship of the lymphoid and transdifferentiated, nonlymphoid malignancy in the given patient, the presence of identical chromosomal aberrations, foremost gene translocations, or tumor-restricted, pathogenic mutations also can document the common cell origin of the concomitant yet histologically different entities. Similar to transdifferentiation, dedifferentiation may be identified by the same diverse analysis of genomic structural alterations with an additional need, however, to evaluate the B-cell receptor for the presence of somatic hypermutations to determine if the emerged malignant immature cells are truly derived from the fully mature, antigen-exposed B lymphocytes. B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia following follicular lymphoma became an index entity for this dedifferentiation phenomenon.7-9 In summary, thanks to the submitted large number of fascinating cases representative of both transformation and transdifferentiation combined with in-depth molecular analysis of many of these cases, the workshop generated a cornucopia of knowledge regarding these processes, as presented and discussed in the seven workshop-related reports published in this journal’s issue.
DOI: 10.1093/ajcp/aqac169
Authors: Mariusz A Wasik, Ahmet Dogan
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4376226732