Special Issue "Classification of Lymphomas and Hematological Neoplasia in the Era of Genomic Research: A Themed Issue in Honor of Dr. Elaine S. Jaffe"

A special issue of Hemato (ISSN 2673-6357). This special issue belongs to the section "Lymphomas".

Deadline for manuscript submissions: 31 January 2022.

Special Issue Editors

Dr. Alina Nicolae
E-Mail
Guest Editor
Department of Pathology, CHU Strasbourg, Hautepierre Hospital, Avenue Molière 1 67098 STRASBOURG Cedex, France
Interests: lymphoma diagnosis; T-cell lymphomas; Hodgkin’s lymphoma; EBV-driven lymphoproliferative disorders; lymphomagenesis; molecular genetics; lymphoma microenvironment; biomarkers; immunology
Prof. Dr. Antonino Carbone
E-Mail Website
Guest Editor
Professor of Pathology, Former Chairman of Department of Pathology, Centro di Riferimento Oncologico (CRO) Aviano, National Cancer Institute, Aviano, Italy
Interests: hematopathology; Hodgkin lymphoma; non Hodgkin lymphoma; HIV-associated lymphoma; virus-associated lymphoma; post-transplant lymphoma; pathology; immunohistochemistry; tumour microenvironment; telepathology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to a visionary woman in science, Dr. Elaine Jaffe. Her love of biology, dedication to disease discovery and mentorship have shaped hematopathology over the last decades. A singular lymphoma classification, with no differences on either side of the Atlantic, was sculpted by her remarkable work. The microscope served in Dr. Jaffes’s hands as a tool for lymphoma discovery. Through her eyes, multiple neoplasms of lymphoid tissue have been delineated. Through her voice, outstanding hematopathology teaching was spread. This distinguished investigator has advocated for the integration of basic research and clinical diagnosis in the day-to-day work of the hematopathologist. Through this intermingled clinical and investigational research, our understanding of malignant lymphomas’ pathobiology and their relationship with the normal immune system has been enhanced. This has led to unprecedented advancements in prognostication and management of patients with hematological malignancies.

In one of her earliest articles, a Citation Classic (N Engl J. Med l974; 290: 8l3–8l9), Dr Jaffe showed evidence of follicular lymphoma origin from normal follicular B cells. Since then, she has unveiled many pathologically and clinically relevant “guises and disguises” of follicular lymphoma. She described in situ follicular lymphoma, offering clues about the initial genetic changes in follicular lymphomagenesis. She identified histiocytic/dendritic cell tumors occurring with follicular lymphoma, providing the first evidence for the lineage plasticity of mature lymphoid cells. Understanding the genetic and epigenetic events involved in mediastinal B-cell lymphoma biology and, in particular, the mechanisms that cause a B-cell to become a Hodgkin cell and the role of tumor cell interaction with the microenvironment also engaged Dr. Jaffe’s research interest.

The content of this Special Issue promises to be an outstanding “voyage through the eyes of a hematopathologist”, aiming to carry the reader to follow and project the evolution of lymphoma classification, with the discovery of new clinicopathological entities and achieving a better understanding of the molecular mechanisms involved in hematolymphoid neoplasms.

Dr. Alina Nicolae
Prof. Dr. Antonino Carbone
Guest Editors

Manuscript Submission Information

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Keywords

  • Lymphoma diagnosis and classification
  • Immunophenotypic studies
  • Genetics and genomics
  • Immunology
  • Histiocytic/dendritic cells

Published Papers

This special issue is now open for submission, see below for planned papers.

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Lymphomas in PLWH. How much they have enriched the knowledge to classify lymphomas
Authors: Mark Bower 1; Antonino Carbone 2
Affiliation: 1. Department of Oncology and National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London SW109NH, UK
2. Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via F. Gallini 2, I-33081 Aviano, Italy
Abstract: After the introduction of combined anti-retroviral therapy (CART) the most common lymphomas in people living with human immunodeficiency virus (PLWH) are diffuse large B-cell lymphomas and Burkitt lymphoma, and Hodgkin lymphomas among the non-AIDS defining cancers. New subtypes occurring specifically in these patients are observed more frequently in PLWH than in non infected individuals. They include primary effusion lymphoma (PEL), large B-cell lymphomas arising in multicentric Castleman disease (MCD) and plasmablastic lymphoma (PBL) of the oral cavity-type. The heterogeneity of lymphomas in PLWH likely depends on the complexity of involved mechanisms and especially on co-infection with the gamma-herpesviruses and the dysregulation of the immune responses controlling these viruses. HHV8/ KSHV was only discovered because of the emergence of Kaposi sarcoma in PLWH. Following the discovery of KSHV it was quickly identified in MCD and subsequently in PEL and some PBL and also in the rare cases of these diseases that occur in HIV negative individuals. This has led to a revision of the WHO classification of lymphoma to include KSHV associated lymphomas.

Title: An epidemiologic and pathologic overview on Burkitt lymphoma: time to drop endemic, sporadic, and immunodeficiency-associated subtype labels in biological studies
Authors: Sam M. Mbulaiteye
Affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, United States of America
Abstract: The report by Denis Burkitt in 1958 of 38 African children with aggressive jaw sarcomas introduced Burkitt lymphoma (BL) in the modern literature and unwittingly reshaped modern global oncology. Characterization of the pathology of BL enabled cases to be identified worldwide, highlighting the geographic variability of BL, codified as endemic and sporadic, as a potent clue for discovery of pathogens, Epstein-Barr virus, falciparum and, later, HIV, as co-factors for BL. Tumor studies revealed chromosomal translocations as a central abnormality in BL, with potential to clarify disease classification and direct therapy. This review will summarize epidemiological and pathology studies that have shaped our understanding of BL, highlight opportunities to integrate genomic, pathogen, and epidemiological data into unifying molecular hypothesis of BL, suggest molecular applications for diagnosis or disease monitoring.

Title: Classic Hodgkin Lymphoma and Its Boundaries
Authors: Alina Nicolae 1, Annunziata Gloghini 2, Antonino Carbone 3
Affiliation: 1 Department of Pathology, CHU Strasbourg, Hautepierre Hospital, Strasbourg, France
2 Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
3 Centro di Riferimento Oncologico di Aviano, IRCCS, Italy
Abstract: Hodgkin lymphoma (HL) is a hematological neoplasm subclassified into classic HL (CHL), which accounts for 95% of cases and nodular lymphocyte predominant HL (NLPHL). CHL exhibit heterogeneous clinical, pathological, and immunologic features, with a sizable proportion of cases being EBV related. HL classification has not changed over the last two decades. Recent updates mainly concerned NLPHL and lymphocyte-rich CHL (LRCHL), which shares features with NLPHL and other subtypes of CHL. In LRCH, the tumor cells co-express CD30 and CD15, may express or completely lack B-cell differentiation, and may be infected by EBV. The 2017 WHO classification also acknowledged a B-cell lymphoma, unclassifiable, with features intermediate between primary mediastinal large B-cell lymphoma (PMBL) and CHL, previously called mediastinal grey zone lymphoma (MGZL). It often presents with sheets of tumor cells, numerous with Hodgkin/Reed-Sternberg (HRS)-like morphology embedded within an inflammatory infiltrate resembling that of CHL and show variable degree of sclerosis and necrosis. Commonly, the neoplastic lymphocytes display a complete B-cell phenotype. Distinguishing these lymphomas from newly recognized EBV+ DLBCL, not otherwise specified, can be challenging, as the latter can have CD30 expression and manifest a downregulation of B-cell phenotype. However, the co-expression of CD30 and CD15 by typical HRS cells within an appropriate microenvironment rich in inflammatory effector cells and sclerosing fibrosis are useful criteria to distinguish CHL from other B-cell lymphomas and pathologic conditions. The recent research on HL have not only impacted their pathological classification, but most importantly allowed a better understanding of their pathophysiology with unprecedently outgrowth of innovative treatment strategies.

Title: Mantle cell lymphoma, a heterogeneous group of B-cell lymphoma with variable genomic and biological profiling
Authors: Drs. Jenna McCracken and Ken H. Young
Affiliation: Division of Hematopathology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710
Abstract: Major advances in the areas of pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have been successfully presented during the recent few years. Heterogeneity in the biology genomics and clinical features of MCL—indolent vs aggressive—is closely associated with the mutational status of the variable region of immunoglobulin heavy chain, epigenetic profiling, and SOX-11 expression. Cyclin-D1 negative MCL, in situ MCL neoplasia, CCND/IGVH FISH negative MCL, and impact of the karyotypic complex on prognosis are intriguing. In addition to proliferation and morphology pattern (typical and blastoid or pleomorphic), the proliferation gene signature further refines the prognostic prediction. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact. Genetic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes support risk stratification and treatment refinement. Recent novel chemo-immunotherapy has induced durable remissions in some patients. The therapeutic options in MCL are constantly evolving, toward more nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations are being. Several key aspects of MCL continue to pose a challenge to the diagnosis and therapeutic selection include the better understanding of the heterogeneity, microenvironmental components, minimal residual disease, clonal evolution, BTK inhibitor resistance, and. disease transformation. Next-generation based clinical trials would personalize the treatment by integrating the genomic profile of individual patient with clinical features. Recent advances in the field of MCL are presented.

Title: The duodenal-type follicular lymphoma
Authors: Tadashi Yoshino
Affiliation: Department of Pathology, Okayama University Medical School, Okayama, Japan
Abstract: We have shown that FL is often detected in the second portion of the duodenum and this is a distinct subtype of follicular lymphoma: unique follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.

Title: The NKL-code – a gene signature to evaluate deregulated NKL homeobox genes in Hodgkin lymphoma
Authors: Stefan Nagel
Affiliation: Leibniz-Institute DSMZ, Department of Human and Animal Cell Lines, Braunschweig, Germany
Abstract: We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, aberrant overexpression of NKL-code-members or ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, we provide an overview of the NKL-code in normal hematopoiesis and discuss the oncogenic role of deregulated NKL homeobox genes in Hodgkin lymphoma.

Title: Primary cold agglutinin-associated lymphoproliferative disease: a distinct clonal B-cell disorder of the bone marrow
Authors: Fina Climent 1, Joan Cid 2 and Anna Sureda 3
Affiliation: 1 Department of Pathology. Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; [email protected]
2 Apheresis & Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, IDIBAPS, University of Barcelona, Hospital Clínic, Barcelona, Spain; [email protected]
3 Hematology Department, Institut Català d’Oncologia, IDIBELL, Universitat de Barcelona, Barcelona, Spain; [email protected]
Abstract: Cold agglutinin disease (CAD) is a distinct clinicopathologic entity characterized by clonal B-cell lymphoproliferative disorder in the bone marrow. B-cell gene mutations affect NF-ΚB as well as chromatin modification and remodeling pathways. Clonal immunoglobulins produced by B cells bind to red cells (RBC) at cold temperatures causing RBC aggregation, complement cascade activation, and cold-autoantibody autoimmune hemolytic anemia (cAIHA). Clinical picture shows cold-induced symptoms and cAIHA. Therapeutic options include “wait & see”, rituximab-based regimens, and complement-directed therapies. Steroids must not be used for treating CAD. New targeted therapies are possibly identified after recent molecular studies.

Title: Epigenenetic modifications in lymphoma and their role in diagnosis and classification
Authors: Sean Harrop; Miles Prince
Affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3000, Australia
Abstract: The characterisation of the lymphoma epigenome has provided an insight into mechanisms leading to lymphomagenesis. Lymphomagenesis can be associated with epigenetic changes involving histone modifications, chromatin remodelling and DNA-methylation. Moreover, certain subtypes of lymphoma demonstrate mutations of key epigenetic regulators; such mutations have been utilised to aid in the classification of both B- and T-cell lymphomas. Treatments targeting such mutations are also in development. In this review we summarise the available literature on epigenetic dysregulation in lymphoma and how it has been utilised in diagnosis and classification.

Title: Genetics of transformed follicular lymphoma
Authors: Miguel Alcoceba1, María García-Álvarez1, Jessica Okosun2, Simone Ferrero3, Marco Ladetto4, Jude Fitzgibbon2, Ramón García-Sanz1
Affiliation: 1 Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC, and Cancer Research Center–IBMCC (USAL-CSIC), Salamanca, Spain
2 Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
3 Department of Molecular Biotechnologies and Health Sciences - Hematology Division, University of Torino, Torino, Italy
4 Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; Division of Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
Abstract: Histological transformation (HT) to a more aggressive disease –mostly diffuse large B-cell lymphoma– is considered to be one of the most dismal events in the clinical course of follicular lymphoma (FL). Current knowledge has not found a single biological event specific for HT, although different studies have stand out common genetic alterations, such as TP53 and CDKN2A/B loss, and MYC translocations, among others. Altogether, they increase genomic complexity and mutational burden at HT. A better knowledge of pathogenesis of HT would presumably help to find biomarkers at diagnosis allowing the identification of patients in high-risk of HT development, as well as the discrimination from patients with FL recurrence, and from those who will remain in remission. In the present review we provide a comprehensive overview of the genetic events frequently described in transformed FL probably responsible of the aggressiveness gain, and we will discuss about current open questions in the field of HT.

Title: Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: Current understanding and outstanding questions
Authors: Craig R. Soderquist; and; Govind Bhagat
Affiliation: Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
Abstract: Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic and clinical characterization of these disorders have led to increased awareness and a better understanding of disease pathogenesis. However, many questions remain unanswered, including elucidation of the cell(s) of origin, inciting environmental factors and molecular pathways underlying disease progression and transformation. In this review, we discuss recent findings regarding the immunophenotypic and genomic spectrum of these lymphoproliferative disorders and highlight unresolved issues.

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